PathoLecoDeco2 Flashcards
(1217 cards)
1
Q
Histopathology - Neuro-oncology
Usually 1st and 2nd decade - 20% of CNS tumours below 14 years
Common in NF1
MRI: well circumscribed, cystic, enhancing lesion
Often cerebellar, optic-hypothalamic, brainstem
Hallmark: piloid “hairy” cell
Very often Rosenthal fibres and granular bodies
Slowly growing: low mitotic activity
BRAF mutation (KIAA1549-BRAF fusion) in 70% of PA
A
PILOCYTIC ASTROCYTOMA (WHO GRADE I)
2
Q
Histopathology - Neuro-oncology
Hallmark: piloid “hairy” cell
Very often Rosenthal fibres and granular bodies
Slowly growing: low mitotic activity
A
PILOCYTIC ASTROCYTOMA (WHO GRADE I)
3
Q
Histopathology - Neuro-oncology
Patients usually 20-40 years
MRI: T1 hypointense, T2 hyperintense, non-enhancing lesion.
Low choline / creatinine ratio at MRSpec.
Low to moderate cellularity
Mitotic activity is negligible or absent
Vascular proliferation and necrosis are absent
Mutation of IDH1/2: in >80% of cases
A
DIFFUSE ASTROCYTOMA (GRADE II)
4
Q
Histopathology - Neuro-oncology
Low to moderate cellularity
Mitotic activity is negligible or absent
Vascular proliferation and necrosis are absent
Mutation of IDH1/2: in >80% of cases
What tumour?
A
DIFFUSE ASTROCYTOMA (GRADE II)
5
Q
Histopathology - Neuro-oncology
Where do most astrocytomas present?
A
Cerebral hemispheres most common site
Progression to higher grade is the rule:
astrocytomas become eventually glioblastoma (in 5-7 years)
Most aggressive and most frequent: de novo glioblastoma (grade IV), IDH wildtype
6
Q
Histopathology - Neuro-oncology
Most patients >50 years
MRI: heterogeneous, enhancing post-contrast
High cellularity and high mitotic activity microvascular proliferation, necrosis
A
GLIOBLASTOMA MULTIFORME (GRADE IV)
7
Q
Histopathology - Neuro-oncology
High cellularity and high mitotic activity microvascular proliferation, necrosis
A
GLIOBLASTOMA MULTIFORME (GRADE IV)
8
Q
Histopathology - Neuro-oncology
5% of all primary brain tumours
Patients usually 20-40 years
Presents with long history of neurological signs – seizure
MRI: no or patchy contrast enhancement; MRI and MRSpec are not predictive of transformation
Round cells with clear cytoplasm (“fried eggs”)
Mutation of IDH1/2 + codeletion 1p/19q: almost 100%
A
OLIGODENDROGLIOMA (GRADE II – III)
9
Q
Histopathology - Neuro-oncology
Presents with long history of neurological signs – seizure
MRI: no or patchy contrast enhancement; MRI and MRSpec are not predictive of transformation
Round cells with clear cytoplasm (“fried eggs”)
A
OLIGODENDROGLIOMA (GRADE II – III)
10
Q
Histopathology - Neuro-oncology
25-30% primary intracranial tumours – second after gliomas
Rare in patients < 40
Any site of craniospinal axis, can be multiple (NF2)
Focal symptoms (seizures, compression)
MRI: extraxial, isodense, contrast-enhancing
80% Grade I: benign, recurrence <25%
20% Grade II: atypical, recurrence 25-50%
1% Grade III: malignant, recurrence 50-90%
A
MENINGIOMA (WHO GRADE I – III)
11
Q
Histopathology - Neuro-oncology
MRI: extraxial, isodense, contrast-enhancing
A
MENINGIOMA (WHO GRADE I – III)
12
Q
Histopathology - Neuro-oncology
Grading (I-III) currently based on histology only:
no radiological features
Complex assessment: proliferation, cell morphology, architecture,
brain invasion…
True or false?
A
T
Most meningiomas are
benign and slowly growing
Histology is crucial
13
Q
Histopathology - Neuro-oncology
What mitoses indicates grades 1/2/3?
A
<4 = grade I
4-20 = grade II
> 20 = grade III
Crucial: determines grade
Time consuming: cases must be thoroughly examined (even 100 fields or more)
14
Q
Histopathology - Neuro-oncology
EMBRYONAL TUMOUR: originates from neuroepithelial precursors of the cerebellum/dorsal brainstem
Rare (2 per 1,000,000 year), but second most common brain tumour in children
“Small blue round cell tumour” with expression of neuronal markers
Molecular classification: WNT-activated, SHH-activated,
non-WNT/non-SHH
Outcome considerably improved with radio-chemotherapy
A
MEDULLOBLASTOMA (WHO GRADE IV)
Medullo-blue
15
Q
Histopathology - Neuro-oncology
second most common brain tumour in children
A
MEDULLOBLASTOMA (WHO GRADE IV)
16
Q
Histopathology - Neuro-oncology
Most frequent CNS tumour in adults (10 x intrinsic tumours)
Increasing incidence due to longer survival
Often multiple
At gray– white junction
Very poor prognosis
A
CNS METASTASES
17
Q
Histopathology - Neurodegeneration
What is a prion disease?
A
Prion (proteinaceous infectious only)
A series of diseases with common molecular pathology
Transmissible factor
No DNA or RNA involved
18
Q
Histopathology - Neurodegeneration
Name 2 prion diseases?
A
Humans Creutzfeldt-Jakob disease Gerstmann-Straüssler-Sheinker syndrome Kuru Fatal familial insomnia
19
Q
Histopathology - Neurodegeneration
When do patients present with vCJD?
A
Sporadic neuropsychiatric disorder Patients <45 yrs old Cerebellar ataxia Dementia Longer duration than CJD Linked to BSE Diagnosed at autopsy since 1990 up to 2 Jul 2018 178 deaths
20
Q
Histopathology - Neurodegeneration
What are the Sx of vCJD
A
Sporadic neuropsychiatric disorder Patients <45 yrs old Cerebellar ataxia Dementia Longer duration than CJD Linked to BSE Diagnosed at autopsy since 1990 up to 2 Jul 2018 178 deaths
21
Q
Histopathology - Neurodegeneration
Extracellular plaques
Neurofibrillary tangles
Cerebral amyloid angiopathy (CAA)
Neuronal loss (cerebral atrophy)
A
Alzheimer’s
22
Q
Histopathology - Neurodegeneration
What is the Neuropathology of Alzheimers
A
Extracellular plaques
Neurofibrillary tangles
Cerebral amyloid angiopathy (CAA)
Neuronal loss (cerebral atrophy)
23
Q
Histopathology - Neurodegeneration
Cortical atrophy
Senile Plaques
Cerebral amyloid angiopathy
A
Alzheimer’s
24
Q
Histopathology - Neurodegeneration
APP
A
Alzheimer’s
25
Histopathology - Neurodegeneration
Tau immunostaining
Alzheimer's
26
Histopathology - Neurodegeneration
Braak staging system is used for what diseases?
Alzheimer's
| Parkinsons
27
Histopathology - Neurodegeneration
What histological staging system is used for Alzheimers
Braak
28
Histopathology - Neurodegeneration
Polymeropoulos in 1997 found that mutations in what gene can result in Parkinsons Disease
α-synuclein gene
29
Histopathology - Neurodegeneration
Spillantini reported that Lewy bodies and Lewy neurites are immunoreactive for what?
α-synuclein
30
Histopathology - Neurodegeneration
What is considered as the diagnostic gold standard for Lewy body?
Now α-synuclein immunostaining is considered as the diagnostic gold standard
31
Histopathology - Neurodegeneration
What histological staging system is used for Parkinson's?
Braak
32
Histopathology - Neurodegeneration
If there are glial inclusions of synuclein staining what does this indicate?
Multiple System Atrophy (MSA)
33
Histopathology - Neurodegeneration
Fronto-temporal atrophy
Marked gliosis and neuronal loss
Balloon neurons
Tau positive Pick bodies
Pick’s disease
34
Histopathology - Neurodegeneration
What damage occurs in Pick’s disease?
Fronto-temporal atrophy
Marked gliosis and neuronal loss
Balloon neurons
Tau positive Pick bodies
35
Histopathology - Neurodegeneration
```
Autosomal dominant
Diverse clinical and pathological phenotypes
Abundant tau pathology
>20 pathogenic mutations identified
Missense and splicing mutations
```
FTDP-17 syndromes
36
Histopathology - Neurodegeneration
FTDP-17 syndromes inheritance pattern?
Autosomal dominant
37
Histopathology - Neurodegeneration
Single gene on 17q21
16 exons
Alternative splicing gives rise to 6 isoforms
3R or 4R-tau (microtubule-binding domains)
Two further inserts with unknown function
Shortest form (3R/0N) foetal
Tau
38
Histopathology - Neurodegeneration
Ubiquitin immunostain
FTLD-U
39
Histopathology - Respiratory Disease
Often associated with heart failure (acute or chronic). Very common cause acute and chronic respiratory failure in A&E and community, and common finding at PM
Pulmonary Oedema
40
Histopathology - Respiratory Disease
Define Pulmonary Oedema?
Accumulation of fluid in alveolar spaces as consequence of “leaky capillaries” or “backpressure” from failing left ventricle.
41
Histopathology - Respiratory Disease
List the causes of Pulmonary Oedema?
Left heart failure
Alveolar injury (drugs, inhalation, infection, pancreatitis)
Neurogenic following head injury
High altitude (“altitude sickness)
42
Histopathology - Respiratory Disease
Histological features of pulmonary oedema?
Heavy watery lungs, intra-alveolar fluid on histology
43
Histopathology - Respiratory Disease
Important cause of rapid onset respiratory failure – difficult to treat, patients end up on ICU
Adults – Acute respiratory distress syndrome “shock lung”
Numerous causes in adults
Infection (local or generalised sepsis), aspiration, trauma, inhaled irritant gases, shock, blood transfusion, DIC, drug overdose, pancreatitis, idiopathic.
Neonates - Hyaline membrane disease of newborn
Insufficient surfactant production
Premature babies
44
Histopathology - Respiratory Disease
List causes of ARDS?
Infection (local or generalised sepsis), aspiration, trauma, inhaled irritant gases, shock, blood transfusion, DIC, drug overdose, pancreatitis, idiopathic.
45
Histopathology - Respiratory Disease
What is Hyaline membrane disease of newborn?
Insufficient surfactant production
| Premature babies
46
Histopathology - Respiratory Disease
Lungs are expanded and firm
Plum coloured, airless
Often weigh >1kg
Diffuse alveolar damage
47
Histopathology - Respiratory Disease
What are the phases of ARDS?
EXUDATIVE PHASE
PROLIFERATIVE (HYALINE MEMBRANES)
CELLULAR PHASE
?FIBROTIC
48
Histopathology - Respiratory Disease
ASTHMA defintion
Chronic inflammatory airway disorder with recurrent episodes widespread narrowing of the airways that changes in severity over short periods of time.
49
Histopathology - Respiratory Disease
Prevalence increased in recent decades
>10% children, 5% adults
Presents with wheezing, chest tightness, SOB, night-time cough
In a severe attack patients develop status asthmaticus.
ASTHMA
50
Histopathology - Respiratory Disease
What are the causes/subtypes of asthma?
```
Atopic: genetic tendency to develop allergic reaction to common environmental allergen (e.g. house dust mites):
Non-atopic
Air pollution
Drugs - NSAIDs
Occupational – inhaled gases/fumes
Diet
Genetic factors
Physical exertion – “cold”
Intrinsic
```
51
Histopathology - Respiratory Disease
Describe the acute changes of asthma
Acute change
| Bronchospasm, oedema, hyperaemia, inflammation
52
Histopathology - Respiratory Disease
Describe the chronic changes of asthma
Chronic change
Muscular hypertrophy
Airway narrowing
Mucus plugging
53
Histopathology - Respiratory Disease
| Very common cause chronic respiratory failure. May present with acute (often infective) exacerbations
Chronic Obstructive Pulmonary Disease : COPD
54
Histopathology - Respiratory Disease
Define chronic bronchitis?
Defined as:
Chronic cough productive of sputum
Most days for at least 3 months over at least 2 consecutive years
Chronic injury to airways elicits reactive changes which predispose to further damage.
55
Histopathology - Respiratory Disease
What is seen histologically with chronic bronchitis?
```
Pathology
Dilated airways
Mucus gland hyperplasia
Goblet cell hyperplasia
Mild inflammation
```
56
Histopathology - Respiratory Disease
What are the complications of COPD?
Repeated infections (most common cause of admission and death)
Chronic respiratory failure with hypoxia and reduced exercise tolerance
Chronic hypoxia results in pulmonary hypertension and right sided heart failure (cor pulmonale)
Increased risk of lung cancer independent of smoking
57
Histopathology - Respiratory Disease
Define emphysema?
Emphysema is a permanent loss of the alveolar parenchyma distal to the terminal bronchiole
Damage to alveolar epithelium secondary to inflammation
SMOKING
Alpha 1 antitrypsin deficiency
Rare – IVDU, connective tissue disease
58
Histopathology - Respiratory Disease
Emphysema subtype associated with SMOKING
Loss centred on bronchiole - CENTRILOBULAR
59
Histopathology - Respiratory Disease
Emphysema subtype associated with Alpha 1 antitrypsin deficiency
Diffuse loss of alveolae - PANACINAR
60
Histopathology - Respiratory Disease
Complications of emphysema?
Large air spaces (bullae)
Rupture - pneumothorax
Respiratory failure
Pulmonary hypertension and right sided heart failure.
61
Histopathology - Respiratory Disease
Define Bronchiectasis
Permanent abnormal dilatation of bronchi with inflammation and fibrosis extending into adjacent parenchyma
Variation in site depending on cause (idiopathic often involves lower lobe)
Inflamed scarred lungs with dilated airways
62
Histopathology - Respiratory Disease
Bronchiectasis – causes/associations
Inflammatory
Infection
Post-infectious (especially children or cystic fibrosis)
Abnormal host defense 1º [hypogammagl.] and 2º [chemotherapy, NG]
Ciliary dyskinesia 1º [Kartagener’s] and 2º
Obstruction (extrinsic/intrinsic/middle lobe syn.)
Post-inflammatory (aspiration)
Secondary to bronchiolar disease (OB) and interstitial fibrosis (CFA, sarcoidosis)
Systemic disease (connective tissue disorders)
Asthma
Congenital
63
Histopathology - Respiratory Disease
What are the complications of bronchiectasis?
Recurrent infections
Haemoptysis
Pulmonary Hypertension and right sided heart failure
Amyloidosis
64
Histopathology - Respiratory Disease
Affects 1 in 2,500 live births
Autosomal recessive (approx 1/20 of population are heterozygous carriers)
Cystic Fibrosis
65
Histopathology - Respiratory Disease
What is the most common mutation in CF, and where is the CFTR gene located?
Chr 7q3 = CFTR gene (Cystic Fibrosis Transmembrane Conductance Regulator) = chloride ion transporter protein. >1400 mutations, but commonest Delta F508
66
Histopathology - Respiratory Disease
Abnormality leads to defective ion transport across cell membranes leading to excessive resorption of water from secretions of exocrine glands.
67
Histopathology - Respiratory Disease
What systems, aside from the lungs are affected in CF?
Generalised disease of exocrine glands resulting in abnormally thick mucus secretion - affects all organ systems.
GI tract -> meconium ileus, malabsorption
Pancreas -> pancreatitis, malabsorption
Liver -> cirrhosis
Male reproductive system -> infertility
68
Histopathology - Respiratory Disease
Describe lung involvement of CF?
Lung
Over 90% of patients have lung involvement
Recurrent infections (S.aureus, H. influenzae, P.aeruginosa, B.cepacia)
Haemoptysis, Pneumothorax, Chronic respiratory failure and cor pulmonale, Allergic bronchopulmonary aspergillosis (ABPA), Atelectasis, BRONCHIECTASIS
69
Histopathology - Respiratory Disease
What type of bacteria are seen with aspiration pneumonia?
Mixed aerobic and anaerobic
70
Histopathology - Respiratory Disease
Briefly describe the appearance of bronchopneumonia vs lobar?
Lobar = Acute bacterial infection of a large portion of a lobe or entire lobe. Widespread fibrinosuppurative consolidation
Broncho = Patchy bronchial and peribronchial distribution, often lower lobes, acute inflammation surrounding airways and within alveoli
71
Histopathology - Respiratory Disease
What organisms are seen with bronchopneumonia
Often low virulence organisms - Staphylococcus, Haemophilius, Streptococcus, Pneumococcus,
72
Histopathology - Respiratory Disease
What organism typically causes lobar pneumonia?
90-95% pneumococci (S. pneumoniae)
73
Histopathology - Respiratory Disease
What is the histopathology of lobar pneumonia, by phases?
```
1. Congestion
Hyperaemia
Intra-alveolar fluid
2. Red hepatization
Hyperaemia
Intra-alveolar neutrophils
3. Grey hepatization
Intra-alveolar connective tissue
4. Resolution
Restoration normal architecture.
```
74
Histopathology - Respiratory Disease
What are the complications of infection?
```
Abscess formation
Pleuritis and pleural effusion
Infected pleural effusion (EMPYEMA)
Fibrous scarring
Septicaemia
```
75
Histopathology - Respiratory Disease
| What is a granuloma?
Collection of histiocytes/macrophages +/- multinucleate giant cells
Necrotising or non necrotising
If see this pattern MUST think Tuberculosis
Fairly common in urban community and immunosuppressed.
Other causes include fungi and parasites
History of foreign travel
76
Histopathology - Respiratory Disease
What diagnosis would a granuloma suggest?
Tuberculosis
77
Histopathology - Respiratory Disease
What histological pattern is seen with atypical pneumonias?
Interstitial inflammation (pneumonitis) without accumulation of intra-alveolar inflammatory cells
Chronic inflammatory cells within alveolar septa with oedema +/- viral inclusions
78
Histopathology - Respiratory Disease
Occlusion of pulmonary artery by thromboembolus
Pulmonary Thromboembolism
79
Histopathology - Respiratory Disease
Thrombus formation: Virchows triad
factors promoting blood stasis
damage to endothelium
increased coagulation
80
Histopathology - Respiratory Disease
PE RFs?
- Advanced age, female sex, obesity, immobility, cardiac failure, malignancy, trauma, surgery, childbirth, haemoconcentration, polycythaemia, DIC, contraceptive pill, cannulation, anti-phospholipid syndrome.
81
Histopathology - Respiratory Disease
Presentation of PE?
Patients present with pleuritic chest pain or chronic progressive shortness of breath due to pulmonary hypertension
82
Histopathology - Respiratory Disease
Where does a saddle embolus reside?
Large emboli can occlude the main pulmonary trunk (saddle embolus)
Sudden death, acute right heart failure, or cardiovascular shock occurs in 5% of cases when >60% of pulmonary bed is occluded
If patient survives, the embolus usually resolves
30% develop second or more emboli
83
Histopathology - Respiratory Disease
List causes of non-thrmbotic emboli
```
Bone marrow
Amniotic fluid
Trophoblast
Tumour
Foreign body
Air
```
84
Histopathology - Respiratory Disease
Name a benign lung tumour?
Benign lung tumours
Do not metastasise
Can cause local complications
Airway obstruction
E.g. chondroma
85
Histopathology - Respiratory Disease
List NON-small cell carcinomas?
Squamous cell carcinoma (30%)
Adenocarcinoma (30%)
Large cell carcinoma (20%)
86
Histopathology - Respiratory Disease
Tumour initiators: Polycyclic aromatic hydrocarbons
Tumour promotors: N Nitrosamines, Nicotine, Phenols
Complete carcinogens: Nickel, Arsenic
CSE
87
Histopathology - Respiratory Disease
Other causes of lung carcinoma (non smoke related)
Asbestos exposure (Asbestos + smoking = 50 fold increase risk)
Radiation (Radon exposure, theraputic radiation, uranium miners)
Air pollution
Other: Heavy metals (Chromates, arsenic, nickel)
Genetics Familial lung cancers rare.
Epidemiological evidence of increased risk for first degree relatives
young age, non-smoking cases.
88
Histopathology - Respiratory Disease
Seen in 34% of high risk smokers without SqCC and 60% with SqCC
Basement membrane thickening and vascular budding
Increased density of intramucosal capillary loops (p=0.0003)
Genetic analysis of surface epithelium showed LOH at 3p in 53% of lesions
Clinical significance uncertain
Angiosquamous dysplasia
89
Histopathology - Respiratory Disease
Invasive Squamous Cell Carcinoma, RF, site and behaviour?
```
Frequency
35% pulmonary carcinoma
Risk factor
Closely associated with smoking
Site
Traditionally centrally located arising from bronchial epithelium, however increasing number of peripheral squamous cell carcinomas
Behaviour
Local spread, metastasise late.
```
90
Histopathology - Respiratory Disease
Proliferation of atypical cells lining the alveolar walls.
Increases in size and eventually can become invasive
Atypical adenomatous hyperplasia
Precursor to Adenocarcinoma
91
Histopathology - Respiratory Disease
What is the precursor lesion of adenocarcinoma?
Atypical adenomatous hyperplasia
92
Histopathology - Respiratory Disease
Name mutations seen in adenocarcinoma?
K ras mutation
DNA methylation
p53 (smokers)
EGFR mutation/
amplification (EGFR)
93
Histopathology - Respiratory Disease
Destruction of underlying elastin
Desmoplasia with angular glands and single cell infiltration
adenocarcinoma
94
Histopathology - Respiratory Disease
Frequency
Increasing incidence: 27% pulmonary carcinomas
Risk factor
Smoking + other
Commoner in far east, females and non-smokers
Site
Peripheral and more often multicentric
Behaviour
Extrathoracic metastases common and early (80% present with mets)
Histology
Histology shows evidence of glandular differentiation
Invasive Adenocarcinoma
95
Histopathology - Respiratory Disease
Mucin vacuoles on cytology?
Cytology of adenocarcinoma
96
Histopathology - Respiratory Disease
Peripheral or central 10% of tumours
Poorly differentiated tumours composed of large cells
No histological evidence of glandular or squamous differentiation
BUT on electron microscopy many show some evidence of glandular, squamous or neuroendocrine differentiation
i.e are probably very poorly differentiated adeno/squamous cell carcinomas
Poorer prognosis
Large cell carcinoma
97
Histopathology - Respiratory Disease
```
Frequency
20% tumours
Risk factor
Very close association with smoking
Site
Often central near bronchi
Behaviour
80% present with advanced disease
Although very chemosensitive, have an abysmal prognosis
Paraneoplastic syndromes
Histology
Small poorly differentiated cells
p53 and RB1 mutations common
```
Small cell carcinoma
98
Histopathology - Respiratory Disease
What mutations are tested for when molecular testing for lung carcinomas?
EGFR mutation
Responder mutation
Resistance mutation
Alk translocation
Ros1 translocation
99
Histopathology - Respiratory Disease
What is Excision Repair cross-complimentation group 1 protein (ERCC1) a predictor for?
In advanced stage NSCLC ERCC1 positive tumours have poor response to cisplatin based chemo
ERCC1 protein removes Drug-DNA adducts
100
Histopathology - Respiratory Disease
Membrane receptor tyrosine kinase
Regulates angiogenesis, proliferation, apoptosis and cell migration
EGFR
101
Histopathology - Respiratory Disease
Name a drug targeting EGFR?
Cetuximab
102
Histopathology - Respiratory Disease
Indication for use of TKI
Young, female, non-smokers
Responder mutation (del exon 19 & L858R mutation exon 21 - 90% of EGFR mutations)
EGFR amplification
Currently used for recurrent adenocarcinoma
BUT 60-70% patients acquire resistance to TKI
mutation 790M in EGFR
Met amplification
103
Histopathology - Respiratory Disease
Contraindications for use of TKI
Kras mutation
| Resistance mutation - 790M mutation
104
Histopathology - Respiratory Disease
Translocations results in gain of function for Alk = kinase
EML4-ALK
Translocation seen in 3.8-7% lung cancers
Younger age, adenocarcinoma, light or never smokers
Solid or signet ring pattern
EGFR or kras mutations rare
105
Histopathology - Respiratory Disease
Can TKIs be used in EML4-ALK?
No benefit from TKI
| New targeted therapy = ALKinase inhibitor
106
Histopathology - Respiratory Disease
What targetted therapy can be used in EML4-ALK?
No benefit from TKI
| New targeted therapy = ALKinase inhibitor
107
Histopathology - Respiratory Disease
TNM stagingt
```
T TUMOUR (T1-4)
Size
Invasion pleura, pericardium
N LYMPH NODE METASTASIS (N0-2)
N0 – lymph node not involved by tumour
N1 or N2 - lymph nodes involved by tumour
1 vs 2 depends on extent of involvement
M DISTANT METASTASIS (M0 or 1)
M1 – tumour has spread to distant sites
E.g. tumour in liver, bones, brain
```
108
Histopathology - Respiratory Disease
What are the Local effects of Lung Carcinoma?
1. Bronchial obstruction
Collapse of distal lung
Shortness of breath
Impaired drainage of bronchus
Chest infection
Pneumonia, abscess
```
3. Invasion of local structures
Invasion of local airways and vessels
Haemoptysis, cough
Invasion around large vessels
Superior vena cava syndrome- venous congestion of head and arm oedema and ultimately circulatory collapse
Oesophagus
Dysphagia
Chest wall
Pain
Nerves
Horners syndrome
```
4. Extension through pleura or pericardium
Pleuritis or pericarditis, with effusions
Breathlessness
Cardiac compromise
Diffuse lymphatic spread within lung
Shortness of breath, very poor prognostic features
109
Histopathology - Respiratory Disease
What is a paraneoplastic syndrome?
Paraneoplastic Syndromes: Systemic effect of tumour due to abnormal expression by tumour cells of factors (e.g. hormones and other factors) not normally expressed by the tissue from which the tumour arose
1-10% lung cancer patients
Can precede development of detectable lung lesion
110
Histopathology - Respiratory Disease
Name 2 paraneoplastic tumours?
1. Antidiuretic hormone (ADH)
“Syndrome of inappropriate antidiuretic hormone” causing hyponatremia (especially small cell carcinoma
2. Adrenocorticotropic hormone (ACTH)
Cushing’s syndrome (especially small cell carcinoma)
3. Parathyroid hormone-related peptides
Hypercalcaemia (especially squamous carcinoma)
4. Other
Calcitonin ->Hypocalcaemia
Gonadotropins ->Gynecomastia
Serotonin ->“Carcinoid syndrome” (especially carcinoid tumors; rarely small cell carcinoma)
NON-endocrine
Haematologic/coagulation defects, skin, muscular, miscellaneous disorders
111
Histopathology - Respiratory Disease
Malignant tumour of pleura (lining of the lung and chest wall)
Frequency
<1% of cancer deaths, but increasing incidence
? Peak in incidence in about 2010.
Aetiology
asbestos exposure
Behaviour
Essentially a fatal disease
Medicolegal implications of diagnosis
compensation
Mesothelioma
112
Histopathology - Respiratory Disease
Most patients have history of asbestos exposure
Long lag time: Tumour develops decades after exposure
males>females, approx 3:1
50-70 years of age
Present with shortness of breath, chest pain
Dismal prognosis
Mesothelioma
113
Haematology - Haematological Changes in systemic disease
A patient with newly diagnosed lymphoma on biopsy of a neck node has new onset:
Jaundice
Anaemia
Raised LDH
What's the DDx?
Lymphoma with pathological nodes compressing the bile duct & anaemia of inflammation (post hepatic)
Lymphoma Stage 4 with BM and liver infiltration (hepatic)
Lymphoma Stage 1 & auto immune haemolytic anaemia (pre hepatic)
114
Haematology - Haematological Changes in systemic disease
Lab findings for Fe deficiency?
Reduced ferritin, transferrin saturation
| Raised TIBC
115
Haematology - Haematological Changes in systemic disease
What is Leuco-erythroblastic anaemia?
(red cell and white cell precursor anaemia)
variable degree of anaemia
Teardrop RBCs (+aniso and poikilocytosis)
Nucleated RBCs
Immature myeloid cells
116
Haematology - Haematological Changes in systemic disease
What changes are seen on blood film for leuco-erythroblastic anaemia?
Teardrop RBCs (+aniso and poikilocytosis)
Nucleated RBCs
Immature myeloid cells
117
Haematology - Haematological Changes in systemic disease
What are the causes of a leucoerythroblastic film?
Malignant
Haemopoietic: leukaemia/lymphoma/ myeloma
Non Haemopoietic: breast/ bronchus/prostate
Severe infection
miliary TB
Severe fungal infection
Myelofibrosis
Massive splenomegaly
Dry tap on BM aspirate
118
Haematology - Haematological Changes in systemic disease
shortened red cell survival
Haemolytic anaemias
119
Haematology - Haematological Changes in systemic disease
Common Laboratory features of all haemolytic anaemias
```
Anaemia (though may be compensated)
Reticulocytosis
Unconjugated bilirubin raised (pre-hepatic)
LDH raised
Haptoglobins reduced
```
120
Haematology - Haematological Changes in systemic disease
Name the inherited haemolytic anaemias?
Membrane: eg Hereditary Spherocytosis
Cytoplasm/enzymes: eg G6PD deficiency
Haemoglobin: Sickle cell disease (structural) Thalassaemia (quantitative)
121
Haematology - Haematological Changes in systemic disease
What does the DAT / Coombs test actually mean?
Differentiates between Immune-related (+ve) and non-immune-related (-ve) causes of haemolytic anaemia
122
Haematology - Haematological Changes in systemic disease
Malignancy : eg Lymphoma or CLL
Auto immune: eg SLE
Infection: eg mycoplasma
DAT +ve or -ve?
+ve
| Immune related haemolytic anaemias
123
Haematology - Haematological Changes in systemic disease
```
Anaemia
reticulocytosis
raised bilirubin unconjugated
raised LDH
positive DAT
```
What are the DDx?
Underlying Immune disorder
- Auto immune eg SLE
- Malignancy of immune cells eg CLL or lymphoma
OR
Idiopathic
124
Haematology - Haematological Changes in systemic disease
Acquired haemolytic anaemia
Positive / negative DAT?
(Non-Immune/DAT negative)
125
Haematology - Haematological Changes in systemic disease
Name acquired haemolytic anaemias?
```
Infection
malaria
Micro-angiopathic Haemolytic anaemia (MAHA)
Underlying adenocarcinoma
Haemolytic uraemic syndrome
```
126
Haematology - Haematological Changes in systemic disease
What changes are seen on a microangiopathic film?
MAHA:
RBC fragments
Thrombocytopenia
127
Haematology - Haematological Changes in systemic disease
Micro-angiopathy is associated with wht type of cancer?
Adenocarcinoma
128
Haematology - Haematological Changes in systemic disease
What changes are seen on a microangiopathic film of an adenocarcinoma [low grade DIC]?
Platelet activation
Fibrin deposition and degradation
Red cell fragmentation (microangiopathy)
Bleeding (low platelets and coag factor deficiency)
129
Haematology - Haematological Changes in systemic disease
Questions to ask in abnormal WCC?
[not really a Q]
How high or low is the count?
Is it part of a pancytopenia (eg RBC and Platelets abnormal too)
Which lineage(s) is are abnormal ?
1 lineage raised others suppressed or all suppressed
Are the cells normal or abnormal in appearance ?(morphology)
Are the cells; mature should be in PB, or immature should never be in PB eg blasts and myelocytes?
130
Haematology - Haematological Changes in systemic disease
WBC increased mature cells
CLL/ALL
CLL
131
Haematology - Haematological Changes in systemic disease
WBC increased immature cells
CML/AML?
AML
132
Haematology - Haematological Changes in systemic disease
List causes of neutrophilia?
```
corticosteroids
underlying neoplasia
tissue inflammation (e.g.colitis, pancreatitis)
myeloproliferative/ leukaemic disorders
infection
```
133
Haematology - Haematological Changes in systemic disease
Which infections characteristically produce no neutrophilia?
Brucella, typhoid, many viral infections.
134
Haematology - Haematological Changes in systemic disease
Neutrophilia basophilia plus immature cells myelocytes, and splenomegaly. Suggest what?
CML
135
Haematology - Haematological Changes in systemic disease
Neutropenia plus Myeloblasts, suggest what?
AML
136
Haematology - Haematological Changes in systemic disease
Give examples of when you would see a reactive eosinophilia?
Parasitic infestation
allergic diseases e.g. asthma, rheumatoid, polyarteritis,pulmonary eosinophilia.
Underlying Neoplasms, esp. Hodgkin’s, T-cell NHL (reactive eosinophilia)
Drugs (reaction erythema mutiforme)
137
Haematology - Haematological Changes in systemic disease
FIP1L1-PDGFRa Fusion gene
Chronic Eosinophilic leukaemia
138
Haematology - Haematological Changes in systemic disease
In what conditions may you see a monocytosis?
TB, brucella, typhoid
Viral; CMV, varicella zoster
sarcoidosis
chronic myelomonocytic leukaemia (MDS)
139
Haematology - Haematological Changes in systemic disease
sIg
CD 19, 22, 79
HLA-DR
FMC7
What cell?
Mature B cells
140
Haematology - VTE
Consequences of thromboembolism
Death - 5% mortality,
Recurrence - 20% in first 2 yrs
Thrombophlebitic syndrome (recurrent pain, swelling and ulcers) - severe TS in 23% at yrs
Pulmonary hypertension - 4% 2 yrs
141
Haematology - VTE
Virchow's triad
blood coagulability
vessel wall damage
Stasis
142
Haematology - VTE
Protein C+S inhibit what?q
factors VIIIa, Va
143
Haematology - VTE
Antithrombin inhibits what?
thrombin and FXa
144
Haematology - VTE
TFPI inhibits what?
TF/FVIIa
145
Haematology - VTE
What anticoagulant molecules are expressed by the vessel wall?
Thrombomodulin
Endothelial protein C receptor
Tissue factor pathway inhibitor
Heparans
146
Haematology - VTE
What antiplatelet factors are secreted by the vessel wall?
Prostacyclin
| NO
147
Haematology - VTE
Inflammation/injury makes the vessel wall prothrombotic
T/F?
True
Anticoagulant molecules (eg TM) are down regulated
Adhesion molecules upregulated
TF may be expressed
Prostacyclin production decreased
148
Haematology - VTE
What prothrombotic changes occur with vessel wall damage?
Anticoagulant molecules (eg TM) are down regulated
Adhesion molecules upregulated
TF may be expressed
Prostacyclin production decreased
149
Haematology - VTE
Why does stasis promote thrombosis?
It causes:
Accumulation of activated factors
Promotes platelet adhesion
Promotes leukocyte adhesion and transmigration
Hypoxia produces inflammatory effect on endothelium
150
Haematology - VTE
Immobility Surgery, Paraparesis, Travel
Compression - Tumour, pregnancy
Viscosity - Polycythaemia, Paraprotein
Congenital - Vascular abnormalities
151
Haematology - VTE
List immediate anticoagulant drugs
Heparin
Unfractionated heparin
Low molecular weight heparin
Direct acting anti-Xa and anti-IIa
152
Haematology - VTE
Name a delayed anticoagulant
Vitamin K antagonists
| Warfarin
153
Haematology - VTE
MoA of heparins?
All act by potentiating antithrombin
Provide immediate effect (eg for treatment of thrombosis)
Long term disadvantage - injections, risk of osteoporosis
Variable renal dependence
154
Haematology - VTE
Disadvantages of heparins?
All act by potentiating antithrombin
Provide immediate effect (eg for treatment of thrombosis)
Long term disadvantage - injections, risk of osteoporosis
Variable renal dependence
155
Haematology - VTE
Which heparin always requires monitoring?
What needs monitoring?
Unfractionated heparin (UFH)
Variable kinetics
Variable dose-response
Always monitor therapeutic levels with APTT or anti-Xa
```
Low molecular weight heparin (LMWH)
Reliable pharmacokinetics so not usually required
Can use anti-Xa assay eg:
Renal failure (CrCl<50)
Extremes of weight or risk
```
156
Haematology - VTE
Name Anti-Xa Direct acting anticoagulants
Rivaroxaban, apixaban, edoxaban
157
Haematology - VTE
Name Anti-IIa Direct acting anticoagulants
Dabigatran
158
Haematology - VTE
What procoagulants fall with warfarin?
Given orally
Indirect effect by preventing recycling of Vit K
Therefore onset of action is delayed
Levels of procoagulant factors II, VII, IX & X fall
Levels of anticoagulant protein C and protein S also fall
159
Haematology - VTE
What must be measured with warfarin Rx, and why?
Always essential
Measure of effect is the INR
International normalised ratio (INR)
Derived from prothrombin time
```
Difficult because numerous interactions
Dietary Vitamin K
Variable absorption
Interactions with other drugs
Protein binding, competition/induction of cytochromes
Teratogenic
```
160
Haematology - VTE
Which anticoagulant is safe in pregnancy?
Heparins, NOT warfarin
161
Haematology - VTE
Identify patients at increased risk of thrombosis
Medical in patients
Infection/inflammation, immobility (inc stroke), age
Patients with cancer
Procoag molecules, inflammation, flow obstruction
Surgical patients
Immobility, trauma, inflammation
Previous VTE, Family history, genetic traits
Obese
Elderly
162
Haematology - VTE
Describe typical thromboprohylaxis used in hospitals
Low molecular weight heparin (LMWH)
Eg: Tinzaparin 4500u/ Clexane 40mg od
Not monitored
```
TED Stockings (for surgery or if heparin C/I)
Flotron - Intermittent compression (increases flow)
```
Sometimes DOAC +/- aspirin (orthopaedics)
163
Haematology - VTE
All admissions to hospital should be assessed for thrombotic risk and unless contraindication exists, receive heparin prophylaxis. 2010
True or false?
T
164
Haematology - VTE
For treatment of DVT/PE
Immediate anticoagulation is essential (v high risk of death from PE)
Start LMWH eg Tinzaparin 175u/kg
+ warfarin
Stop LMWH when INR >2 for 2 days
Continue for 3-6 months
---OR---
Start DOAC
Continue for 3-6 months
165
Haematology - VTE
When is thrombolysis indicated for VTE?
Only for life threatening PE or limb threatening DVT
Risk of haemorrhage (ICH) ~4%
Reduces subsequent post-phlebitic syndrome
Indications broadening slowly
166
Haematology - VTE
PT gets 1st DVT post surgery
Do they need LONG term prophylactic anticoagulation
Very low after surgical precipitant
| No need for long term anticoagulation
167
Haematology - VTE
PT gets 1st DVT idiopthically
Do they need LONG term prophylactic anticoagulation
High after idiopathic VTE (10-20% in 2yrs)
| Consider long term anticoagulation
168
Haematology - VTE
PT gets 1st DVT after minor precipitants
Do they need LONG term prophylactic anticoagulation
After minor precipitants (COCP, flights, trauma)
Usually 3 months adequate
Longer duration may be dictated by presence of other thrombotic and haemorrhagic risk factors
169
Haematology -Myelodysplastic syndromes and Aplastic anaemia
What are Myelodysplastic syndromes (MDS)?
Biologically heterogeneous group of acquired haemopoietic stem cell disorders (~ 4 per 100,000 persons)
Characterized by:
The development of a clone of marrow stem cells with abnormal maturation resulting in -
functionally defective blood cells AND
a numerical reduction
This results in:
i. Cytopenia(s).
ii. Qualitative (i.e. functional) abnormalities of erythroid, myeloid and megakaryocyte maturation.
iii. Increased risk of transformation to leukaemia
170
Haematology -Myelodysplastic syndromes and Aplastic anaemia
What cellular changes are seen with Myelodysplastic syndromes (MDS)?
Biologically heterogeneous group of acquired haemopoietic stem cell disorders (~ 4 per 100,000 persons)
Characterized by:
The development of a clone of marrow stem cells with abnormal maturation resulting in -
functionally defective blood cells AND
a numerical reduction
This results in:
i. Cytopenia(s).
ii. Qualitative (i.e. functional) abnormalities of erythroid, myeloid and megakaryocyte maturation.
iii. Increased risk of transformation to leukaemia
171
Haematology -Myelodysplastic syndromes and Aplastic anaemia
Name morphological features of MDS?
Pelger-Huet anomaly (bilobed neutrophils)
Dysganulopoieses of neutrophils
Dyserythropoiesis of red cells
Dysplastic megakaryocytes – e.g. micro-megakaryocytes
Increased proportion of blast cells in marrow (normal < 5%)
172
Haematology -Myelodysplastic syndromes and Aplastic anaemia
What is mselokathexis?
Myelokathexis is a congenital disorder of the white blood cells that causes severe, chronic leukopenia (a reduction of circulating white blood cells) and neutropenia (a reduction of neutrophil granulocytes). The disorder is believed to be inherited in an autosomal dominant manner.
173
Haematology -Myelodysplastic syndromes and Aplastic anaemia
| Auer Rods
AML
174
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Pyknotic neutrophil nuclei with lengthening and thinning of intrasegmented filaments and vacuoles?
Myelokathexis
175
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Refractory anaemia (RA)
with ringed sideroblasts (RARS)
without ringed sideroblasts
Refractory cytopenia with multilineage dysplasia (RCMD)
Refractory anaemia with excess of blasts (RAEB)
RAEB-I (BM blasts 5-9%)
RAEB-II (BM blasts 10-19%)
5q- syndrome
Unclassified MDS: MDS with fibrosis, childhood MDS, others
WHO classification of MDS 2008
176
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Prognostic Scoring System in MDS?
Revised International Prognostic Scoring System (IPSS-R) in MDS (2012)
177
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Describe the evolution of myelodysplasia?
Clue = rule of 1/3rds
1. Deterioration of blood counts
• Worsening consequences of marrow failure
2. Development of acute myeloid leukaemia
– Develops in 5-50%< 1 year (depends on subtype)
– Some cases of MDS are much slower to evolve
– AML from MDS has an extremely poor prognosis and is usually not curable
3. As a rule of thumb
• 1/3 die from infection
• 1/3 die from bleeding
• 1/3 die from acute leukaemia
178
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What two treatment options exist for MDS?
At present, the only two treatments that can prolong survival are:
allogeneic stem cell transplantation (SCT)
intensive chemotherapy
but only a minority of MDS patients can really benefit from them
179
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Describe the supportive care for MDS?
Blood product support
Antimicrobial therapy
Growth factors (Epo, G-CSF)
180
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What biological modifiers can be used for MDS?
Immunosuppressives: azacytidine, decitabine, lenalidomide (hypomethylating agents)
181
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Describe chemotherapeutic options for myelodysplastic syndromes?
Oral: hydroxyurea
Low dose: subcut cytarabine
Intensive (for high risk MDS) AML type regimens
182
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Results from damage or suppression of stem or progenitor cell
Bone Marrow Failure
183
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Name 4 primary BM failures?
Congenital: Fanconi’s anaemia (multipotent stem cell)
Diamond-Blackfan anaemia (red cell progenitors)
Kostmann’s syndrome (neutrophil progenitors)
Acquired: Idiopathic aplastic anaemia (multipotent stem cell)
184
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Name causes of secondary BM failures?
```
Marrow infiltration:
Haematological ( leukaemia, lymphoma, myelofibrosis)
Non-haematological (Solid tumours, )
Radiation
Drugs
Chemicals (benzene)
Autoimmune
Infection (Parvovirus, Viral hepatitis
```
185
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What drugs are associated with BM failure?
```
PREDICTABLE (dose-dependent, common)
Cytotoxic drugs
IDIOSYNCHRATIC (NOT dose-dependent, rare)
Phenylbutazone
Gold salts
ANTIBIOTICS
Chloramphenicol
Sulphonamide
DIURETICS
Thiazides
ANTITHYROID DRUGS
Carbimazole
```
186
Haematology - Myelodysplastic syndromes and Aplastic anaemia
2-5 cases/million/yr (world-wide)
All age groups can be affected
Peak incidence:
i. 15 to 24 yrs
ii. over 60 yrs
1. Anaemia Fatigue, breathlessness
2. Leucopenia Infections
3. Platelets Easy bruising/bleeding
Aplastic anaemia
187
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What is the Triad of Bone Marrow Failure findings
1. Anaemia Fatigue, breathlessness
2. Leucopenia Infections
3. Platelets Easy bruising/bleeding
188
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What is the pathophysiology of idiopathic AA?
* Failure of BM to produce blood cells
* “Stem cell” problem (CD34, LTC-IC) [Long-Term Culture-Initiating Cells]
• Immune attack:
Humoral or cellular (T cell) attack against multipotent haematopoietic stem cell.
189
Haematology - Myelodysplastic syndromes and Aplastic anaemia
1. Blood Cytopenia
2. Marrow Hypocellular
APLASTIC ANAEMIA
190
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What are the two classifications [NOT BY AETIOLOGY] of aplastic anaemia?
1. Severe aplastic anaemia (SAA)
| 2. Non-severe aplastic anaemia (NSAA)
191
Haematology - Myelodysplastic syndromes and Aplastic anaemia
DDx vs aplastic anaemia?
Hypoplastic MDS / Acute Myeloid Leukaemia
Hypocellular Acute Lymphoblastic Leukaemia
Hairy Cell Leukaemia
Mycobacterial (usually atypical) infection
Anorexia Nervosa
Idiopathic Thrombocytopenic Purpura
192
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What is the Camitta criteria for?
What are the three peripheral blood features?
Detecting SEVERE APLASTIC ANAEMIA
1. Reticulocytes < 1% (<20 x 109/l)
2. Neutrophils < 0.5 x 109/l
3. Platelets < 20 x 109/l
Bone marrow <25% cellularity
193
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Supportive Rx for aplastic anaemia?
```
SUPPORTIVE
Blood products
Leucodepleted
(CMV negative)
(Irradiated)
Antimicrobials
```
Iron Chelation Therapy
(when ferritin > 1000 ug/l)
194
Haematology - Myelodysplastic syndromes and Aplastic anaemia
idiopathic AA specific Rx?
```
A. Immunosuppressive therapy – older patient
Anti-Lymphocyte Globulin (ALG)
Ciclosporin
B. Androgens – oxymethalone
C. Stem cell transplantation
Younger patient with donor (80% cure)
VUD/MUD for > 40 yrs (50% survival)
```
195
Haematology - Myelodysplastic syndromes and Aplastic anaemia
WHAT ARE THE LATE COMPLICATIONS FOLLOWING IMMUNOSUPPRESSIVE THERAPY FOR AA
Relapse of AA (35% over 15 yrs)
Clonal haematological disorders
Myelodysplasia
Leukaemia
~ 20% risk over 10 yrs
PNH (paroxysmal nocturnal haemoglobinuria)
May be a transient phenomenon
Solid tumours ~ 3% risk
196
Haematology - Myelodysplastic syndromes and Aplastic anaemia
The most common form of inherited aplastic anaemia.
Autosomal recessive or X-linked inheritance
Heterozygote frequency may be 1:300
Multiple mutated genes are responsible.
When these genes become mutated, this results in:
Abnormalities in DNA repair
Chromosomal fragility
(breakage in the presence of in-vitro mitomycin or diepoxybutane)
Fanconi Anaemia
197
Haematology - Myelodysplastic syndromes and Aplastic anaemia
```
Short Stature
Hypopigmented spots and café-au-lait spots
Abnormality of thumbs
Microcephaly or hydrocephaly
Hyogonadism
Developmental delay
No abnormalities 30%
```
Fanconi anaemia
198
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What are the Sx of fanconi anaemia?
```
Short Stature
Hypopigmented spots and café-au-lait spots
Abnormality of thumbs
Microcephaly or hydrocephaly
Hypogonadism
Developmental delay
No abnormalities 30%
```
199
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What percentage of Fanconi patients get AA?
90%
Median = age 9
200
Haematology - Myelodysplastic syndromes and Aplastic anaemia
An inherited disorder characterised by:
Marrow failure
Cancer predisposition
Somatic abnormalities
Patients may present with the Classical Triad of
Skin pigmentation
Nail dystrophy
Leukoplakia
DYSKERATOSIS CONGENITA (DC)
201
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What is the triad of symptoms seen in DYSKERATOSIS CONGENITA (DC)?
Patients may present with the Classical Triad of
Skin pigmentation
Nail dystrophy
Leukoplakia
202
Haematology - Myelodysplastic syndromes and Aplastic anaemia
What percentage of patients get BM failure in dyskeratosis congenita?
85.5
203
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Telomere length is reduced marrow failure diseases
T/F?
T
especially short in patients with DC
204
Haematology - Myelodysplastic syndromes and Aplastic anaemia
Is dyskeratosis congenita inheritance AD, AR or X-linked?
All
X-linked recessive trait — the most common inherited pattern (mutated DKC1 gene - defective telomerase function).
Autosomal dominant trait — (mutated TERC gene - encodes the RNA component of telomerase).
Autosomal recessive trait — The gene for this form of DC has not yet been identified
205
Haematology - Lymphoma 1
Where do lymphomas exist?
lymph nodes, bone marrow and/or blood (the lymphatic system)
lymphoid organs; spleen or the gut-associated lymphoid tissue
Skin (often T cell disease)
Rarely “anywhere” (CNS, occular, testes, breast, etc.)
206
Haematology - Lymphoma 1
Give two reasons why lymphocytes, in general, are at risk of lymphoma generation?
DNA molecules are 1) cut and rejoined plus 2) undergo deliberate point mutation: generates immunoglobulin and T cell receptor diversity
Potential for recombination errors and new point mutations
Dependent on apoptosis (90% of normal lymphocytes die in the Germinal centre!)
Ensures antibody specificity Prevents auto-immune disease
Apoptosis is “switched off” in germinal centre
Acquired DNA mutation in pro apototic genes
Rapid cell proliferation in the germinal centre
Cell division = risk of DNA replication error
207
Haematology - Lymphoma 1
What are the general RFs for lymphomas?
Majority cases no identifiable risk factor
Known risk factors
Constant antigenic stimulation
Infection( direct viral infection of lymphocytes)
Loss of T cell function
208
Haematology - Lymphoma 1
What lymphoma is H.pylori related to?
H.Pylori : Gastric MALT (mucosa associated lymphoid tissue) Marginal Zone NHL of stomach
209
Haematology - Lymphoma 1
What lymphoma is Sjogren syndrome related to?
Sjogren syndrome : Marginal Zone NHL of Parotid lymphoma
210
Haematology - Lymphoma 1
What lymphoma is Coeliac disease related to?
Coeliac disease: small bowel T cell lymphoma EATL (enteropathy associated T-Cell Non Hodgkin lymphoma)
211
Haematology - Lymphoma 1
Name the virus that predisposes to adult T cell leukaemia lymphoma?
HTLV1 infects T cells by vertical transmission
Carribean and Japan carriers
May develop Adult T cell leukaemia lymphoma (2.5% at 70 years)
212
Haematology - Lymphoma 1
How are lymphomas diagnosed and staged?
```
Histological
Anatomical (CT/MRI/PET/BM)
Prognostic factors - LDH, b2 microglobulin,
Albumen,
kidney/BM function)
```
213
Haematology - Lymphoma 1
1% of all cancer, 3:100,000 population
More common in males than females.
Bimodal age incidence
Most common age 20-29, young women NS subtype
Second smaller peak affecting elderly >60 years old
Painless enlargement of lymph node/nodes.
May cause obstructive symptoms/signs
Constitutional symptoms; fever, night sweats weight loss (the B symptoms) and pruritis may be present. Rarely alcohol induced pain
Hodgkin Lymphoma
214
Haematology - Lymphoma 1
Sx of Hodgkin Lymphoma?
Painless enlargement of lymph node/nodes.
May cause obstructive symptoms/signs
Constitutional symptoms; fever, night sweats weight loss (the B symptoms) and pruritis may be present. Rarely alcohol induced pain
215
Haematology - Lymphoma 1
What are the four subtypes of hodgkins?
Classical HL
Nodular sclerosing 80% Good prognosis (causes the peak incidence in young women)
Mixed cellularity 17% Good prognosis
Lymphocyte rich (rare) Good prognosis
Lymphocyte depleted (rare) Poor Prognosis
Nodular Lymphocyte predominant HL 5% (disorder of the elderly multiple recurrences)
216
Haematology - Lymphoma 1
How is hodgkins staged?
Staging: Following pathological diagnosis of a lymph node biopsy patients are ‘staged’ this has prognostic significance and also may determine the best approach for therapy.
FDG-PET/CT scan
Consider biopsy of other site if possibly infiltrated e.g. liver
NB cHL spreads contiguously (what does that mean for staging ?)
217
Haematology - Lymphoma 1
What are the four stages of hodgkins?
```
Stage
I; one group of nodes
II; >1 group of nodes same side of the diaphragm
III; nodes above and below the diaphragm
IV; extra nodal spread
Suffix A if none of below, B if any of below
Fever
Unexplained Weight loss >10% in 6 months
Night sweats
```
218
Haematology - Lymphoma 1
What is the chemotherapy Rx for hodgkins? TIP ABVD
```
ABVD
Adriamycin
Bleomycin
Vinblastine
DTIC
```
ABVD, is given at 4-weekly intervals.
```
Effective treatment
Preserves fertility (unlike MOPP the original chemo)
Can cause (long term)
Pulmonary fibrosis
cardiomyopathy
```
219
Haematology - Lymphoma 1
Radiotherapy remains an effective Rx for hodgkins. What is the risk?
Modern practice involved field only
Low/negligible risk of relapse within field
Risk of damage to normal tissue (collateral damage)
Ca breast (risk 1:4 after 25 years)
Leukaemia/mds (3%@10years)
Lung or skin cancer
Combined modality greatest risk of 2o malignancy (two mechanisms of DNA damage)
220
Haematology - Lymphoma 1
How many cycles of ABVD therapy can be performed for hodgkins?
Chemotherapy required for all cases (ABVD)
ABVD 2-6 cycles (depending on stage)
+/- Radiotherapy
PET CT
Interim: post x2 cycles, response assessment
End of Treatment: Guides need for radiotherapy
221
Haematology - Lymphoma 1
Cure rate of hodgkins?
Outcome of therapy
Older patients generally do less well as do those with lymphocyte-depleted histology.
```
Prognosis:
This depends principally on stage.
Cure rate ranges from 50-90%.
Over 80% of patients with stage I or II disease are cured
Only 50% of stage IV patients are cured
```
What does cure mean ?
Overall 80% are long term survivors can we improve
10% die from relapse of HL (first 10 years)
10% die from long term treatment complications (after 10 years)
Eradicating HL in a 25-year old patient with highly toxic lymphoma therapy does not guarantee long term survival
222
Haematology - Lymphoma 1
Where is the generative lymphoreticular system?
Bone marrow and thymus
| Function - generation/maturation of lymphoid cells
223
Haematology - Lymphoma 1
Where is the reactive lymphoreticular system?
Lymph nodes and spleen
| Function - development of immune reaction
224
Haematology - Lymphoma 1
Where is the acquired lymphoreticular system?
Extranodal lymphoid tissue
E.g. Skin, stomach, lung
Function - development of local immune reaction
225
Haematology - Lymphoma 1
Describe the anatomy of the B cell area of a lymphoid follicle?
Outside follicle = paracortical T cell zone
Lymphoid follicle:
Outer = mantle zone - naive unstimulated B cells
Inner = B cell + APC
226
Haematology - Lymphoma 1
Comprises
T cells
Antigen presenting cells
High endothelial vessels
This is where T cells which bind antigen epitopes are selected and activated
T cell area of lymphoid follicle
227
Haematology - Lymphoma 1
Most common lymphoma
B cell Non-Hodgkin lymphomas most common type (80-85 %)
228
Haematology - Lymphoma 1
Morphology
Cytology: Look at single cells aspirated from a lump
```
Histology: look at tissue sections
Architecture
Nodular
Diffuse
Cells
Small round
Small cleaved
Large (centroblastic, immunoblastic, plasmablastic)
```
Morphology
Cytology: Look at single cells aspirated from a lump
```
Histology: look at tissue sections
Architecture
Nodular
Diffuse
Cells
Small round
Small cleaved
Large (centroblastic, immunoblastic, plasmablastic)
```
229
Haematology - Lymphoma 1
Used to identify proteins on/in cells in tissue sections
Use labelled antibody to cell surface receptor
Dye label is visible under light microscope in tissue sections
Immunohistochemistry
230
Haematology - Lymphoma 1
Follicular lymphoma
Small lymphocytic lymphoma/chronic lymphocytic leukaemia
Marginal zone lymphoma
Mantle zone lymphoma
What grade of lymphomas are these?
Low grade
231
Haematology - Lymphoma 1
Name a high grade lymphoma
Diffuse large B cell lymphoma
232
Haematology - Lymphoma 1
```
Clinical
Lymphadenopathy MA/elderly
Histopathology
Follicular pattern
Germinal centre cell origin CD10, bcl-6+
Molecular
14;18 translocation involving bcl-2 gene
Indolent but can transform to high grade lymphoma
```
Follicular Lymphoma
233
Haematology - Lymphoma 1
How do neoplastic and reactive follicles appear different with BCL2 expression?
Neoplastic B cells express bcl-2
| - Appear darker with staining
234
Haematology - Lymphoma 1
```
Clinical
MA/elderly; nodes or blood
Histopathology
Small lymphocytes, Naïve or post-germinal centre memory B cell
CD5, CD23 +
Molecular
Multiple genetic abnormalities
Indolent, but can transform to high grade lymphoma (Richter transformation)
```
Small lymphocytic lymphoma/CLL
235
Haematology - Lymphoma 1
Arise mainly at extranodal sites (many sites, e.g. gut, lung, spleen)
Thought to arise in response to chronic antigen stimulation (e.g. by Helicobacter in stomach)
Post germinal centre memory B cell
Indolent but can transform to high grade lymphoma
Can treat low grade disease with non-chemotheraputic modalities - i.e. remove antigen
E.g Helicobacter eradication
Marginal zone lymphoma/MALT lymphoma
236
Haematology - Lymphoma 1
```
Clinical
MA male predominence
Lymph nodes, GI tract
Disseminated disease at presentation
Histopathology
Located in mantle zone
Pre-germinal centre cell
Aberrant CD5, cyclin D1 expression
Molecular
11;14 translocation
Cyclin D1 over expression
Median SR 3-5 yrs
```
Mantle cell lymphoma
237
Haematology - Lymphoma 1
```
Clinical
Jaw or abdominal mass children/young adults
Endemic
Sporadic
Immunodeficiency
EBV associated
Histopathology
Germinal center cell origin
“starry-sky” appearance
Molecular
C-myc translocation (8:14, 2:8, 8;22)
Aggressive disease
```
Burkitt’s lymphoma
238
Haematology - Lymphoma 1
Clinical
MA/elderly
Lymphadenopathy
Histopathology
Germinal center or post-germinal center B cell
Sheets of large lymphoid cells
Germinal center phenotype = good prognosis
p53 positive, high proliferation fraction = poor prognosis
Diffuse large B cell lymphoma
239
Haematology - Lymphoma 1
```
MA/elderly
Lymphadenopathy and extranodal sites
Large T lymphocytes
Often with associated reactive cell population, esp eosinophils
Aggressive
```
T cell lymphomas
240
Haematology - Lymphoma 1
```
Clinical
Children/young adults
Lymphadenopathy
Histopathology
Large “epithelioid” lymphocytes
T cell or null phenotype
Molecular
2;5 translocation
Alk-1 protein expression
Aggressive
Alk-1 positive better prognosis
```
Anaplastic large cell lymphoma
241
Haematology - Lymphoma 1
Clinical
Isolated lymphadenopathy
Germinal centre B cell (positive for some germinal centre B cell markers)
No association with EBV
Histopathology
B cell rich nodules with scattered L&H cells
Indolent
Can transform to high grade B cell lymphoma
Nodular LP Hodgkins Lymphoma
242
Haematology - Lymphoma 2
Neoplastic proliferation of lymphoid cells.
Originates in lymphoid tissue (lymph nodes, bone marrow, spleen)
Incidence rising 200/million population/year
Non Hodgkin Lymphoma
243
Haematology - Lymphoma 2
fastest growing human cancer
(Burkitt Lymphoma)
244
Haematology - Lymphoma 2
Painless lymphadenopathy
Compression symptoms
B symptoms
Managing Non Hodgkin Lymphoma
245
Haematology - Lymphoma 2
How is NHL staged?
CT scan
PET scan (indicated in aggressive lymphomas)
BM biopsy
Lumbar puncture (if risk of CNS involvement )
246
Haematology - Lymphoma 2
List the prognostic markers & Important tests in NHL?
LDH
Performance status
HIV serology (if appropriate HTLV1 serology)
Hepatitis B serology (risk of reactivation if B cell depleting therapy given)
247
Haematology - Lymphoma 2
Burkitt Lymphoma
T or B cell Lymphoblastic leukaemia/lymphoma
Indolent or very/aggressive?
very aggressive
248
Haematology - Lymphoma 2
Diffuse Large B cell
Mantle cell
Indolent or very/aggressive?
Aggressive
249
Haematology - Lymphoma 2
Follicular
Small lymphocytic/CLL
Mucosa associated (MALT
Indolent
250
Haematology - Lymphoma 2
```
Aggressive B cell NHL
30-40% of all NHL
Prognosis and treatment determined by
Precise histological diagnosis
Anatomical stage
IPI (International Prognostic Index)
Age > 60y
serum LDH > normal
performance status 2-4
stage III or IV
more than one extranodal site
```
Diffuse Large B cell lymphoma
251
Haematology - Lymphoma 2
What is the Rx of Diffuse Large B cell lymphoma
Treated by x 6-8 cycles of R-CHOP (Rituximab-CHOP)
combination chemotherapy using a mixture of drugs usually including an anthracycline (e.g. doxorubicin).
```
Combination drug regimens e.g. CHOP
Cyclophosphamide 750 mg/m2 i.v. D1
Adriamycin 50 mg/m2 i.v. D1
Vincristine 1.4 mg/m2 i.v. D1
Prednisolone 40 mg/m2 p.o. D1‑D5
```
R is Immunotherapy using the anti CD20 monoclonal antibody Rituximab
Aim of therapy is curative (overall approx 50%)
Relapse: Autologous Stem Cell transplant salvage 25% of patients
252
Haematology - Lymphoma 2
Indolent lymphoma
35% of NHL
Associated with t(14;18) which results in over-expression of bcl2 an anti-apoptosis protein
FLIPI score (modified IPI)
Incurable, median survival 12-15 years
May require 2-3 different chemotherapy schedules over the 12-15 year period
Indolent slow progressing B cell NHL
Incurable
variable/long natural history
At presentation Watch and wait only treat “if clinically indicated”
Nodes compressing;eg bowel, ureter, vena cava
Massive painful nodes, recurrent infections
Treatment
combination Immuno-chemotherapy R-CVP
Maintenance rituximab delays Time to next progression
Conventional treatment is not curative
Follicular NHL
253
Haematology - Lymphoma 2
NHL involving extranodal lymphoid tissue (ie mucosa-associated lymphoid tissue MALT)
Comprise ~ 8% of all NHL
Chronic antigen stimulation
Sjogrens syndrome ; parotid lymphoma (MZL)
H.Pylori ; Gastric MALT lymphoma (MZL)
Hashimoto’s Thyroid; Thyroid (MZL)
Lachrymal gland (?Psittaci infection)
Median age at presentation 55-60y
Most commonly arise in stomach, usually present with dyspepsia or epigastric pain
Usual presentation is Stage I[E]
‘B’-symptoms uncommon
Marginal Zone lymphomas
254
Haematology - Lymphoma 2
What is the pathophysiology of Marginal zone lymphomas?
MALT lymphomagenesis
Proliferation polyclonal
Antigen specific B cells
Because: Chronic gastritis
Caused by H.Pylori infection
P15 p16
methylation
t(11;18)
```
Antigen dependent
Transformed B-cell
clone
- this is Antibiotic
Sensitive MALT
```
Eventually:
Antigen independent
Transformed B cells
Antibiotic insensitive MALT
255
Haematology - Lymphoma 2
Gastric MALT Rx?
```
Gastric MALT Stage I-II disease
Omep 20mg/Clarith 500mg/amox 1gm bd
Repeat breath test at 2 months
Repeat endoscopy every 6 months for 1st 2years then annually
Results
Durable remission in 75% of patients
response may be delayed until 1yr
If fails eradication therapy then may require chemotherapy
```
256
Haematology - Lymphoma 2
Is a T cell NHL seen in patients with Coeliac disease
mature T cells (not precursor)
Involving small intestine Jejunum and Ileum
Has an aggressive (not indolent clinical course)
Chronic antigen stimulation
Gluten in a Gluten sensitive individual
Presentation & Clinical course
Abdominal pain, obstruction perforation, GI bleeding
Malabsorption
Systemic symptoms
Responds poorly to chemo generally fatal
Aim to prevent (strict adherence to Gluten free diet)
Enteropahy Associated T cell lymphoma (EATL)
257
Haematology - Lymphoma 2
What is Enteropahy Associated T cell lymphoma (EATL)?
What does it anatomically involve?
Is a T cell NHL seen in patients with Coeliac disease
mature T cells (not precursor)
Involving small intestine Jejunum and Ileum
Has an aggressive (not indolent clinical course)
Chronic antigen stimulation
Gluten in a Gluten sensitive individual
Presentation & Clinical course
Abdominal pain, obstruction perforation, GI bleeding
Malabsorption
Systemic symptoms
Responds poorly to chemo generally fatal
Aim to prevent (strict adherence to Gluten free diet)
258
Haematology - Lymphoma 2
What cell overproliferates in Chronic Lymphocytic Leukaemia (CLL) ?
* Proliferation of mature B-lymphocytes
* Commonest leukaemia in the western world
Caucasian
UK incidence 4.2/100,000/year
Age at presentation median 72 (10% aged <55yrs)
Relatives x7 increased incidence
259
Haematology - Lymphoma 2
* Proliferation of mature B-lymphocytes
* Commonest leukaemia in the western world
Caucasian
UK incidence 4.2/100,000/year
Age at presentation median 72 (10% aged <55yrs)
Relatives x7 increased incidence
Chronic Lymphocytic Leukaemia (CLL)
260
Haematology - Lymphoma 2
* Lymphocytosis between 5 and 300 x 109/l
* Smear cells
* Normocytic normochromic anaemia
* Thrombocytopenia
• Bone marrow Lymphocytic replacement of normal
marrow elements
Chronic Lymphocytic Leukaemia (CLL)
261
Haematology - Lymphoma 2
Proliferation of mature B cells (CD19) co-expressing CD5
Further immuno studies CLL score 4-5
Chronic Lymphocytic Leukaemia (CLL)
262
Haematology - Lymphoma 2
What can be used as prognostic factors in CLL?
Clinical (quantify the burden of malignant cells)
Rai staging
Binet staging
Laboratory/malignant cell based
CD38 expression bad prognosis
Cytogenetics (FISH panel)
Immunglobulin gene mutation status
IgH mutated
IgH unmutated = bad
263
Haematology - Lymphoma 2
Median survival unmutated vs mutated in CLL?
Mutated 25 Unmutated 8
264
Haematology - Lymphoma 2
Describe the complications associated with each of the below, in CLL?
Malignant (non functional) mature B cells+ hypogammaglobulinaemia
Proliferate within Bone marrow (efface)
Circulate to nodes, spleen and blood
Acquire further mutations
Disease of “immune cells”
Increase risk of infection
Bone marrow failure
Lymphadenopathy+/splenomegaly, lymphocytosis
Transform to high grade lymphoma
Auto-immune complications e.g. haemolytic anaemia
265
Haematology - Lymphoma 2
What is the Rx for CLL?
```
Supportive treatment
Vaccination
Anti-infective prophylaxis and treatment
Specific scenarios
Auto-immune cytopaenias
High grade (Richter) transformation
```
Leukaemia directed treatment
Tailored to patient
266
Haematology - Lymphoma 2
List the prophylaxis a CLL patient will receive?
Aciclovir
PCP prophylaxis for those receiving fludarabine or alemtuzumab (Campath)
IVIG is recommended for those with hypogammaglobulinemia and recurrent bacterial infections
Immunisation against pneumococcus, and seasonal flu
267
Haematology - Lymphoma 2
How is the autoimmune phenomena Rx in CLL?
1st Line Steroids. 2nd Line Rituximab
| Irradiated Blood products if risk of TA GVHD
268
Haematology - Lymphoma 2
What percentage of CLL transforms to high grade lymphoma?
Transformation to high grade lymphoma
Richter’s syndrome
~1% per year
Treat as high grade lymphoma with CHOP-R
269
Haematology - Lymphoma 2
CLL is: Incurable by chemotherapy
Protocol is to watch and wait versus active treatment
What are the indications for Rx in CLL?
Progressive lymphocytosis
lymphocyte doubling time <6 months
Progressive marrow failure
Hb < 100, platelets <100, neutrophils <1
Massive or progressive lymphadenopathy/splenomegaly
Systemic symptoms (B symptoms)
Autoimmune cytopenias (treat with steroids)
270
Haematology - Lymphoma 2
FCR
Fludarabine Cyclophosphamide Rituximab (anti CD20 moab)
Rituximab-Bendamustine
Obinutuzumab (anti CD20) +Chlorambucil
Supportive care only
First line chemo for CLL
```
Top = only for fittest patients
Bottom = for elderly/weaker
```
271
Haematology - Lymphoma 2
What are high risk CLL patients?
Name two new Rx available for CLL high risk patients?
Patients with TP53/17p deleted CLL 1st Line
Refractory disease or early relapse (<24 months)
Ibrutinib (Bruton Tyrosine Kinase Inhibitor [Bcell Receptor])
Venetoclax (anti Bcl2 oral agent)
272
Haematology - MPD and CML
Raised Hb concentration and Haematocrit %
Polycythaemia
273
Haematology - MPD and CML
Name a relative cause of polycythaemia?
(lack of plasma) (non-malignant)
274
Haematology - MPD and CML
What is a true primary polycythaemia?
Primary (myeloproliferative neoplasm)
275
Haematology - MPD and CML
List the Ph negative polycythaemias?
```
Polycythaemia vera (PV)
Essential Thrombocythaemia (ET)
Primary Myelofibrosis (PMF)
```
276
Haematology - MPD and CML
List the Ph positive polycythaemias?
Chronic myeloid leukaemia (CML)
277
Haematology - MPD and CML
FBC shows
Hb 200g/l (Normal: 135-175)
Haematocrit 0.56 (Normal: 0.41-0.53)
This is a polycythaemia but is it:
Relative polycythaemia
True Polycythaemia?
If a True Polycythaemia is it
Secondary (reactive)
Primary Polycythaemia Vera (MPD)
What tool will enable this differentation?
Dilution studies \Fick principle
Red Cell Mass: 51 Cr labelled RBC
Plasma Vol: 131 I labelled albumin
278
Haematology - MPD and CML
FBC shows
Hb 200g/l (Normal: 135-175)
Haematocrit 0.56 (Normal: 0.41-0.53)
This is a polycythaemia but is it:
Relative polycythaemia
True Polycythaemia?
It turns out to be a True Polycythaemia is it
Secondary (reactive)
Primary Polycythaemia Vera (MPD)
What tool will aid this differentiation?
EPO
Primary polycythemia vera
(reduced EPO)
Secondary Polycythaemia
(elevated EPO)
279
Haematology - MPD and CML
What is a pseudopolycythaemia?
Normal red cell mass but reduced plasma volume
Caused by
Alcohol, obesity, diuretics
280
Haematology - MPD and CML
True secondary (non malignant) polycythemia
What test yields a high result?
Erythropoietin
Appropriate
High altitude
Hypoxic lung disease
Cyanotic heart disease
High affinity haemoglobin
Inappropriate
```
Renal disease (cysts, tumours inflammation)
uterine myoma
other tumours (liver, lung)
```
281
Haematology - MPD and CML
What percentage of blasts seen in BM is classed as AML?
20%
282
Haematology - MPD and CML
What percentage of blasts in the BM is deemed as myelodysplasia?
5-15%
283
Haematology - MPD and CML
Transmit cell growth signals from surface receptor to nucleus
Activated by transferring phosphate groups
Promote cell growth, do not block maturation
- what?
tyrosine Kinases
284
Haematology - MPD and CML
Name the philadelphia positive myeloproliferative disorder?
CML
285
Haematology - MPD and CML
JAK2 V617F mutation is seen in what myeloproliferative disorders?
100% - Polycythaemia Vera
60% - essential thrombocytopenia
60% - Primary myelofibrosis
286
Haematology - MPD and CML
Annual incidence 2-3/100000
Slightly more in males 1.2:1
Mean age at diagnosis 60 years
5% below age of 40 years
```
Incidental diagnosis routine FBC (median Hb 184g/l, Hct 0.55)
Symptoms of increased hyper viscosity:
Headaches, light-headedness, stroke
Visual disturbances
Fatigue, dyspnoea
Increased histamine release:
Aquagenic pruritus
Peptic ulceration
Test for JAK2 V617F mutation
```
PV
287
Haematology - MPD and CML
What are the Sx of PV?
```
Symptoms of increased hyper viscosity:
Headaches, light-headedness, stroke
Visual disturbances
Fatigue, dyspnoea
Increased histamine release:
Aquagenic pruritus
Peptic ulceration
Test for JAK2 V617F mutation
```
288
Haematology - MPD and CML
How is PV treated?
```
Aim to reduce HCT : target HCT <45%
Venesection
Cytoreductive therapy hydroxycarbamide
Aim to reduce risks of thrombosis
Control HCT
Aspirin
Keep platelets below 400x109/l (see treatment of ET)
```
289
Haematology - MPD and CML
What is essential thrombocythaemia?
Chronic MPN mainly involving megakaryocytic lineage
| Sustained thrombocytosis >600x109/L
290
Haematology - MPD and CML
Sustained thrombocytosis >600x109/L
Incidence 1.5 per 100000
Mean age two peaks 55 years and minor peak 30 years
Females :males equal first peak but females predominate second peak
essential thrombocythaemia
291
Haematology - MPD and CML
What are the Sx of essential thrombocythaemia?
```
Incidental finding on FBC (50% cases)
Thrombosis: arterial or venous
CVA, gangrene, TIA
DVT or PE
Bleeding: mucous membrane and cutaneous
Headaches, dizziness visual disturbances
Splenomegaly (modest)
```
292
Haematology - MPD and CML
What are the Rx for essential thrombocythaemia?
Aspirin: to prevent thrombosis
Hydroxycarbamide: antimetabolite. Suppression of other cells as well.
Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing
293
Haematology - MPD and CML
Prognosis of essential thrombocythaemia?
Normal life span may not be changed in many patients.
Leukaemic transformation in about 5% after >10 years
Myelofibrosis also uncommon, unless there is fibrosis at the beginning
294
Haematology - MPD and CML
A clonal myeloproliferative disease associated with reactive bone marrow fibrosis
Extramedullary haematopoieisis
Primary presentation:
Incidence 0.5-1.5 /100000
Males=females
7th decade. Less common in younger patients
Other MPDs (ET & PV) may transform to PMF
PMF
295
Haematology - MPD and CML
What is PMF?
A clonal myeloproliferative disease associated with reactive bone marrow fibrosis
Extramedullary haematopoieisis
Primary presentation:
Incidence 0.5-1.5 /100000
Males=females
7th decade. Less common in younger patients
Other MPDs (ET & PV) may transform to PMF
296
Haematology - MPD and CML
```
Incidental in 30%
Presentations related to:
Cytopenias: anaemia or thrombocytopenia
Thrombocytosis
Splenomegaly: may be massive
Budd-Chiari syndrome
Hepatomegaly
Hypermetabolic state:
Weight loss
Fatigue and dyspnoea
Night sweats
Hyperuricaemia
```
PMF
297
Haematology - MPD and CML
What are the Sx of PMF?
```
Incidental in 30%
Presentations related to:
Cytopenias: anaemia or thrombocytopenia
Thrombocytosis
Splenomegaly: may be massive
Budd-Chiari syndrome
Hepatomegaly
Hypermetabolic state:
Weight loss
Fatigue and dyspnoea
Night sweats
Hyperuricaemia
```
298
Haematology - MPD and CML
Blood film:
Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes
PMF
299
Haematology - MPD and CML
DNA : JAK2 or CALR mutation
PMF
300
Haematology - MPD and CML
What are the mutations seen in PMF?
DNA : JAK2 or CALR mutation
301
Haematology - MPD and CML
Bone marrow:
```
‘Dry tap’
Trephine:
Increased reticulin or collagen fibrosis
Prominent megakaryocyte hyperplasia and clustering with abnormalities
New bone formation
```
PMF
302
Haematology - MPD and CML
Prognosis of PMF
```
Median 3-5 years but very variable
Bad prognostic signs:
Severe anaemia <100g/L
Thrombocytopenia <100x109/l
Massive splenomegaly
Prognostic scoring system (DIPPS)
Score 0 -- median survival 15years
Score 4-6– median survival 1.3 years
```
303
Haematology - MPD and CML
What are the Rx for PMF?
Limited range of options:
Supportive: RBC and platelet transfusion often ineffective because of splenomegaly
Cytoreductive therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia)
Ruxolotinib: JAK2 inhibitor (high prognostic score cases)
Allogeneic SCT (potentially curative reserved for high risk eligible cases)
304
Haematology - MPD and CML
What is the name of the JAK2 inhibitor used in PMF?
Ruxolotinib
305
Haematology - MPD and CML
Leukaemia that has an:
• Incidence 1-2/100,000
M:F 1.4:1
• 40-60 years @ presentation
Radiation exposure risk factor
CML
306
Haematology - MPD and CML
•History
Lethargy/ hypermetabolism/ thrombotic event : monocular blindness CVA, bruising bleeding
Exam
Massive splenomegaly +/- hepatomegaly
FBC
Hb and platelets well preserved or raised
Massive leucocytosis 50-200x109/L
Blood film
Neutrophils and myelocytes (not blasts if chronic phase)
Basophilia
CML
307
Haematology - MPD and CML
What are the FBC changes seen in CML?
FBC
Hb and platelets well preserved or raised
Massive leucocytosis 50-200x109/L
308
Haematology - MPD and CML
What are the blood film changes seen in CML?
Blood film
Neutrophils and myelocytes (not blasts if chronic phase)
Basophilia
309
Haematology - MPD and CML
```
Leucocytosis between 50 – 500x109/l
Mature myeloid cells
Bi phasic peak Neutrophils and myelocytes
Basophils
No excess (<5%) myeloblasts
Platelet count raised/upper normal
```
CML
310
Haematology - MPD and CML
What occurred with the clinical course of CML before imatinib?
Eventual blast crisis
| - Whereby CML -> ALL
311
Haematology - MPD and CML
9:22
Philadelphia
BCR-ABL fusion
312
Haematology - MPD and CML
What methods can be use to detect translocation/fusion genes
Conventional Karyotyping
FISH metaphase or interphase karyotyping
RT-PCR amplification and detection
313
Haematology - MPD and CML
Problems of TKI imatinib with CML?
Failure to achieve CCyR
Non compliance
Side effects; fluid retention pleural effusions
Loss of MMR
Acquiring abl point mutations leading to resistance
Evolution to blast crisis
314
Haematology - MPD and CML
How can CML Rx response be assessed?
Haematological response
Complete Haematological Response WBC<10x109/l
```
Cytogenetic response (on 20 metaphases)
Partial 1-35% Philadelphia positive
Complete 0% Ph positive
```
Molecular ( reduction in % BCR-ABL transcripts)
BCR-ABL transcripts reduce 100% > 10% > 1% > 0.1%
Major Molecular response (MMR) <0.1% (3 log reduction)
315
Haematology - MPD and CML
What is the Rx rationale with regards to TKI CML Rx?
Chronic phase Tyrosine kinase Inhibitor (TKI)
Imatinib (1Gen,) Dasatanib Nilotonib (2G) Bosutinib (3G)
Failure (1) > switch to 2G or 3G TKI
No complete cytogenetic response @ 1year
Respond but acquire resistance
Failure (2) > consider allogeneic SCT
Inadequate response or intolerant of 2G TKIs
Progression to accelerated or blast phase
316
Haematology - MPD and CML
53 year old male with weight loss and abdo discomfort
O/E hepatomegaly and spleen 6 cm below costal margin
Hb 98g/l WBC 20x109/l platelets 60x109/l
BCR-ABL transcripts not detected
JAK2 V617F 20%
BM aspirate dry tap
PMF
317
Haematology - MPD and CML
```
22 year old male
Cyanotic congenital heart disease
Hb 210g/l and Haematocrit 60%
No splenomegaly
Select the most likely Lab test results
Serum erythropoietin
JAK2 mutation analysis
```
Serum erythropoietin - H
JAK2 mutation analysis - N
Appropriate polycythaemia
318
Haematology - MPD and CML
What is the accelerated phase in CML?
Accelerated phase = (10-19% blasts)
319
Haematology - Obstetric Haematology
Describe the full blood count in pregnancy
```
Mild anaemia
Red cell mass rises (120 -130%)
Plasma volume rises (150%)
Macrocytosis
Normal
Folate or B12 deficiency
Neutrophilia
Thrombocytopenia
increased platelet size
```
320
Haematology - Obstetric Haematology
What should daily Fe absorption be in pregnancy?
Iron requirement
300mg for fetus
500mg for maternal increased red cell mass
RDA 30mg;
Increases daily iron absorption: from 1-2mg to 6mg
321
Haematology - Obstetric Haematology
What are folate requirements in pregnancy?
Folate requirements increase
Growth and cell division
Approx additional 200mcg/day required
THEREFORE 400MCG INTAKE RECOMMENDED
322
Haematology - Obstetric Haematology
Complications of iron deficiency in pregnancy?
Iron deficiency: may cause IUGR, prematurity, postpartum haemorrhage
323
Haematology - Obstetric Haematology
A Cochrane review found Fe/Folate supplements had no effect on measures of maternal or fetal outcome
T/F?
T
BUT
Maternal Hb higher, Fe reserves higher, fetal ferritin higher
324
Haematology - Obstetric Haematology
Platelet count falls in pregnancy
T/F?
T
13% women
Platelets <150 x 109/L
325
Haematology - Obstetric Haematology
What are the causes of thrombocytopenia in pregnancy?
Physiological:
‘gestational’/incidental thrombocytopenia
Pre-eclampsia
Immune thrombocytopenia (ITP)
Microangiopathic syndromes
All other causes: bone marrow failure, leukaemia, hypersplenism, DIC etc.
326
Haematology - Obstetric Haematology
Physiological decrease in platelet count ~ 10%
>50x109/l sufficient for delivery (>70 for epidural)
Mechanism poorly defined
Dilution + increased consumption
Baby not affected
Platelet count rises D2 – 5 post delivery
Gestational thrombocytopenia
327
Haematology - Obstetric Haematology
```
50% get thrombocytopenia
Proportionate to severity
Probably due to increased activation and consumption
Associated with coagulation activation
(incipient DIC – normal PT, APTT)
Usually remits following delivery
```
Preeclampsia and thrombocytopenia
328
Haematology - Obstetric Haematology
```
5% of thrombocytopenia in pregnancy
TP may precede pregnancy
Early onset
Treatment options (for bleeding or delivery)
IV immunoglobulin
Steroids etc.
(Anti-D where Rh D +ve)
Baby may be affected
Unpredictable (platelets <20 in 5%)
Check cord blood and then daily
May fall for 5 days after delivery
Bleeding in 25% of severely affected (IVIG if low)
Usually normal delivery
```
Immune thrombocytopenia (ITP)
329
Haematology - Obstetric Haematology
Deposition of platelets in small blood vessels
Thrombocytopenia
Fragmentation and destruction of rbc within vasculature
Organ damage (kidney, CNS, placenta)
Microangiopathic haemolytic anaemia (MAHA)
330
Haematology - Obstetric Haematology
What changes are seen with coagulation in pregnancy?
Why are these changes seen?
HYPERCOAGULABLE
HYPOFIBRINOLYTIC
Factor VIII and vWF increase 3-5 fold
Fibrinogen increases 2 fold
Factor VII increases 0.5 fold
(Factor X)
Protein S falls to half basal
PAI-1 increase 5 fold
PAI-2 produced by placenta
Increased thrombin generation
Increased fibrin cleavage
Reduced fibrinolysis
Interact with other maternal factors
Rapid control of bleeding from placental site (700ml/min)
at time of delivery
331
Haematology - Obstetric Haematology
List factors increasing risk of thrombosis in pregnancy
```
N:
Changes in blood coagulation
Reduced venous return
~85% Left DVT
Vessel wall
```
```
Variable
Hyperemesis/dehydration
Bed rest
Obesity
- BMI>29 3x risk of PE
Pre-eclampsia
Operative delivery
Previous thrombosis/thrombophilia
Age
Parity
Multiple pregnancy
Other medical problems:
-HbSS, nephrotic syndrome
IVF: ovarian hyperstimulation
```
332
Haematology - Obstetric Haematology
Prevention of VTE in pregnancy?
Women with risk factors should receive prophylactic heparin +TED stockings
Either throughout pregnancy
Or in peri-post- partum period
Highest risk get adjusted dose LMWH heparin
Mobilise early
Maintain hydration
333
Haematology - Obstetric Haematology
How can VTE be treated in pregnancy?
Management
LMWH as for non-pregnant
Does not cross placenta
RCOG recommend once or twice daily
Do not convert to warfarin (crosses placenta)
After 1st trimester monitor anti Xa
4 hour post 0.5-1.0u/ml
Stop for labour or planned delivery, esp. for epidural
Epidural: wait 24 hours after treatment dose, 12 hours after prophylactic dose
334
Haematology - Obstetric Haematology
What is Antiphospholipid Syndrome?
Recurrent miscarriage + persistent Lupus anticoagulant (LA)/ anticardiolipin antibodies (ACL)
335
Haematology - Obstetric Haematology
Adverse pregnancy outcome: three or more consecutive miscarriages before 10 weeks of gestation
One or more morphologically normal fetal losses after the 10th week of gestation
One or more preterm births before the 34th week of gestation owing to placental disease.
Antiphospholipid Syndrome
336
Haematology - Obstetric Haematology
What two medications aid APLS?
Aspirin
| Heparin
337
Haematology - Obstetric Haematology
17% of maternal deaths are caused by what?
Obstetric haemorrhage
338
Haematology - Obstetric Haematology
Post Partum Haemorrhage (PPH) definition
> 500 mL blood loss
5% of pregnancies have blood loss >1 litre at delivery.
Requiring transfusion post partum
1% after vaginal delivery
1-7% after C-Section
339
Haematology - Obstetric Haematology
RFs for PPH?
major factors are
uterine atony
trauma
haematological factors minor except
dilutional coagulopathy after resuscitation
DIC in abruption, amniotic fluid embolism etc
340
Haematology - Obstetric Haematology
DIC in pregnancy RFs?
```
Amniotic fluid embolism
Abruptio placentae
Retained dead fetus
Preeclampsia (severe)
Sepsis
```
341
Haematology - Obstetric Haematology
‘the most catastrophic event in modern obstetrics’
1 in 20000-30000 births
Sudden onset shivers, vomiting, shock. DIC
86% mortality
16 deaths in last triennium
Presumed due to Tissue Factor in amniotic fluid entering maternal bloodstream
Almost all >25 years
Usually third trimester
Drugs used to induce labour e.g. misoprostol increase risk
Amniotic fluid embolism
342
Haematology - Obstetric Haematology
Complications of a sickle-cell mother in pregnancy?
Complications:
Fetal growth restriction,
Miscarriage, Preterm labour, ? Pre-eclampsia
Venous thrombosis
343
Haematology - Obstetric Haematology
How is sickle-cell managed n pregnancy?
Management
Red cell transfusion (top up or exchange)
Prophylactic transfusion
reduces number of vaso-occlusive episodes
Not clear whether affects fetal or maternal outcome
Alloimmunisation -extended phenotype: Rh D c E, Kell
344
Haematology - Obstetric Haematology
Differences in haematinics of IDA and thalassaemia
RBC Increased in thalassaemia, decreased in IDA
RDW N in thalassaemia, low in IDA
Electrophoresis normal in IDA [and a-thal]
345
Haematology - Multiple Myeloma
Cancer of transformed plasma cells, terminally differentiated B cells that secrete Ig and are the effector cells of the specific humoral immune response
Multiple myeloma
346
Haematology - Multiple Myeloma
Premalignant condition for MM?
MGUS
347
Haematology - Multiple Myeloma
2nd most common haematopoietic malignancy (after the B cell lymphomas) and affects >4000 people every year in the UK
MM
348
Haematology - Multiple Myeloma
What two genomic changes are seen with MGUS
Monoclonal gammopathy of undetermined significance?
Deletion of chromosome 13
| Translocation at 14q21
349
Haematology - Multiple Myeloma
What mutations result in MGUS -> MM formation?
N-RAS - 30%
| K-RAS - 40%
350
Haematology - Multiple Myeloma
List features of MM?
DONT FORGET THE CRAAAAB
```
C- calcium elevated
R - renal impairment
A - anaemia
B - bone lesions
M - monoclonal protein
```
```
Monoclonal PCs
Osteolytic lesions
Anaemia
Infections
Kidney failure
Paraprotein
```
```
Other Sx
Back pain
Fatigue
Pneumonia
Paralysis - Cord compression
```
351
Haematology - Multiple Myeloma
MGUS
Monoclonal serum protein ____
BM plasma cells ____
annual risk of progression to MM ____
Rare in young, increasing incidence with age ____
Monoclonal serum protein < 30g/L
BM plasma cells < 10%
annual risk of progression to MM 1-2%
Rare in young, increasing incidence with age (5% >70y
352
Haematology - Multiple Myeloma
Aetiology of MM?
increased risk in farmers, laxative takers, cosmetologists, radiologists
asbestos, petroleum products, pesticides, rubber/wood products
High-dose radiation (>100cGy, 4-5x risk in Hiroshima/Nagasaki survivors)
Chronic infection/inflammation (rheumatoid arthritis; viral – HHV8/HIV?)
353
Haematology - Multiple Myeloma
What are the BM aspirate findings in MM?
Mature plasmacytic myeloma cells (A, B) with clumped chromatin, low nuclear-tocytoplasmic ratio, abundant cytoplasm, rare nucleoli.
Immature plasmablastic myeloma cells (C, D) with prominent nucleoli, reticular chromatin, less abundant cytoplasm
354
Haematology - Multiple Myeloma
Multiple myeloma immunophenotype
Positive: CD38, CD138, CD56/58, monotypic cytoplasmic Ig, LC restricted
Negative: CD19 and CD20, surface Ig
355
Haematology - Multiple Myeloma
How is MM bone disease detected?
Magnetic resonance imaging (MRI)
High sensitivity for marrow infiltration
Response monitoring possible
Expensive & limited availability
NB CT can detect very small lesions
PET detects active disease
356
Haematology - Multiple Myeloma
How does renal injury occur in MM?
Free Light Chains activate inflammatory mediators in the proximal tubule epithelium
Proximal tubule necrosis
Fanconi syndrome (renal tubule acidosis) with FLC crystal deposition.
Cast nephropathy
357
Haematology - Multiple Myeloma
What 4 Rx pathways exist for MM?
Steroids
Proteasome inhibitors
IMIDs (eg thalidomide)
Classic cytostatics - Melphalan
358
Haematology - Multiple Myeloma
MoA of Melphalan (cytostatic)
nitrogen mustard-type alkylating agent
adds alkyl group (CnH2n+1) to DNA (guanine) crosslinks G/blocks DNA replication
Mustard gas widely used in WW1; stocked but not used in WW2
359
Haematology - Multiple Myeloma
How is Melphalan used in MM?
stem cell collection from the blood and storage
high-dose melphalan to kill myeloma cells
re-infusion of stem cells to rescue blood formation
360
Haematology - Multiple Myeloma
MoA of proteosome inhibitors
Misfolded proteins are recycled by the proteasome in a process termed ER-associated degradation (ERAD)
Proteasome inhibitors cause fatal ER stress and intracellular amino acid starvation
361
Haematology - Blood Transfusion
Complication of giving unmatched blood?
Massive intravascular haemolysis
362
Haematology - Blood Transfusion
Name other blood antigens
Rhesus C,c,E,e
Kell
Duffy
Kidd
- These are only ever matched if the patient has a corresponding antibody
363
Haematology - Blood Transfusion
What percentage of the population is rhesus positive?
85%
364
Haematology - Blood Transfusion
What happens if anti-D from the mother is exposed to RhD in the baby?
Immune Anti-D made by a Rh negative mother exposed to Rh positive blood, can cause haemolytic disease of the newborn or severe fetal anaemia and heart-failure (hydrops fetalis) in RhD-negative females of child bearing potential.
365
Haematology - Blood Transfusion
How are ABO groups tested?
Addition of anti-A, anti-B and anti-D reagents to patients RBCs
Also a control with known positive
POSITIVE reaction = agglutination
NEGATIVE reaction = no agglutination, cells sink
366
Haematology - Blood Transfusion
What is the indirect antiglobulin technique? AKA antibody screen?
INDIRECT ANTIGLOBULIN TECHNIQUE
Patients plasma incubated (37deg) with Red cells known to contain ALL important red cell antigens.
(bridges red cells coated by IgG, which can’t themselves bridge 2 red cells – to form a visible clump. Takes 30 mins’ incubation at 37°C)
367
Haematology - Blood Transfusion
Red cell storage
Stored at 4°C for 35 days.
| Must be transfused within 4 hours of leaving fridge
368
Haematology - Blood Transfusion
| How long does it take to transfuse 1 unit of blood?
2-3 hrs
369
Haematology - Blood Transfusion
Storage of platelets?
Stored at 22°C for 7days
370
Haematology - Blood Transfusion
How long does it take to transfuse 1 unit of platelets?
Transfuse 1 unit of platelets over 20-30 minutes
371
Haematology - Blood Transfusion
How long does it take to transfuse 1 unit of FFP?
Transfuse 1 unit over 20-30 minutes
372
Haematology - Blood Transfusion
Does plasma need to be crossmatched?
Give ABO compatible but D group does not matter
No need to cross match but does take 30-40 minutes to thaw
373
Haematology - Blood Transfusion
What are the guidelines for indications of RBC administration [simple]?
IE
- how much bloodless?
- Hb level
Major bloodless >30% blood volume
Peri-Op critical care if Hb <70/80
Post chemo - <80g/L
Symptomatic anaemia IHD, breathless + ECG changes
374
Haematology - Blood Transfusion
What is Maximum Surgical Blood Ordering Schedule (MSBOS)?
Process whereby there is negotiation between surgeons and
transfusion lab about predictable blood loss for ‘routine’ planned
Surgery.
- Reduces wasted blood
375
Haematology - Blood Transfusion
What is cell salvage?
Whereby blood is collected intra or post operatively and rein fused into the patient
All coagulation factors and platelets are removed
376
Haematology - Blood Transfusion
Who receives CMV negative blood?
CMV negative blood - only required for intra-uterine and neonatal transfusions (new guidance 2012). Also for elective transfusion in pregnant women (baby in-utero is exposed to maternal transfusion)
377
Haematology - Blood Transfusion
When is irradiated blood used?
Irradiated blood - required for highly immunosupressed patients, who cannot destroy incoming donor lymphocytes: which can cause (fatal) transfusion associated graft versus host disease (TA-GvHD)
378
Haematology - Blood Transfusion
When is washed blood used?
Washed - red cells and platelets are only given to patients who have severe allergic reactions to some donors’ plasma proteins
379
Haematology - Blood Transfusion
How much is the platelet count increased by in an adult with one unit of platelets typically?
One unit of platelets is an adult treatment dose: usually raises platelet count by 30-40 x109/L
380
Haematology - Blood Transfusion
FFP is the treatment choice to reverse warfarin, T/F?
F
FFP is not the treatment of choice to reverse warfarin: PCC (prothrombin complex concentrate) is (IX, II, X & bit of VII)
381
Haematology - Blood Transfusion
Adult dose of FFP?
The adult dose is 15mL/kg
| 1 unit FFP contains 250mL = adult dose is 4-6 units
382
Haematology - Blood Transfusion
When should FFP be administered with massive transfusion?
Blood loss > 150mL/min
383
Haematology - Blood Transfusion
When should FFP be administered in DIC?
DIC with any bleeding
384
Haematology - Blood Transfusion
When should FFP be administered for liver disease?
PT ratio >1.5x normal
385
Haematology - Blood Transfusion
List 5 possible ACUTE adverse reactions to transfusion?
<24hrs
```
Acute haemolytic (ABO incompatible)
Allergic/anaphylaxis
Infection (bacterial)
Febrile non-haemolytic
Respiratory
Transfusion associated circulatory overload (TACO)
Acute lung injury (TRALI)
```
386
Haematology - Blood Transfusion
List 5 possible DELAYED adverse reactions to transfusion?
>24hrs
```
Delayed haemolytic transfusion reaction (antibodies)
Infection
viral, malaria, vCJD
TA-GvHD
Post transfusion purpura
Iron overload
```
387
Haematology - Blood Transfusion
Acute transfusion reactions are common but most are mild
T/F?
T
388
Haematology - Blood Transfusion
List the symptoms of an acute reaction?
Many acute reactions start as: rise in temp or pulse, or fall in BP, even before patient feels symptoms
Symptoms: depends on cause, but can include:
Fever, rigors, flushing, vomiting, dyspnoea, pain at transfusion site, loin pain/ chest pain, urticaria, itching, headache, collapse etc
389
Haematology - Blood Transfusion
What is Febrile Non-Haemolytic Transfusion Reaction (FNHTR)?
What is the treatment?
During / soon after transfusion (blood or platelets),
rise in temperature of 1C, chills, rigors
Common before blood was leucodepleted, now rarer
Have to stop or slow transfusion; may need to treat
with paracetamol
Cause: White cells can release cytokines during
storage
390
Haematology - Blood Transfusion
What is an allergic transfusion reaction?
What is the treatment?
Allergy to a plasma protein in donor so may not recur again, depending on how common the allergen is.
Common especially with plasma
Mild urticarial or itchy rash sometimes with a
wheeze. During or after transfusion.
Usually have to stop or slow transfusion
IV antihistamines to treat (and prevent in future,
if recurrent)
Commoner in recipients with other allergies and atopy
391
Haematology - Blood Transfusion
What are the symptoms and signs of acute intravascular haemolysis- IgM?
```
Restless, chest/ loin pain, fever, vomiting, flushing, collapse, haemoglobinuria (later);
↓BP & ↑HR (shock), ↑Temp
Take samples for FBC, biochemistry,
coagulation, repeat x-match and Direct
Antiglobulin Test (DAT).
```
392
Haematology - Blood Transfusion
What are the signs and symptoms of bacterial contamination?
Restless, fever, vomiting, flushing, collapse.
↓BP & ↑HR (shock), ↑Temp
Bacterial growth can cause endotoxin production which causes immediate collapse
From the donor (low grade GI, dental, skin infection)
Introduced during processing (environmental or skin)
Platelets >red cells > frozen components (storage temp)
393
Haematology - Blood Transfusion
Methods of prevention of bacterial contamination of blood?
Donor questioning + arm cleaning + diversion of first 20mL into a pouch (used for testing)
Red cells: Store always in controlled fridge 40C; shelf-life 35 days. If out for >½ hour, need to go back in fridge for 6 hours. Complete transfusion of blood within 4.5h of leaving fridge i.e. transfuse over 4hrs max
Platelets: stored at 220C; shelf-life 7 days (as now screened for bacteria before release)
All components: look for abnormalities e.g. clumps of discoloured debris; brown plasma etc
394
Haematology - Blood Transfusion
Signs of anaphylaxis after blood transfusion?
What is the mechanism?
Same + Same
“Severe, life-threatening reaction soon after start of transfusion”
↓BP & ↑HR (shock),
very breathless with wheeze,
often laryngeal &/or facial oedema
Mechanism:
IgE antibodies in patient cause mast cell release of granules & vasoactive substances. Most allergic reactions are not severe, but some can be e.g. in
IgA deficiency:
1:300 - 1:700 (common); where in 25%, anti-IgA antibodies develop in response to exposure to IgA (transfusion – especially with plasma);
But only minority ever have transfusion reactions- frequency is 1:20,000 - 1:47,000.
395
Haematology - Blood Transfusion
What is TACO?
AKA transfusion associated circulatory overload?
What are the clinical features?
How is it diagnosed?
Pulmonary oedema / fluid overload;
Often lack of attention to fluid balance, especially in cardiac failure, renal impairment, hypoalbuminaemia; very young and very old.
1 unit of blood may be enough to raise Hb in smaller patients
Clinical features: SOB, ↓O2 sats, ↑HR, ↑BP;
CXR: fluid overload / cardiac failure.
396
Haematology - Blood Transfusion
What is a TRALI?
TRANSFUSION RELATED ACUTE LUNG INJURY
What are the Sx?
Anti-wbc antibodies (HLA or neutrophil Abs) in donor
Interact with corresponding ag on patient’s wbc’s
Aggregates of wbc’s get stuck in pulmonary capillaries → release neutrophil proteolytic enzymes & toxic O2 metabolites → lung damage
Acute lung injury/ARDS
SOB, ↓O2 sats, ↑HR, ↑BP; (similar to TACO)
CXR: bilateral pulmonary infiltrates during/within 6 hr of transfusion, not due to circulatory overload or other likely causes
Prevention - male donors for plasma & platelets (no pregnancy or transfusion, so no HLA/HNA antibodies)
397
Haematology - Blood Transfusion
What is a Delayed Haemolytic Transfusion Reaction?
1-3% of all patients transfused develop an ‘immune’ antibody to a RBC antigen they lack
= ALLOMMUNISATION
If the patient has another transfusion with RBCs expressing the same antigen, antibodies cause RBC destruction
= EXTRAVASCULAR HAEMOLYSIS (as IgG) so takes 5-10 days.
398
Haematology - Blood Transfusion
What Ix confirm delayed haemolytic transfusion reactions?
Haemolysis tests: bilirubin, Hb, retics haemoglobinuria over few days
Test U&Es – as can cause renal failure
Repeat G&S for potential new antibody
399
Haematology - Blood Transfusion
What is Transfusion Associated Graft-Versus-Host Disease (TaGVHD)?
Fatal condition whereby donor blood contains lymphocytes. Normally the immune system will destroy these.
If immunocompromised: lymphocytes not destroyed.
They attack PTs gut/liver/skin
Causes severe diarrhoea, liver failure, skin desquamation, bone marrow failure death weeks to months post transfusion
Prevent: irradiate blood components for very immunosuppressed; or patients having HLA matched components.
400
Haematology - Blood Transfusion
What are the Sx of TA-GVHD?
Causes severe diarrhoea, liver failure, skin desquamation, bone marrow failure death weeks to months post transfusion
Prevent: irradiate blood components for very immunosuppressed; or patients having HLA matched components.
401
Haematology - Blood Transfusion
How can TA-GVHD be prevented?
Causes severe diarrhoea, liver failure, skin desquamation, bone marrow failure death weeks to months post transfusion
Prevent: irradiate blood components for very immunosuppressed; or patients having HLA matched components.
402
Haematology - Blood Transfusion
What is Post Transfusion Purpura?
Purpura appears 7-10 days after transfusion of blood or platelets and usually resolves in 1 to 4 weeks but can cause life threatening bleeding
Due to very low platelets: <20x109/L
Affects HPA -1a negative patients - previously immunised by pregnancy or transfusion (anti-HPA-1a antibody)
?exact mechanism of own platelet destruction, as HPA-1a negative! ?innocent bystander mechanism
Treatment – infusion of IVIG
403
Haematology - Blood Transfusion
What can occur with repeat blood transfusion?
How can this be prevented?
If lots of transfusion (eg:>50) over time accumulate iron (not excreted); 200-250mg of iron per unit of blood
Can cause organ damage - liver, heart, endocrine etc
Prevent by iron chelation (exjade) with transfusions once ferritin >1000 eg: used in Thalassaemics - monthly transfusions
404
Haematology - Blood Transfusion
What is the mechanism of RhD sensitisation?
Foetus is RhD positive.
Rhesus D red cells cross the placenta (mainly during delivery)
Anti-D forms in mother (6 months later)
2nd pregnancy - Mothers anti-D (IgG) can cross placenta
Coats foetal RhD + cells and destroys in foetal liver and spleen
405
Haematology - Blood Transfusion
What are the clinical features of HDFN?
Fetal anaemia (haemolytic)
Haemolytic disease of newborn (anaemia plus high bilirubin - which builds up after birth as no longer removed by placenta)
Hydrops fetalis
Kernicterus
406
Haematology - Blood Transfusion
How is HDFN prevented/Rx?
All pregnant women have G&S at around 12 weeks
(booking) and again at 28 weeks to check for RBC
Antibodies. If antibody present:
check if father has the antigen (so baby could inherit it)
monitor level of antibody (high or rising - more likely to affect fetus)
Check ffDNA sample
Monitor fetus for anaemia – MCA Doppler ultrasound
Deliver baby early, as HDN gets a lot worse in last few weeks of pregnancy
If necessary, intra-uterine transfusion can be given to fetus
Specialised centres, highly skilled - needle in umbilical vein
At delivery - monitor baby’s Hb and bilirubin for several days as HDN can get worse for few days
Can give exchange transfusion to baby if needed to bilirubin and Hb; plus phototherapy to bilirubin
Note: subsequent pregnancies usually
worse
Can give intra-muscular
injection of anti-D immunoglobulin, at times when mother
is at risk of a fetomaternal bleed e.g. at delivery
407
Haematology - Blood Transfusion
When must anti-D injections be given to be effective?
AT what points will this be used?
To be effective - must give anti-D injection within 72 hours of the ‘sensitising event’
it does not work if the mother has already been sensitised (developed anti-D) in the past
1. Give anti-D at delivery if baby is RhD positive
2. Give anti-D Ig for ‘sensitising events’ during pregnancy, where FoetoMaternoHaemorrhage is likely to occur**
spontaneous miscarriages if surgical evacuation needed and therapeutic terminations
amniocentesis and chorionic villous sampling
abdominal trauma (falls and car accidents)
external cephalic version (turning the fetus)
stillbirth or intrauterine death
3. ROUTINE ANTENATAL ANTI-D PROPHYLAXIS
About 1% of pregnancies have no obvious ‘sensitising events’, yet RhD negative mothers become sensitised
To prevent this, routine anti-D prophylaxis can be given in 3rd trimester
Usually, dose of 1500 iu anti-D Ig at 28-30 weeks
408
Haematology - Blood Transfusion
What are the minimum doses before and after 20w pregnancy?
At least 250 iu - for events before 20 weeks of pregnancy
| At least 500 iu - for events any time after 20 weeks of pregnancy (including delivery)
409
Haematology - Blood Transfusion
What is Routine antenatal anti-D prophylaxis (RAADP)
About 1% of pregnancies have no obvious ‘sensitising events’, yet RhD negative mothers become sensitised
To prevent this, routine anti-D prophylaxis can be given in 3rd trimester
Usually, dose of 1500 iu anti-D Ig at 28-30 weeks
410
Haematology - Blood Transfusion
What other antigens can cause severe HDN?
Anti-c and anti-Kell can cause severe HDN
Kell causes reticulocytopenia in fetus as well as haemolysis
IgG Anti-A and anti-B antibodies from Group O mothers
can cause mild HDN
usually not severe (phototherapy)
411
Haematology - Blood Transfusion
What effect does Kell HDN also have, aside from haemolysis?
Kell causes reticulocytopenia in fetus as well as haemolysis
412
Haematology - BM Transplantation
List complications of stem cell therapy?
Graft failure
Infections
Graft-versus-host disease (GVHD): allografting only
Relapse
413
Haematology - BM Transplantation
Name the scoring system used to estimate survival post BMT?
EBMT prognostic score
414
Haematology - BM Transplantation
RFs for acute GVHD?
```
Degree of HLA disparity
Recipient age
Conditioning regimen
R/D gender combination
Stem cell source
Disease phase
Viral infections
```
415
Haematology - BM Transplantation
List Rx for GVHD?
```
Corticosteroids
Cyclosporin A
FK506
Mycophenylate mofetil
Monoclonal antibodies
Photopheresis
Total lymphoid irradiation
```
416
Haematology - BM Transplantation
List drugs used to prevent GVHD?
```
Methotrexate
Corticosteroids
Cyclosporin A
CsA plus MTX
FK506
```
T-cell depletion
Post-transplant cyclophosphamide
417
Haematology - Paediatric Haematology
There are no gender differences in paeds blood counts, T/F?
T
418
Haematology - Paediatric Haematology
Glucose-6-phosphate dehydrogenase (G6PD) concentration is about 50% lower than in adults. T/F?
F
50% higher
419
Haematology - Paediatric Haematology
The neonate will have higher percentage of haemoglobin F than at any other time of life so disorders of beta globin genes are much less likely to be manifest
T/F?
T
420
Haematology - Paediatric Haematology
Name two causes of polycythaemia in the foetus?
Twin-to-twin transfusion
Intrauterine hypoxia
Placental insufficiency
421
Haematology - Paediatric Haematology
Name two causes of anaemia in the foetus?
Twin-to-twin transfusion
Fetal-to-maternal transfusion
Parvovirus infection (virus not cleared by immature immune system)
Haemorrhage from the cord or placenta
422
Haematology - Paediatric Haematology
The first mutation that subsequently leads to childhood leukaemia often occurs in utero
T/F?
T
423
Haematology - Paediatric Haematology
a2b2 globin
Haemoglobin A
424
Haematology - Paediatric Haematology
a2d2 globin
Haemoglobin A2
425
Haematology - Paediatric Haematology
a2g2 globin
Haemoglobin F
426
Haematology - Paediatric Haematology
What test is used to detect sickle cell disease prior to symptom onset?
Why does symptom onset occur later?
Guthrie spot
HbF still present in early life
- Formed of A2G2 chains (no B)
427
Haematology - Paediatric Haematology
Sickle cell anaemia in the infant and child differs from the same disease in the adult
Why is that?
The distribution of red bone marrow (susceptible to infarction) differs—the hand/foot syndrome
The infant still has a functioning spleen—splenic sequestration can occur
The infant has an immature immune system and has not developed immunity to pneumococcus or parvovirus
The infant and child is growing rapidly and has a greater need for folic acid
428
Haematology - Paediatric Haematology
What is splenic sequestration?
Splenic sequestration is the acute pooling of a large percentage of circulating red cells in the spleen
The spleen enlarges acutely
The Hb falls acutely and death can occur
This doesn’t happen in older children and adults because recurrent infarction has left the spleen small and fibrotic
However, having a small and fibrotic spleen has other disadvantages
The spleen is an important part of the immune system
It is very important for filtering out bacteria and parasites
As the risk of splenic sequestration wanes the risk of hyposplenism waxes
429
Haematology - Paediatric Haematology
Why does folic acid matter more in a child with sickle cell disease than in a normal child or an adult?
Hyperplastic erythropoiesis requires folic acid
Growth spurts require folic acid
Red cell life span is shorter so anaemia can rapidly worsen
430
Haematology - Paediatric Haematology
Define B thalassaemia.
At what age do you think it would first be manifest?
How can it be suspected at birth?
Beta thalassaemia is a condition resulting from reduced synthesis of beta globin chain and therefore haemoglobin A
You might expect it to become apparent in the first 3‒6 months of life
Guthrie spots again
431
Haematology - Paediatric Haematology
B thalassaemia heterozygosity is deadly. T/F?
F
Beta thalassaemia heterozygosity or trait is harmless but genetically important
432
Haematology - Paediatric Haematology
Clinical effects of poorly treated thalassaemia major
Anaemia -> heart failure, growth retardation
Erythropoietic drive -> bone expansion, hepatomegaly, splenomegaly
Iron overload -> heart failure, gonadal failure
433
Haematology - Paediatric Haematology
How do we manage an infant/child with beta thalassaemia major?
Accurate diagnosis and family counselling
Blood transfusion
Once iron overload starts to occur, chelation therapy (desferioxamine, deferiprone)
Consideration of the child as an individual and as part of a family
434
Haematology - Paediatric Haematology
Name the two important acquired haemolytic anaemias in children?
Autoimmune haemolytic anaemia
| Haemolytic uraemic syndrome
435
Haematology - Paediatric Haematology
Blood film shows spherocytosis
Positive direct antiglobulin test (Coombs’ test)
What disease?
AIHA
436
Haematology - Paediatric Haematology
Haemolysis
Uraemia
HUS
437
Haematology - Paediatric Haematology
That means that the red cells are damaged in capillaries and are fragmented by the process
Small angular fragments and microspherocytes are formed
MAHA
| -Aka from HUS
438
Haematology - Paediatric Haematology
Presentation of haemophilia A and B
Bleeding following circumcision
Haemarthroses when starting to walk
Bruises
Post-traumatic bleeding
439
Haematology - Paediatric Haematology
Haemophilia DDx
Inherited thrombocytopenia or platelet functional defect
Acquired defects of coagulation, e.g. autoimmune thrombocytopenic purpura, acute leukaemia
Non-accidental injury
Henoch‒Schönlein purpura
440
Haematology - Paediatric Haematology
Presentation of von Willebrand disease
Mucosal bleeding
Bruises
Post-traumatic bleeding
441
Haematology - Paediatric Haematology
Differential diagnosis of von Willebrand disease
Haemophilia A
442
Haematology - Paediatric Haematology
Diagnosis for VW?
```
Family history (mainly autosomal dominant)
Coagulation screen
Factor VIII assay
? Bleeding time (maybe not)
Platelet aggregation studies
```
443
Haematology - Paediatric Haematology
Treatment of von Willebrand disease
Lower purity factor VIII concentrates
444
Haematology - Paediatric Haematology
Autoimmune thrombocytopenic purpura presentation
Petechiae
Bruises
Blood blisters in mouth
445
Haematology - Paediatric Haematology
Ddx for A/I thrombycyopenic Purpura
```
Henoch‒Schönlein purpura
Non-accidental injury
Coagulation factor defect
Inherited thrombocytopenia
Acute leukaemia
```
446
Haematology - Paediatric Haematology
Rx of A/I thrombycyopenic Purpura
Observation
Corticosteroids
High dose intravenous immunoglobulin
Intravenous anti Rh D (if Rh-positive)
447
Haematology - Paediatric Haematology
Most common childhood leukaemia?
ALL
448
Haematology - Paediatric Haematology
Most common leukaemia in <1yo?
AML
449
Haematology - Acute Leukaemia
A 3-year-old girl develops pain in her legs and is found to have generalised lymphadenopathy and a palpable spleen. Her blood count shows WBC 35.4 × 109/l, Hb 77 g/l and platelet count 85 × 109/l. The most likely diagnosis is
Acute lymphoblastic leukaemia
Chronic lymphocytic leukaemia
Acute myeloid leukaemia
Chronic myeloid leukaemia
ALL
450
Haematology - Acute Leukaemia
What is acute leukaemia?
```
A neoplastic condition characterized by
Rapid onset
Early death if untreated
Immature cells (blast cells)
Bone marrow failure
Anaemia: fatigue, pallor, breathlessness
Neutropenia: infections
Thrombocytopenia: bleeding
```
451
Haematology - Acute Leukaemia
Dominant cell in acute leukaemias
Blast cells
452
Haematology - Acute Leukaemia
Acute myeloid leukaemia (AML) epidemiology?
Increases with age
Prognosis worse with increasing age
40% of adults cured
453
Haematology - Acute Leukaemia
AML chromosomal translocations?
AML chromosomal inversion?
T(15;17)
T(5;8)
Inv(16)
454
Haematology - Acute Leukaemia
Chromosomal duplication AML areas?
Disease hotspots
+8
+21 gives predisposition
455
Haematology - Acute Leukaemia
Chromosomal deletions in AML?
```
Disease hotspots
deletions and loss of 5/5q & 7/7q
Possible loss of tumour suppressor genes
Alternative explanation ‒ one copy of an allele may be insufficient for normal haemopoiesis
Possible loss of DNA repair systems
```
456
Haematology - Acute Leukaemia
AML RFs?
```
Familial or constitutional predisposition
Irradiation
Anticancer drugs
Cigarette smoking
Unknown
```
457
Haematology - Acute Leukaemia
What's the distinction between type 1 and type 2 abnormalities in AML?
Type 1 abnormalities
promote proliferation & survival
```
Type 2 abnormalities
block differentiation (which would normally be followed by apoptosis)
```
458
Haematology - Acute Leukaemia
Translocation seen in curable form of acute promyelocytic leukaemia?
T(15;17)
459
Haematology - Acute Leukaemia
T(15;17)
Acute promyelocytic leukaemia with t(15;17)
A very special type of acute leukaemia
The molecular mechanism is understood
Molecular treatment can be applied
The great majority of patients can now be cured
An excess of abnormal promyelocytes
Disseminated intravascular coagulation (DIC)
Two morphological variants but the same disease
460
Haematology - Acute Leukaemia
FLT3 -ITD
Acute promyelocytic leukaemia
Type 1 abnormalities
FLT3 -ITD
461
Haematology - Acute Leukaemia
t(15;17) PML-RARA
Acute promyelocytic leukaemia
Type 2 abnormalities
t(15;17) PML-RARA
462
Haematology - Acute Leukaemia
If histologically you can see fine granules on a blood smear, is it AML or ALL?
AML
463
Haematology - Acute Leukaemia
What stains detects granules and detects AML?
Sudan Black B
Non - specific esterase
Myeloperoxidase can be stained for
464
Haematology - Acute Leukaemia
Specific immunophenotype for ALL?
ALL:
B-cell: CD19, CD20, TdT, CD10 +/-
T-cell: CD2, CD3, CD4, CD8,TdT
- TDT USEFUL TO REMEMBER
465
Haematology - Acute Leukaemia
Specific immunophenotype for AML?
AML: MPO, CD13, CD33, CD14, CD15, glycophorin (E), platelet antigens
466
Haematology - Acute Leukaemia
Clinical features of AML?
Bone marrow failure
- Anaemia
- Neutropenia - infections, nec fasc
- Thrombocytopenia (DIC)
Local infiltration
- Splenomegaly
- Hepatomegaly
- Gum infiltration (if monocytic)
- Lymphadenopathy (only occasionally)
- Skin, CNS or other sites
467
Haematology - Acute Leukaemia
Skin infiltration, gum infiltration & organomegaly are particularly associated with which subtype of AML?
Acute monocytic leukaemia
468
Haematology - Acute Leukaemia
CNS disease is associated with which subtype of AML?
Monocytic differentiation
469
Haematology - Acute Leukaemia
Auer rods
AML
470
Haematology - Acute Leukaemia
If you suspect AML, but detect no leukaemic cells in the blood, can it be leukaemia?
Yes, you must do a BM aspirate
471
Haematology - Acute Leukaemia
How is AML Rx?
```
Supportive care
Red cells
Platelets
Fresh frozen plasma/ cryoprecipitate if DIC
Antibiotics
Long line
Allopurinol, fluid and electrolyte balance
Chemotherapy
Targeted molecular therapy
Transplantation
```
472
Haematology - Acute Leukaemia
What is the chemotherapy regimen for AML?
```
Mainly cell cycle specific drugs
4‒5 courses
remission induction × 2
consolidation × 2‒3
About 6 months of therapy
Consider transplantation if poor prognosis
```
473
Haematology - Acute Leukaemia
What targeted molecular therapy exists for Acute proMyelocytic Leukaemia?
ATRA
| All-trans-retinoic acid (ATRA) and A2O3 for acute promyelocytic leukaemia
474
Haematology - Acute Leukaemia
What targeted molecular therapy exists for ph+ AML?
TKI Imatinib
475
Haematology - Acute Leukaemia
Peak incidence in childhood
Most common childhood malignancy
85% of children cured
Prognosis worse with increasing age
ALL
476
Haematology - Acute Leukaemia
Clinical features of ALL?
```
Bone marrow failure — effects of
Anaemia
Neutropenia
Thrombocytopenia
Local infiltration
Lymphadenopathy (± thymic enlargement)
Splenomegaly
Hepatomegaly
Testes, CNS, kidneys or other sites
Bone (causing pain)
```
```
Peripheral blood
Anaemia
Neutropenia
Thrombocytopenia
Usually lymphoblasts
Bone marrow and other tissues
Lymphoblast infiltration
Lymphoblasts may be B-lineage or T-lineage
```
B-lineage
Starts in the bone marrow
T-lineage
Can start in the thymus and thymus may be enlarged
There are quite different genetic defects in B-lineage and T-lineage ALL
477
Haematology - Acute Leukaemia
Good prognosis ALL?
Hyperdiploidy, t(12;21), t(1;19) — good prognosis
t(9;22) — Philadelphia - improved prognosis with tyrosine kinase inhibitors (imatinib)
478
Haematology - Acute Leukaemia
Poor prognosis ALL?
t(4;11), hypodiploidy — poor prognosis
479
Haematology - Acute Leukaemia
Percentage ALL T cell VS B cell?
15% T cell
| 85% B cell
480
Haematology - Acute Leukaemia
Rx of ALL?
```
Specific therapy
systemic chemotherapy
CNS-directed therapy
molecularly targeted treatment
transplantation
Supportive care
blood products
antibiotics
general medical care
```
Central venous catheter
Red blood cell and platelet transfusions
Broad spectrum antibiotics for fever
Prophylaxis for Pneumocystis jirovecii infection
Hyperuricaemia: hydration, urine alkalinization and allopurinol or rasburicase
Hyperphosphataemia; aluminum hydroxide, calcium
Hyperkalemia: fluids, diuretics
Extreme leukocytosis (WBC > 200 × 109/l): leukapheresis
Sometimes haemodialysis
481
Haematology - Acute Leukaemia
Chemotherapy regimen in ALL?
```
Induction cycle
Intensification/consolidation cycles
Early intrathecal chemotherapy for all (to treat occult CNS disease)
Prolonged continuation/maintenance phase
Two to three years of therapy
Special measures for poor prognosis
```
482
Haematology - Acute Leukaemia
Why is cranial irradiation no longer used?
It causes cognitive impairment
| Now that more children are cured thinking about long term morbidity of treatment is increasingly important
483
Haematology - Acute Leukaemia
What mAb is useful in ALL?
Rituximab
| CD20
484
Haematology - Interactive Leukaemia cases
A 5-year-old boy of Indian ethnic origin presented with lymphadenopathy and a mediastinal mass on chest radiology
WBC 180 × 109/l, Hb 93 g/l and platelet count 43 × 109/l
```
The most likely cause of the mediastinal mass is
Thymoma
Acute myeloid leukaemia
Acute lymphoblastic leukaemia
Haemorrhage into the mediastinum
Pneumonia with a leukaemoid reaction
```
ALL
The very high WBC (180 × 109/l) in a child means a diagnosis of leukaemia is almost certain
The low Hb (93 g/l) and platelet count (43 × 109/l) are the result of bone marrow infiltration
The mediastinal mass is the thymus, which is infiltrated by T lymphoblasts
485
Haematology - Interactive Leukaemia cases
```
48-year-old male – railway engineer
2-week history bleeding gums
Attended dentist - severe bleeding
1 episode of haematuria
Minor bruising
Attended Accident and Emergency department
```
Left subconjunctival haemorrhage
Small bruises over abdomen
No enlarged lymph nodes
No hepatosplenomegaly
Normal Renal function
Minor liver derangement (longstanding)
Alanine transaminase 97 iu/l (0‒37)
Alkaline phosphatase 72 iu/l (30‒130)
Bilirubin 24 μmol/l (0‒17)
FBC
WBC 7.5 × 109/l (4.0‒11)
Hb 109 g/l (130‒170)
MCV 83 fl (83‒01)
Platelets 21 × 109/l (120‒400)
BM shows granular cells
```
Which diagnosis do you suspect?
Chronic myeloid leukaemia
Acute promyelocytic leukaemia
Some other type of acute myeloid leukaemia
Acute lymphoblastic leukaemia
```
What Rx would you use?
AML
The patient was treated with platelets, chemotherapy and all-trans-retinoic acid (ATRA) and entered complete remission
He has approaching 90% chance of being alive at 5 years
486
Haematology - Interactive Leukaemia cases
```
A 68-year-old retired secretary
Gradual onset of fatigue, lethargy and exertional dyspnoea
Non-smoker, not much alcohol, good diet
On examination
Pallor (conjunctival and nail bed)
Mild ankle oedema
What one test would you do next?
```
FBC
487
Haematology - Interactive Leukaemia cases
```
A 68-year-old retired secretary
Gradual onset of fatigue, lethargy and exertional dyspnoea
Non-smoker, not much alcohol, good diet
On examination
Pallor (conjunctival and nail bed)
Mild ankle oedema
```
```
FBC
WBC 4.7 × 109/l (3.7–9.5)
Hb 76 g/l (115–150)
MCV 110 fl 82–98 fl
Neutrophil count 1.4 × 109/l (NR 1.7–6.1)
Platelet count 182 × 109/l (NR 145–350)
```
```
Which test should be done next?
Blood film
Bone marrow aspirate
Liver function tests
Thyroid function tests
Serum vitamin B12 and red cell folate
```
Blood film
488
Haematology - Interactive Leukaemia cases
```
A 68-year-old retired secretary
Gradual onset of fatigue, lethargy and exertional dyspnoea
Non-smoker, not much alcohol, good diet
On examination
Pallor (conjunctival and nail bed)
Mild ankle oedema
```
```
FBC
WBC 4.7 × 109/l (3.7–9.5)
Hb 76 g/l (115–150)
MCV 110 fl 82–98 fl
Neutrophil count 1.4 × 109/l (NR 1.7–6.1)
Platelet count 182 × 109/l (NR 145–350)\
```
Serum vitamin B12 — normal
Red cell folate — normal
Liver function tests — normal
Thyroid function tests — normal
Ferritin — 875 μg/l (normal range 20–200)
What do you suspect and what would you do next?
Bone marrow aspirate
- IF YOU DONT FIND ANYTHING IN THE FILM DON'T FORGET TO BM ASPIRATE
489
Haematology - Interactive Leukaemia cases
```
A 68-year-old retired secretary
Gradual onset of fatigue, lethargy and exertional dyspnoea
Non-smoker, not much alcohol, good diet
On examination
Pallor (conjunctival and nail bed)
Mild ankle oedema
```
```
FBC
WBC 4.7 × 109/l (3.7–9.5)
Hb 76 g/l (115–150)
MCV 110 fl 82–98 fl
Neutrophil count 1.4 × 109/l (NR 1.7–6.1)
Platelet count 182 × 109/l (NR 145–350)\
```
```
Serum vitamin B12 — normal
Red cell folate — normal
Liver function tests — normal
Thyroid function tests — normal
Ferritin — 875 μg/l (normal range 20–200)
```
Bone marrow aspirate
12% blast cells (normal < 5%)
45% of erythroblasts were ring sideroblasts
What's the diagnosis?
MDS with excess of blasts
Initially the patient tolerated the anaemia and required no treatment
Later she needed red cell transfusion
Later still she needed platelet transfusions
Predicted survival was 1.1 years
However, she was still alive 7 years later
490
Haematology - Interactive Leukaemia cases
```
A 72-year-old Indian woman
Vegetarian, teetotal, non-smoker
Shortness of breath on exertion
Fatigue
Painful gums and tongue
Unable to eat spicy food
On examination: pallor only
```
WBC normal
Hb 52 g/l
MCV 122 fl
Platelet count normal
Blood film shows hypersegmented neutrophils.
```
What is the most important test
Vitamin B12 and folate assays
Liver function tests
Thyroid function tests
Bone marrow aspirate
Blood alcohol level
```
Vitamin B12 and folate assays
491
Haematology - Interactive Leukaemia cases
```
A 72-year-old Indian woman
Vegetarian, teetotal, non-smoker
Shortness of breath on exertion
Fatigue
Painful gums and tongue
Unable to eat spicy food
On examination: pallor only
```
WBC normal
Hb 52 g/l
MCV 122 fl
Platelet count normal
Blood film shows hypersegmented neutrophils.
Vitamin B12 180 ng/l (NR 125‒600)
Red cell folate 227 pg/l (NR 215‒650)
Thyroid function normal
Liver function tests mildly impaired (bilirubin 20 μm/l, AST 110 iu/l (NR 40‒135)
Lactate dehydrogenase (LDH) 3870 iu/l (NR 50‒450)
What do you do next?
BM aspirate
Finds giant metamyelocyte and megaloblast
492
Haematology - Interactive Leukaemia cases
```
A 72-year-old Indian woman
Vegetarian, teetotal, non-smoker
Shortness of breath on exertion
Fatigue
Painful gums and tongue
Unable to eat spicy food
On examination: pallor only
```
WBC normal
Hb 52 g/l
MCV 122 fl
Platelet count normal
Blood film shows hypersegmented neutrophils.
Vitamin B12 180 ng/l (NR 125‒600)
Red cell folate 227 pg/l (NR 215‒650)
Thyroid function normal
Liver function tests mildly impaired (bilirubin 20 μm/l, AST 110 iu/l (NR 40‒135)
Lactate dehydrogenase (LDH) 3870 iu/l (NR 50‒450)
BM aspirate finds giant metamyelocyte and megaloblast
Do you think the patient has a myelodysplastic syndrome?
1 Yes
2 No
No, just B12 deficiency.
Check
Parietal cell antibodies: positive
Intrinsic factor antibodies: positive
493
Haematology - Interactive Leukaemia cases
A 70-year-old woman was referred to a vascular surgeon because of gangrenous toes
Not diabetic
Had smoked 20‒30 cigarettes a day since age of 18 years
Breathless on exertion and morning cough
Reduced femoral and distal pulses on side of affected toes
Not breathless at rest, no cyanosis
Plethora, conjunctival suffusion
Spleen not felt
```
Blood gases were normal
Blood count was not
WBC 18.6 × 109/l
Hb 180 g/l
Platelet count 1648 × 109/l
Ultrasound examination of the abdomen showed normal kidneys and increased splenic size
```
```
The most likely diagnosis is
Chronic myeloid leukaemia
Essential thrombocythaemia
Polycythaemia vera
Chronic obstructive pulmonary disease
```
Polycythaemia
494
Haematology - Quiz
FBC of an 83-year-old man with no abnormal physical findings
Blood count shows lymphocytosis with smear cells
```
Acute lymphoblastic leukaemia
Chronic lymphocytic leukaemia
HIV infection
Infectious mononucleosis
Whooping cough
```
CLL
495
Haematology - Quiz
FBC of a 67-year-old woman with facial plethora
She is a smoker and has coronary artery disease
She is polycythaemic, thrombocytic, neutrophilic and basophilic
FBC of a 67-year-old woman with facial plethora—most likely diagnosis?
```
Chronic myeloid leukaemia
Polycythaemia vera
Pseudo-polycythaemia
Renal artery stenosis
Smoking induced hypoxia
```
List the Ix which would confirm this?
Polycythaemia Vera
The RBC, Hb and PCV are high
The WBC, neutrophil count and basophil count are high
The platelet count is high
The most likely diagnosis is polycythaemia vera
Analysis for JAK2 V617F mutation
Bone marrow aspiration and trephine biopsy
Serum erythropoietin
496
Haematology - Quiz
A 69-year-old man in the Intensive Care Unit
He has extensive atheromatous disease and diabetes mellitus
He has had an abdominal aortic aneurysm replaced by a graft and has had a stormy post-operative course with
Sepsis
Acute renal failure
Respiratory impairment
```
His FBC shows:
WBC 37.5 x 109/l H
Neutrophil count 35 x 109/l H
Lymphocyte count 0.8 x 109/l L
Monocyte count 1.2 x 109/l H
Myelocytes and metamyelocytes 0.5 x 109/l H
Hb 11.0 g/dl L
MCV 89 fl N
Platelet count 514 x 109/l
H
```
Film comments:
Toxic granulation and vacuolation
Left shift
Rouleaux
1. Chronic myeloid leukaemia
2. Normal for age and gender
3. Reactive neutrophilia
4. Laboratory error
5. Acute myeloid leukaemia
REACTIVE NEUTROPHILIA
- Don't be drawn to MM -> there are no other indications here. Rouleaux are seen in infection, alongside:
Waldestroms macroglobulinaenia
DM
497
Haematology - Quiz
FBC of a 64-year-old Spanish woman with splenomegaly
```
She is
afebrile
and does
not feel
unwell
```
FBC shows leucocytosis with myelocytes and basophilia
1. Chronic myeloid leukaemia
2. Normal for age and gender
3. Reactive neutrophilia
4. Laboratory error
5. Acute myeloid leukaemia
CML
498
Haematology - Quiz
Elderly man came to Haematology OPD
Bruises on elbow
On this day his platelet count was 13 x 109/l
A week earlier it had been 3 x 109/l with a normal Hb and WBC
Autoimmune thrombocytopenic purpura
499
Haematology - Quiz
Name vascular abnormality that can cause gangrene?
Diabetic vascular disease
500
Haematology - Quiz
Write down three abnormalities of the blood that could contribute to gangrene development?
Polycythaemia
Thrombocytosis
Cryoglobulinaemia
Cold agglutinin
501
Haematology - Quiz
FBC of a North African woman with an 18-month-old baby.
Microcytic anaemia
Increased RBC count
Increased RDW
Film:
Microcytic, hypochromic, anisocytosis, elongated red cells
1. Normal for a North African
2. Beta thalassaemia major
3. Lead poisoning
4. Beta thalassaemia trait
5. Iron deficiency anaemia
IDA
502
Haematology - Quiz
List possible associated haematological abnormalities of rheumatoid A?
Anaemia of chronic disease
Iron deficiency anaemia resulting from use of aspirin or non-steroidal anti-inflammatory drugs (NSAID)
Neutropenia or thrombocytopenia from drug toxicity
Felty’s syndrome
Increased erythrocyte sedimentation rate (ESR)
503
Haematology - Quiz
What is Felty syndrome
Rare autoimmune disease characterized by the triad of rheumatoid arthritis, enlargement of the spleen and too few neutrophils in the blood.
504
Haematology - Quiz
A 10-year-old girl presented with a painful right knee that had started when she knocked her knee in a swimming pool
The next day she had become unwell with malaise, anorexia and fever
Her GP prescribed amoxicillin for ‘otitis media’
Next day her mother took her to an Accident and Emergency Department
She was afebrile
Her right knee was painful and swollen
X-ray of the knee showed patchy changes in density in the right medial tibial plateau
Blood tests showed
WBC 6.6 x 109/l
ESR 60 mm in 1 h (NR 0-10)
C-reactive protein (CRP) 27 mg/dl (NR 0-1)
```
Septic arthritis
Haemophilia A
Osteomyelitis
Thrombocytopenia
Haemophilia B
```
Osteomyelitis
The diagnosis was osteomyelitis resulting from Staphylococcus aureus infection
Other diagnoses you might have considered are septic arthritis, haemorrhage into the joint following minor trauma, non-accidental injury
505
Haematology - Quiz
A 1-year-old boy, an only child, presented to an Accident and Emergency department with a swollen right elbow following minor trauma
On clinical examination and radiology there was no evidence of bony injury
He was sent home
What analgesic would you NOT use?
Don’t use aspirin in children (particularly if febrile) because of the possibility of Reye syndrome
506
Haematology - Quiz
A 1-year-old boy, an only child, presented to an Accident and Emergency department with a swollen right elbow following minor trauma
On clinical examination and radiology there was no evidence of bony injury
He was sent home
Three days later he was brought back with increased pain and swelling
Joint aspiration yielded haemorrhagic fluid
He was started on antibiotics and sent home
Four weeks later he was brought back as the effusion had not resolved
The joint was surgically explored (dark blood) and a biopsy was taken (‘synovitis’)
Post operatively the wound bled persistently
What test would you do?
A coagulation screen showed a normal prothrombin time (PT) and a prolonged activated partial thromboplastin time (aPTT)
507
Haematology - Quiz
A 1-year-old boy, an only child, presented to an Accident and Emergency department with a swollen right elbow following minor trauma
On clinical examination and radiology there was no evidence of bony injury
He was sent home
Three days later he was brought back with increased pain and swelling
Joint aspiration yielded haemorrhagic fluid
He was started on antibiotics and sent home
Four weeks later he was brought back as the effusion had not resolved
The joint was surgically explored (dark blood) and a biopsy was taken (‘synovitis’)
Post operatively the wound bled persistently
The aPTT was 96 s (NR 24-35s)
The prolonged aPTT was corrected by mixing the infant’s plasma with normal plasma
What is the most likely diagnosis?
What is the significance of the mixing test
Haemophilia
It shows it is a clotting factor deficiency not an inhibitor
508
Haematology - Quiz
A 21-year-old woman presented with abdominal pain, bruising and altered level of consciousness
She had a low grade fever
Her platelet count was 15 x 109/l
Her bilirubin was increased and LDH was greatly increased
Her creatinine was marginally increased
Blood film showed poikilocytes, lack of central pallor, anisocytosis
```
Autoimmune thrombocytopenic purpura
Hereditary spherocytosis
Infectious hepatitis
Meningococcal meningitis
Thrombotic thrombocytopenic purpura
```
TTP
Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in blood clots forming in small blood vessels throughout the body.
This results in a low platelet count, low red blood cells due to their breakdown, and often kidneys, heart, and brain dysfunction.
Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache.
- Caused by bacterial infection
```
What is the nature of the anaemia?
Microangiopathic haemolytic anaemia
What is the differential diagnosis?
Haemolytic-uraemic syndrome
Meningococcal septicaemia
Thrombotic thrombocytopenic purpura
```
509
Haematology - Quiz
What is the pentad that TTP comprises of?
Thrombotic thrombocytopenic purpura is diagnosed from a classic pentad of clinical features
```
Microangiopathic haemolytic anaemia
Thrombocytopenia
Fever
Neurological abnormalities
Renal impairment
```
510
Haematology - Quiz
Name the deficiency plasma protein in TTP?
The underlying defect in thrombotic thrombocytopenic purpura is a deficiency of a plasma protein called von Willebrand factor cleaving protease (or ADAMTS13)
The deficiency is autoimmune in origin
The low levels of the protease lead to high levels of very large multimers of vWF, which cause platelet thrombi to form
The widespread platelet thrombi are responsible for the clinicopathological features
511
Haematology - Quiz
How is TTP managed?
Treatment is by plasma exchange
| Platelet transfusions should NOT be given
512
Haematology - Quiz
A previously healthy 20-year-old man presented with fever, sore throat, malaise, dyspnoea and abdominal pain
Ten days before admission he had fallen on his left side and had attended Accident and Emergency with pain in the left chest wall
Chest X-ray had been normal but he was observed overnight
On this presentation, temperature 39.7°C, BP 115/95, pulse rate 96 beats/minute, generalized lymphadenopathy, pharynx inflamed, mild hepatomegaly, spleen palpable 2 cm below left costal margin, abdomen tender
WBC 11.2 x 109/l, lymphocyte count 7.8 x 109/l, Hb 10.9 g/dl, numerous atypical lymphocytes
What diagnosis?
Why does he have abdominal pain and tenderness?
Infectious mononucleosis
EBV EBNA
EBVDNA
Heterophile
Splenic damage and intraperitoneal haemorrhage should be suspected and urgent imaging should be done
```
An urgent abdominal ultrasound showed splenomegaly and detachment of the inferolateral part of the spleen, 9 cm from the tip with subcapsular haematoma formation
There was no intraperitoneal bleeding
What should be done now?
Emergency splenectomy was performed
The spleen weighed 588 g (normal 200 g)
```
Splenomegaly occurs in c 50% of patients with infectious mononucleosis
Splenic rupture occurs in 0.1-0.5% of patients
Mortality has been estimated at 30%, mainly because of delayed diagnosis
There is often a history of recent trauma, which may be very trivial (e.g. coughing, turning over in bed)
513
Haematology - Quiz
What are the risks of hyposplenism?
Overwhelming bacterial sepsis (particularly pneumococcal or Haemophilus influenzae)
Fatal malaria
Fatal Capnocytophaga canimorsus infection
514
Haematology - Quiz
What is the general management post splemectomy?
```
Vaccinate for pneumococcus, meningococcus type C and Haemophilus influenzae type b
Vaccinate against influenza
Prescribe life-long penicillin
Advise the patient on
Dog bites
Travel to malaria zones
Prompt treatment of infection
Issue a splenectomy card and information sheet
```
515
Haematology - Quiz
63-year-old retired professional man
Referred to haematology outpatients from gastroenterology clinic
Microcytic anaemia ? cause
Oesophageal reflux, confirmed by barium swallow
Normal gastroscopy otherwise
Symptoms resolved on omeprazole
Also complained of rectal bleeding
Proctoscopy: prolapsed haemorrhoids
Colonoscopy: normal
Presented again a year later
3 kg weight loss in one month
Progressive anaemia
Cervical lymph node felt and later disappeared
Serum ferritin 308
Serum vitamin B12 and red cell folate normal
Haemoglobin electrophoresis: normal Hb A2
C-reactive protein 87
Repeat gastroscopy and duodenal biopsy: normal
Chest X-ray and abdominal ultrasound normal
Referred to haematology
Generally well
Some recent weight loss, initially deliberate
Denies other symptoms
Complicated past medical history
```
Splenomegaly since 1973
investigated by bone marrow aspirate (no records found)
Ischaemic Heart Disease
CABG 1992
Angioplasty 1998
Mild hypercholesterolaemia and hypertension
Renal colic
1980 & 1985, but
Persistent microscopic haematuria
normal renal function
```
```
Gout
for over 5 years
Chronic cough
First investigated 1993
Re-referred 1997
Normal pulmonary function tests and chest X-ray
Gastro-oesophageal reflux disease
```
```
Current Medication
Aspirin 150 mg od
Losartan 50 mg od
Omeprazole 30 mg od
Allopurinol 200 mg od
No known allergies
Ex-smoker of 35 years
No relevant family history
```
```
On examination:
Thin
BP 120/100
Chest clear
HS normal
? Palpable spleen
```
Ddx?
Anaemia of chronic disease
[Nodular sclerosis Hodgkin lymphoma]
516
Haematology - Quiz
1% cancer registrations per annum
3 per 100 000 in UK
Peak in adolescence and > 50 years
Commonly presents with painless supra-diaphragmatic lymphadenopathy
One third present with B symptoms
Fever, drenching night sweats or > 10% loss of body weight in last 6 months
Increased risk in families of affected patients
Association with HLA DPB1
Epstein-Barr virus found in >79% of over 50s
Hodgkins
517
Haematology - Interactive case histories
```
Scenario A&E
Age 36
Sex Female
History 2years SOBOE
FBC Hb 32 g/ l (120-160g/l)
```
1. WBC 7 x 109/l (2-10.5 x 109/l)
2. platelets 452 x 109/l (150-400 x 109/l)
3. MCV 54fl ( 80-100fl)
What Ddx?
Iron deficiency
Thalassaemia
Anaemia of chronic disease (low or normal)
518
Haematology - Interactive case histories
Scenario Haematology clinic
Age 68
Sex male
History 6 weeks nosebleeds + fatigue
Hb 60 g/dl (135-175g/l)
WBC 0.1 x 109/l (2-10.5 x 109/l)
Platelets 4 x 109/l (150-400 x 109/l)
DDx?
PANCYTOPENIA DDx
```
Aplastic anaemia
Leukemia
Infiltration e.g.Lymphoma, carcinoma
Drugs e.g. chemotherapy
B12/folate deficiency
```
519
Haematology - Interactive case histories
Scenario Haematology clinic
Age 68
Sex male
History 6 weeks nosebleeds + fatigue
Hb 60 g/dl (135-175g/l)
WBC 0.1 x 109/l (2-10.5 x 109/l)
Platelets 4 x 109/l (150-400 x 109/l)
Abnormal granular cells seen on blood smear.
Diagnosis?
AML
520
Haematology - Interactive case histories
Scenario Surgical in-patient
Age 40
Sex male
History Admitted 4 days earlier with 35% burns
Now bleeding nose/venepuncture sites
Hb 120g/ l (135-175g/ l)
WBC 10 x 109/l (2-10.5 x 109/l)
Platelets 28 x 109/l (150-400 x 109/l)
COAGULATION SCREEN
- APTT 54 seconds (control 40s)
- INR 2.1
What could cause low platelets and abnormal clotting?
```
Low platelets and abnormal clotting
DIC
Alcohol
Drugs
Leukemia
```
521
Haematology - Interactive case histories
List causes of a low platelet count, in terms of NOT MAKING ENOUGH VS PREMATURE DESTRUCTION
NOT MAKING PLATELETS
- drugs e.g. chemotherapy, thiazides,
- bone marrow disorders e.g. leukemia, aplastic, myelodysplasia, myeloma, infiltration with carcinoma
PREMATURE DESTRUCTION OF PLTS
- ITP (auto-immune)
- Disseminated intravascular coagulation
- heparin
522
Haematology - Interactive case histories
list cause of DIC
Relatively common causes include sepsis, surgery, major trauma, cancer, and complications of pregnancy.
Less common causes include snake bites, frostbite, and burns.
523
Chemical Pathology - Uric Acid Metabolism
What is deficient in Lesch Nyhan syndrome?
HGPRT deficiency ( hypoxanthine-guanine phosphoribosyltransferase)
524
Chemical Pathology - Uric Acid Metabolism
What are the clinical Sx of flesh nyhan syndrome aka hypoxanthine-guanine phosphoribosyltransferase deficiency?
```
Normal at birth
Developmental delay apparent at 6/12
Hyperuricaemia
Choreiform movements (1 year)
Spasticity, mental retardation
Self mutilation (85%) aged 1-16
```
525
Chemical Pathology - Uric Acid Metabolism
What are the crystals in gout?
Monosodium urate crystals
Can be acute (Podagra) or chronic (Tophaceous)
Males 0.5 – 3% prevalence
Females 0.1 – 0.6% prevalence
Post pubertal males and post menopausal females
526
Chemical Pathology - Uric Acid Metabolism
Clinical Sx of acute gout?
```
Rapid build up of pain
“Exquisite”
Affected joint red, hot and swollen
1st MTP joint first site in 50%
This joint is involved in 90% overall
```
527
Chemical Pathology - Uric Acid Metabolism
What is the Rx of acute gout?
```
Acute gout.
NSAIDs
Colchicine
Glucocorticoids
Do NOT attempt to modify plasma urate concentration
```
528
Chemical Pathology - Uric Acid Metabolism
What is the Rx of non-acute gout?
```
Interval (non acute) gout.
Drink plenty (water!)
Reverse factors putting up urate
Reduce synthesis with allopurinol
Increase renal excretion with probenecid: “uricosuric”
```
529
Chemical Pathology - Uric Acid Metabolism
How is gout diagnosed?
Tap effusion
View under polarised light
Use red filter
530
Chemical Pathology - Uric Acid Metabolism
PPP of pseudo gout?
Pseudogout, calcium Pyrophosphate, Positive Birefringeance
Birefringeance = Look at the direction of the axis of the filter.
Negatively birefringent crystals will be blue perpendicular to this.
531
Chemical Pathology - Lipoprotein Metabolism
HDL or LDL, which transports 17% of cholesterol
HDL
532
Chemical Pathology - Lipoprotein Metabolism
HDL or LDL, which transports 70% of cholesterol
LDL
533
Chemical Pathology - Lipoprotein Metabolism
What percentage of cholesterol do chylomicrons transport?
5%
534
Chemical Pathology - Lipoprotein Metabolism
Rate limiting enzyme step ni cholesterol formation?
HMG CoA Reductase
535
Chemical Pathology - Lipoprotein Metabolism
Trigylcerides are transported by which lipoprotein predominantly?
Chylomicrons <5%
VLDL - 55%
LDL - 29%
HDL - 11%
536
Chemical Pathology - Lipoprotein Metabolism
dominant mutations of LDL receptor, apoB or PCSK9 genes. Rarely, autosomal recessive inheritance (LDLRAP1).
Familial hypercholesterolaemia (type II)
537
Chemical Pathology - Lipoprotein Metabolism
Sx of Familial hypercholesterolaemia?
Tendon xanthoma
Cholesterol eyelid deposits
CVD - atheroma
538
Chemical Pathology - Lipoprotein Metabolism
Function of PCSK9?
Function is to bind to LDL receptor and promote its degradation.
539
Chemical Pathology - Lipoprotein Metabolism
What is increased in familial type 1 primary hypertriglyceridaemia?
Chylomicrons
| lipoprotein lipase or apoC II deficiency
540
Chemical Pathology - Lipoprotein Metabolism
What is increased in familial type 4 primary hypertriglyceridaemia?
VLDL
541
Chemical Pathology - Lipoprotein Metabolism
Lomitapide MoA?
Microsomal Triglyceride Transfer Protein (MTP) inhibitor (lomitapide)
542
Chemical Pathology - Lipoprotein Metabolism
```
Success = > 50% ↓ in excess weight (i.e. actual – ideal)
Diabetes ↓ 72%
Serum triglyceride ↓ 50-60%
HDL cholesterol ↑13-47%
Fatty liver ↓
Hypertension ↓
```
Post-op mortality 0.1-2%
Bariatric surgery
543
Haematology - Haemolytic Anaemia
Normal RBC lifespan
120 days
544
Haematology - Haemolytic Anaemia
Two types of haemolysis
Haemolysis defined as shortened red cell survival
May be predominantly:
Intravascular - within circulation
Extravascular - removal/destruction by
reticuloendothelial(RE) system
Inherited or acquired
545
Haematology - Haemolytic Anaemia
Name 2 extravascular haemolytic anaemias?
Extravascular
Autoimmune
Alloimmune
Hereditary spherocytosis
546
Haematology - Haemolytic Anaemia
Name 2 intravascular haemolytic anaemias
Intravascular
```
Malaria
G6PD deficiency
Mismatched blood transfusion (ABO)
Cold antibody haemolytic syndromes
Drugs
Microangiopathic haemolytic anaemia
e.g. haemolytic uraemic syndrome,
thrombotic thrombocytopenic purpura
Paroxysmal nocturnal haemoglobinuria
```
547
Haematology - Haemolytic Anaemia
Name consequences of hereditary spherocytosis
Anaemia(+/-)
Erythroid hyperplasia with increased rate of red cell production and circulating reticulocytes
Increased folate demand
Susceptibility to effect of parvovirus B19
Propensity to gallstones(cholelithiasis)
Increased risk of:
Iron overload
Osteoporosis
548
Haematology - Haemolytic Anaemia
| Perl’s stain
Hepatic siderosis
549
Haematology - Haemolytic Anaemia
```
Pallor
Jaundice
Splenomegaly
Pigmenturia
Family history
```
Anaemia
Increased reticulocytes
Polychromasia
```
Hyperbilirubinaemia
Increased LDH
Reduced/absent haptoglobins
Haemoglobinuria
Haemosiderinuria
```
Gilberts
550
Haematology - Haemolytic Anaemia
```
Defects in:
Band 3
Protein 4.2
Ankyrin
B Spectrin
```
Hereditary spherocytosis
551
Haematology - Haemolytic Anaemia
Defects in
A+B Spectrin
Protein 4.1
Hereditary elliptocytosis
552
Haematology - Haemolytic Anaemia
Genetic defect of red cell cytoskeleton
Family history in 75% - typically autosomal dominant
25% recessive or de novo mutation
In vitro red cells show increased sensitivity to lysis in
hypotonic saline (osmotic fragilty test)
Reduced binding of dye eosin-5-maleimide
Hereditary spherocytosis
553
Haematology - Haemolytic Anaemia
Affects up to 400 million worldwide
Prevalent in areas of malarial endemicity - selection
X-linked - clinical effects seen predominantly in hemizygous males and homozygous females
Enzyme catalyses first step in pentose phosphate(hexose monophosphate) pathway - generates NADPH required to maintain intracellular glutathione(GSH)
Clinical effects
Neonatal jaundice
Acute haemolysis(triggered by oxidants/infection)
Chronic haemolytic anaemia(rare)
Glucose-6-phosphate dehydrogenase deficiency
554
Haematology - Haemolytic Anaemia
Clinical effects
Neonatal jaundice
Acute haemolysis(triggered by oxidants/infection)
Chronic haemolytic anaemia(rare)
Glucose-6-phosphate dehydrogenase deficiency
555
Haematology - Haemolytic Anaemia
Enzyme catalyses first step in pentose phosphate(hexose monophosphate) pathway - generates NADPH required to maintain intracellular glutathione(GSH)
Glucose-6-phosphate dehydrogenase deficiency
556
Haematology - Haemolytic Anaemia
List agents which may provoke haemolysis in G6PD deficiency
```
Anti-malarials
Primaquine
Antibiotics
Sulphonamides
Ciprofloxacin
Nitrofurantoin
Other drugs
Dapsone
Vitamin k
Fava beans
Mothballs
```
557
Haematology - Haemolytic Anaemia
First line investigations for haemolysis
```
Direct antiglobulin test
Urinary haemosiderin/haemoglobin
Osmotic fragility
G6PD +/- PK activity
Haemoglobin separation A and F%
Heinz body stain
Ham’s test/Flow cytometry of GPI-linked proteins
Thick and thin blood film
```
558
Haematology - Haemolytic Anaemia
General treatments for haemolytic anaemias
Folic acid supplementation
Avoidance of precipitating factors e.g. oxidants in G6PD deficiency
Red cell transfusion/exchange
Immunisation against blood borne viruses e.g. hepatitis A and B
Monitor for chronic complications
Cholecystectomy for symptomatic gallstones
Splenectomy if indicated
559
Haematology - Haemolytic Anaemia
What conditions may splenectomy be indicated?
Substantial benefit in
PK deficiency and some other enzymopathies
Hereditary spherocytosis
Severe elliptocytosis/pyropoikilocytosis
Thalassaemia syndromes
Immune haemolytic anaemia
But…risk of overwhelming sepsis
Capsulated bacteria eg Pneumococcus
Penicillin prophylaxis and immunisation
560
Haematology - Haemolytic Anaemia
List the criteria for splenectomy
```
Criteria
Transfusion dependence
Growth delay
Physical limitation Hb < 8g/dl
Hypersplenism
```
Age not < 3 years
before 10 years to maximise prepubertal growth
561
Histopathology - Fundamentals
Ziehl Neelson
AFB
562
Histopathology - Fundamentals
Fontana stain
Melanin
563
Histopathology - Fundamentals
Prussian Blue stain
Haemochromatosis
| Iron staining
564
Histopathology - Fundamentals
Congo Red Positive
Amyloid
565
Histopathology - Fundamentals
Apple green birefringence
Amyloid
566
Immunology - Introduction to Immunology
How do sebaceous glands contribute to the innate immune system?
Hydrophobic oils repel water and microorganisms
Lysozyme destroys structural integrity of bacterial cell wall
Ammonia and defensins have anti-bacterial properties
567
Immunology - Introduction to Immunology
How does mucous contribute to the innate immune system?
Physical barrier to trap invading pathogens
Secretory IgA prevents bacteria and viruses attaching to and penetrating epithelial cells.
Lysozyme and antimicrobial peptides directly kill invading pathogens
Lactoferrin acts to starve invading bacteria of iron.
568
Immunology - Introduction to Immunology
How do commensals contribute to the innate immune system?
100 trillion (1014) bacteria normally reside at surfaces
Compete with pathogenic microorganisms for scarce resources
Produce fatty acids and bactericidins that inhibit the growth of many pathogens.
569
Immunology - Introduction to Immunology
Produced in bone marrow
Migrate rapidly to site of injury
Express receptors for cytokines/chemokines - to detect inflammation
Express pattern recognition receptors – to detect pathogens
Express Fc receptors for Ig - to detect immune complexes
Capable of phagocytosis / oxidative & non-oxidative killing – particularly neutrophils
Release enzymes, histamine, lipid mediators of inflammation from granules
Secrete cytokines and chemokines to regulate inflammation
Neutrophils, Eosinophils and Basophils/Mast cells
570
Immunology - Introduction to Immunology
How do opsonins aid immunity?
Name 3
Opsonins act as a bridge between the pathogen and the phagocyte receptors
Antibodies binding to Fc receptors
Complement components binding to complement receptors
Acute phase proteins eg C reactive protein (CRP)
571
Immunology - Introduction to Immunology
What is the equation for oxidative killing?
NADPH oxidase complex converts oxygen into reactive oxygen species – superoxide and hydrogen peroxide
Myeloperoxidase catalyses production of hydrochlorous acid from hydrogen peroxide and chloride
Hydrochlorous acid is a highly effective oxidant and anti-microbial
H202 + 2Cl -> 2HOCl
572
Immunology - Introduction to Immunology
Present within blood and may migrate to inflamed tissue
Express inhibitory receptors for self-HLA molecules that prevent inappropriate activation by normal self
Express a range of activatory receptors including natural cytotoxicity receptors that recognise heparan sulphate proteoglycans
Integrate signals from inhibitory and activatory receptors
Cytotoxic - kill ‘altered self’ as in malignant or virus infected cells
Secrete cytokines to regulate inflammation – promote dendritic cell function
NK cells
573
Immunology - Introduction to Immunology
Reside in peripheral tissues
Express receptors for cytokines and chemokines - to detect inflammation
Express pathogen recognition receptors – to detect pathogens
Express Fc receptors for Ig - to detect immune complexes
Capable of phagocytosis
Following phagocytosis dendritic cells mature:
Upregulate expression of HLA molecules
Express costimulatory molecules
Migrate via lymphatics to lymph nodes – mediated by CCR7
Present processed antigen to T cells in lymph nodes to prime the adaptive immune response
Express cytokines to regulate the immune response
DCs
574
Immunology - Introduction to Immunology
What are primary lymphoid organs?
Name 2?
- site of T cell maturation
- site of B cell maturation
Definition
Organs involved in lymphocyte development
Bone marrow
Both T and B lymphocytes are derived from haematopoetic stem cells
Site of B cell maturation
Thymus
Site of T cell maturation.
Most active in the foetal and neonatal period, involutes after puberty
575
Immunology - Introduction to Immunology
What is a secondary lymphoid organ?
Definition
Anatomical sites of interaction between naïve lymphocytes and microorganisms
Spleen
Lymph nodes
Mucosal associated lymphoid tissue
576
Immunology - Introduction to Immunology
Recognise
peptides derived from extracellular proteins
presented on HLA Class II molecules (HLA-DR, HLA-DP HLA-DQ)
Immunoregulatory functions via cell:cell interactions and expression of cytokines
Provide help for development of full B cell response
Provide help for development of some CD8+ T cell responses
CD4 T cells
577
Immunology - Introduction to Immunology
Specialised cytotoxic cells
```
Recognise peptides derived from intracellular proteins in association with HLA class I
HLA-A, HLA-B, HLA-C
```
Kill cells directly
Perforin (pore forming) and granzymes
Expression of Fas ligand
Secrete cytokines eg IFNg TNFa
Particularly important in defence against viral infections and tumours
CD8
578
Immunology - Introduction to Immunology
Antigen encounter to B cell results in?
INSTANT - IgM secreting plasma cell
THEN
- Germinal centre reaction -> dependent on CD4
- DC primes CD4
- CD4 causes B cell differentiation via CD40L:CD40
B cell proliferation
Somatic hypermutation
Isotype switching
579
Immunology - Introduction to Immunology
Predominant class of antibody in the secondary response?
IgG
580
Immunology - Introduction to Immunology
> 20 tightly regulated, linked proteins
Produced by liver
Present in circulation as inactive molecules
When triggered, enzymatically activate other proteins in a biological cascade
Results in rapid, highly amplified response
Complement
581
Immunology - Introduction to Immunology
Formation of antibody-antigen immune complexes
Results in change in antibody shape – exposes binding site for C1
Binding of C1 to the binding site on antibody results in activation of the cascade
Dependent upon activation of acquired immune response (antibody)
CLASSICAL C1 C2 C4
582
Immunology - Introduction to Immunology
Activated by the direct binding of MBL to microbial cell surface carbohydrates
Directly stimulates the classical pathway, involving C4 and C2 but not C1
Not dependent on acquired immune response
Mannose binding lectin pathway
583
Immunology - Introduction to Immunology
Directly triggered by binding of C3 to bacterial cell wall components
eg lipopolysaccharide of gram negative bacteria
teichoic acid of gram positive bacteria
Not dependent on acquired immune response
Involves factors B, I and P
Alternative pathway
584
Immunology - Introduction to Immunology
What happens when C3 is activated?
Activation of C3 is the major amplification step in the complement cascade
Triggers the formation of the membrane attack complex via C5-C9
585
Immunology - Introduction to Immunology
Name other effects of complement fragments (aside from MAC formation)
Opsonisation of immune complexes keeps them soluble
Increases vascular permeability and cell trafficking to site of inflammation
Opsonisation of pathogens to promote phagocytosis
Activates
phagocytes
Promotes mast cell/basophil degranulation
Punches holes in bacterial membranes
586
Chemical Pathology - Acid Base Handling
H+ conc in ECF?
35-45 nmol/l
587
Chemical Pathology - Acid Base Handling
Acid base reaction
H+ + HCO3- -> H2CO3 -> CO2 + H2O
588
Chemical Pathology - Acid Base Handling
Where are hydrogen ions excreted?
Hydrogen ion produced in the tissues is transported via the circulation to the kidneys where it is excreted
589
Chemical Pathology - Acid Base Handling
Name the 5 mechanisms of buffering of H+ ions?
```
Bicarbonate
Haemoglobin H+ + Hb- -> HHb
Phosphate H+ + PO4- -> H2PO4
[in renal tubular fluid]
Protein + Bone
```
590
Chemical Pathology - Acid Base Handling
Primary abnormality is increased H+ (decreased pH) with decreased bicarbonate
Due to:
1. Increased H+ production e.g. diabetic ketoacidosis
2. Decreased H+ excretion e.g. Renal tubular acidosis
3. Bicarbonate loss e.g. intestinal fistula
Metabolic acidosis
591
Chemical Pathology - Acid Base Handling
Name three mechanisms of metabolic acidosis
Primary abnormality is increased H+ (decreased pH) with decreased bicarbonate
Due to:
1. Increased H+ production e.g. diabetic ketoacidosis
2. Decreased H+ excretion e.g. Renal tubular acidosis
3. Bicarbonate loss e.g. intestinal fistula
592
Chemical Pathology - Acid Base Handling
Describe the mechanisms of respiratory acidosis?
Primary abnormality is increased CO2 producing increased H+ (decreased pH) and a slight increase in bicarbonate (2-4 mmol/L).
May be due to:
Decreased Ventilation
Poor Lung Perfusion
Impaired Gas Exchange
593
Chemical Pathology - Acid Base Handling
What is the consequence of chronic respiratory acidosis?
Over the course of a few days this leads to increased renal excretion of H+ combined with generation of bicarbonate.
H+ may return to near normal but pCO2 and bicarbonate remain elevated
594
Chemical Pathology - Acid Base Handling
What is the mechanism of metabolic alkalosis?
```
Primary abnormality is decreased H+ (increased pH) with increased bicarbonate
Due to:
H+ loss (e.g. pyloric stenosis)
Hypokalaemia
Ingestion of Bicarbonate
```
595
Chemical Pathology - Acid Base Handling
What are the possible mechanisms of metabolic alkalosis?
Primary abnormality is decreased H+ (increased pH) with increased bicarbonate
Due to:
H+ loss (e.g. pyloric stenosis)
Hypokalaemia
Ingestion of Bicarbonate
596
Chemical Pathology - Acid Base Handling
How is metabolic alkalosis compensated for?
This tends to inhibit the respiratory centre
Identified by a rise in pCO2
H+ returns towards normal
597
Chemical Pathology - Acid Base Handling
What is the mechanism of respiratory alkalosis?
Due to Hyperventilation
Voluntary
Artificial ventilation
Stimulation of respiratory centre
598
Chemical Pathology - Acid Base Handling
How is respiratory alkalosis compensated for?
If prolonged this leads to decreased renal excretion of H+ and less bicarbonate generation
H+ may return to near normal but pCO2 and bicarbonate remain low
599
Chemical Pathology - Acid Base Handling
```
pH 6. 90 (7.35-7.45)
H+ 126 nmol/l (35-46)
pCO2 3.0 kPa (4.7-6.0)
pO2 24.0 kPa (10.0-13.3)
Bicarbonate 6 mmol/l (22-30)
```
An example of severe metabolic acidosis
| with partial respiratory compensation
600
Chemical Pathology - Acid Base Handling
```
64 year old female
3 week history of intermittent vomiting
abdominal pain
weight loss
O/E Dehydrated
Jaundiced
Hypotensive
Oliguric
```
```
pH 7. 55 (7.35-7.45)
H+ 28 nmol/l (35-46)
pCO2 8.2 kPa (4.7-6.0)
pO2 10.0 kPa (10.0-13.3)
Bicarbonate 51 mmol/l (22-30)
```
```
Urea 28.1 mmol/l (2.5-8.0)
Creatinine 387 mmol/l (60-125)
Sodium 129 mmol/l (135-145)
Potassium 1.6 mmol/l (3.5-5.5)
Bicarbonate 56 mmol/l (22-30)
Total protein 89 g/l (64-83)
```
Metabolic Alkalosis
Respiratory compensation
601
Chemical Pathology - Acid Base Handling
```
pH 7. 55 (7.35-7.45)
H+ 28 nmol/l (35-46)
pCO2 3.0 kPa (4.7-6.0)
pO2 14.4 kPa (10.0-13.3)
Bicarbonate 20 mmol/l (22-30)
```
Acute Respiratory Alkalosis
602
Chemical Pathology - Acid Base Handling
```
pH 7. 41 (7.35-7.45)
H+ 39 nmol/l (35-46)
pCO2 10.4 kPa (4.7-6.0)
pO2 7.8 kPa (10.0-13.3)
Bicarbonate 47 mmol/l (22-30)
```
Chronic Respiratory Acidosis / Metabolic Alkalosis
72 year old man
Long history of chronic obstructive airways disease
On diuretics for cardiac failure
Potassium 2.6 mmol/l (3.5-5.5)
603
Chemical Pathology - Metabolic Disorders and Screening 1
Deficient enzyme activity may be due to lack of enzyme or reduced enzyme activity due to defects of post-translational modification, assembly or transportation or to defects of cofactor activation
What does an enzyme deficiency lead to, in general?
Lack of end product
Build up of precursors
Abormal, often toxic metabolites
604
Chemical Pathology - Metabolic Disorders and Screening 1
```
Disadvantage - IQ<50
Common - 1:5000 to 1:15000
Test – blood Phe
Gene - >400 mutations
Treatment - Effective if started early
```
Phenylketonuria (PKU)
605
Chemical Pathology - Metabolic Disorders and Screening 1
Describe newborn testing for MDs and other genetic illnesses?
```
5-8 days of life (in UK)
Heel prick capillary from posterior medial third of foot
Blood spotted
onto Guthrie
card (thick
filter paper)
```
Bloodspot card sent to specialist laboratory in pre-paid, pre-addressed envelope
17 laboratories in the UK
UK Newborn Screening Laboratories Network (UKNSLN)
Bloodspots punched out,
elute blood sample
measure phenylalanine
606
Chemical Pathology - Metabolic Disorders and Screening 1
```
Incidence 1:4000 (wrong on handout)
Inherited in only 15%
Usually dysgenesis/agenesis of thyroid gland
Not always detected clinically
Based on high TSH (in UK)
PPV+ve c.60-70%
```
Congenital hypothyroidism
Also screened for in newborn testing
607
Chemical Pathology - Metabolic Disorders and Screening 1
Immune reactive trypsinogen
CF screening, also done in newborns
608
Chemical Pathology - Metabolic Disorders and Screening 1
List disease screened for in neonates?
```
PKU
Congenital hypothyroidism
SCD
CF
Fatty acid oxidation disorder
(Medium chain AcylCoA dehydrogenase (MCADD))
```
609
Chemical Pathology - Metabolic Disorders and Screening 2
24 y, male
dehydration – nausea & vomiting
```
No diarrohea
Disorientated, tactile hallucinations
Salbutamol prn
Methandrostenolone & creatine supplement
Cannabis
History - ADHD
```
```
Slight physical build, no signs of alcohol
Afrebrile, bp normal, pulse regular
GCS 15, no neck stiffness
Normal speech, gait and power
U&E, LFT, FBC
Prolonged clotting times
PTT 28.5 s (11-16)
APTT 47 s (29-37)
INR 2.2 (0.9-1.2)
```
3/7 represented to A&E, acute confusional state unable to give history and disorientated in time, place, person
Examination similar to first
INR 2.7 (0.9-1.2)
AST 114 U/L (20-39 U/L)
ALP 139 U/L (25-114)
Ammonia 348 μmol/L (<39)
pH 7.504
Bicarb 18 mmol/L
PCO2 2.5 kPa
Hyperammonaemia
Urea cycle disorders
1 in 30,000 incidence
610
Chemical Pathology - Metabolic Disorders and Screening 2
Vomiting without diarrhoea
Resp. alkalosis
Hyperammonaemia
Neurological
Encephalopathy
Avoidance
Change in diet
Flags for Urea cycle disorder
611
Chemical Pathology - Metabolic Disorders and Screening 2
Flags for Urea cycle disorder
Vomiting without diarrhoea
Resp. alkalosis
Hyperammonaemia
Neurological
Encephalopathy
Avoidance
Change in diet
612
Chemical Pathology - Metabolic Disorders and Screening 2
Organic acidurias presentation
Unusual odour
Metabolic acidosis
lethargy, feeding problems, truncal hypotonia / limb hypertonia, myoclonic jerks
Hyperammonaemia with and high anion gap (not lactate)
Hypocalcaemia
Neutropenia, thrombopenia, pancytopenia
613
Chemical Pathology - Metabolic Disorders and Screening 2
Unusual odour
Metabolic acidosis
lethargy, feeding problems, truncal hypotonia / limb hypertonia, myoclonic jerks
Hyperammonaemia with and high anion gap (not lactate)
Hypocalcaemia
Neutropenia, thrombopenia, pancytopenia
Organic acidurias
614
Chemical Pathology - Metabolic Disorders and Screening 2
Recurrent episodes of ketoacidotic coma, cerebral abnormalities,
Vomiting, lethargy, increasing confusion, seizures, decerebration, respiratory arrest
Triggered by: e.g. salicylates, antiemetics, valproate
Reye syndrome
615
Chemical Pathology - Metabolic Disorders and Screening 2
Reye syndrome metabolic screen
Plasma/blood ammonia
Plasma / urine amino acid
Urine organic acids
Plasma/blood glucose and lactate
Blood spot carnitine profile
616
Chemical Pathology - Metabolic Disorders and Screening 2
Hypoketotic hypoglycaemia,
hepatomegaly and cardiomyopathy
Mitochondrial Fatty acid β-oxidation
617
Chemical Pathology - Metabolic Disorders and Screening 2
What tests confirm Mitochondrial Fatty acid β-oxidation?
Lab:
(Blood ketones)
Urine organic acids
Blood spot acylcarnitine profile
618
Chemical Pathology - Metabolic Disorders and Screening 2
Bilateral cataracts in child
Raised gal-1-phosphate causes liver and kidney disease.
Presents with vomiting, diarrhoea, hepatomegaly, hypoglycaemia, sepsis
Conjugated hyperbilirubinaemia
Sepsis
Galactosaemia
619
Chemical Pathology - Metabolic Disorders and Screening 2
Tests for galactosaemia?
Lab:
Urine reducing substances
Red cell Gal-1-PUT
620
Chemical Pathology - Metabolic Disorders and Screening 2
When does MELAS (mitochondrial encephalopathy, lactic acids and stroke-like episodes) present?
5-15yo
621
Chemical Pathology - Metabolic Disorders and Screening 2
When does Barth (cardiomyopathy, neutropenia, myopathy) present?
Birth
622
Chemical Pathology - Metabolic Disorders and Screening 2
When does Kearns-Sayre (Chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia) present?
12-30yo
623
Chemical Pathology - Metabolic Disorders and Screening 2
Defective ATP production leads to multisystem disease especially affecting organs with a high energy requirement such as brain, muscle, kidney, retina and endocrine organs.
Mitochondrial disorders
624
Chemical Pathology - Metabolic Disorders and Screening 2
Tests for mitochondrial disorders?
Lab:
Elevated lactate (alanine) – after periods of fasting (e.g. overnight), before and after meals
(CSF lactate / pyruvate – deproteinised at bedside)
CSF protein (raised in Kearns-Sayre syndrome)
CK
Muscle biopsy
Mitochondrial DNA analysis (not so useful in children)
625
Chemical Pathology - Metabolic Disorders and Screening 2
Multisystem disorders associated with cardiomyopathy, osteopenia, hepatomegaly and (in some cases) dysmorphia facial or otherwise.
E.g. CDG type 1a - abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction.
Mortality 20% in first year.
Congenital disorders of glycosylation
626
Chemical Pathology - Metabolic Disorders and Screening 2
Tests for congenital disorders of glycosylation
Transferrin
| Glycoforms (serum)
627
Chemical Pathology - Metabolic Disorders and Screening 2
Severe muscular hypotonia in neonate
seizures, hepatic dysfunction
including mixed hyperbilirubinaemia
and dysmorphic signs.
```
Infantile profile:
retinopathy often leading to early blindness, sensorineural deafness, hepatic dysfunction, mental deficiency, ftt, dysmorphic signs.
Bony changes involve a large
fontanel which only closes
after the first birthday,
osteopenia of long bones,
and often calcified stippling
especially the patellar region
```
Metabolism of very long chain fatty acids and biosynthesis of complex phospholipids
Peroxisomal disorders
628
Chemical Pathology - Metabolic Disorders and Screening 2
Tests for Peroxisomal disorders
Very long chain fatty acid profile
629
Chemical Pathology - Metabolic Disorders and Screening 2
Intraorganelle substrate accumulation leading to organomagaly (connective tissue, solid organs, cartilage, bone and nervous tissue) with consequent
Dysmorphia and regression
Lysosomal storage diseases
630
Chemical Pathology - Metabolic Disorders and Screening 2
Tests for lysosomal storage diseases
Lab:
Urine mucopolysaccharides and/or oligosaccharides
Leucocyte enzyme activities
631
Chemical Pathology - Metabolic Disorders and Screening 2
Treatment for lysosomal storage diseases?
Bone marrow transplant
Exogenous enzyme
Bone marrow transplant
| Exogenous enzyme
632
Chemical Pathology - Metabolic Disorders and Screening 2
Treatment for lysosomal storage diseases?
Bone marrow transplant
Exogenous enzyme
Bone marrow transplant
| Exogenous enzyme
633
Chemical Pathology - Paediatric Clinical Chemistry
1/3rd of infant deaths are due to those borne of low birthweight, T/F?
F
2/3rs of infant deaths are due to those borne of low birthweight
634
Chemical Pathology - Paediatric Clinical Chemistry
Name 4 common problems encountered with preterm births?
```
Respiratory distress syndrome (RDS)
Intraventricular hemorrhage (IVH)
Patent ductus arteriosus (PDA)
Necrotizing enterocolitis (NEC)
((Retinopathy of prematurity (ROP))
```
635
Chemical Pathology - Paediatric Clinical Chemistry
Inflammation of the bowel wall progressing to necrosis and perforation
Bloody stools
Abdominal distension
Intramural air
Necrotising enterocolitis
636
Chemical Pathology - Paediatric Clinical Chemistry
Discuss the Sx of Necrotising enterocolitis
Bloody stools
Abdominal distension
Intramural air
637
Chemical Pathology - Paediatric Clinical Chemistry
By what week pregnancy are nephrons fully functional?
Nephrons: develop from week 6
start producing urine from week 10
full complement from week 36
NB Functional maturity of GFR is not reached
until about 2 years of age
638
Chemical Pathology - Paediatric Clinical Chemistry
What are the consequences of a low GFR in babies?
Low GFR for surface area; consequences are:
slow excretion of a solute load
limited amount of Na+ available for H+ exchange
639
Chemical Pathology - Paediatric Clinical Chemistry
Children have shorter proximal tubules. What effect does this have?
Short proximal tubule means there is a lower reabsorptive capability than in the adult although:
reabsorption is usually adequate for the small filtered load
640
Chemical Pathology - Paediatric Clinical Chemistry
Loops of Henle/distal collecting ducts are short and juxtaglomerular, having what effect in children?
a reduced concentrating ability with a maximum urine osmolality of 700 mmol/kg
641
Chemical Pathology - Paediatric Clinical Chemistry
In children, the distal tubule is relatively unresponsive to aldosterone. What effect does this have?
Leads to a persistent loss of sodium of c.1.8 mmol/kg/day
Reduced potential potassium excretion.
Serum ULN - adult 5.5 mmol/L
neonate 6.0 mmol/L
642
Chemical Pathology - Paediatric Clinical Chemistry
```
Hyponatraemia/hyperkalaemia
with marked volume depletion
(Hypoglycaemia)
Ambiguous genitalia in female neonates
Growth acceleration (in child)
```
Congenital adrenal hyperplasia (1in15000)
643
Chemical Pathology - Paediatric Clinical Chemistry
Name 3 causes early rises in bilirubin [neonates]
```
Haemolytic disease (ABO, rhesus etc)
G-6-PD deficiency
Crigler-Najjar syndrome
```
644
Chemical Pathology - Paediatric Clinical Chemistry
What is the definition of Prolonged jaundice (NICE)?
Prolonged jaundice is jaundice that lasts for more than 14 days in term babies and more than 21 days in preterm babies.
645
Chemical Pathology - Paediatric Clinical Chemistry
Name causes of prolonged jaundice in babies
Prenatal infection/sepsis/hepatitis
Hypothyroidism
Breast milk jaundice
646
Chemical Pathology - Paediatric Clinical Chemistry
Hypothyroidism is a cause of prolonged jaundice. At how many days is it screened for?
(screened at day 6-8)
647
Chemical Pathology - Paediatric Clinical Chemistry
Conjugated/direct bilirubin >20 mmol/l is always pathological in a child. T or F?
T
biliary atresia, choledocal cyst
1/17 000 UK
20% associated with cardiac malformations, polysplenia, sinus inversus
Early surgery essential
ascending cholangitis in TPN
Related to lipid content
Inherited metabolic disorders:
648
Chemical Pathology - Paediatric Clinical Chemistry
What are 3 causes of increased conjugated bilirubin in babies?
biliary atresia, choledocal cyst
1/17 000 UK
20% associated with cardiac malformations, polysplenia, sinus inversus
Early surgery essential
ascending cholangitis in TPN
Related to lipid content
Inherited metabolic disorders:
649
Chemical Pathology - Paediatric Clinical Chemistry
Preterm and term babies have wider normal ranges for calcium, T/F?
T
Preterm-Term-Adult
Calcium 1.90-2.85 2.10-2.95 2.15-2.65
650
Chemical Pathology - Paediatric Clinical Chemistry
Preterm and term babies have higher normal ranges for phosphate, T/F?
T
Preterm-Term-Adult
Phosphate 0.93-1.72 0.95-1.70 0.80-1.40
651
Chemical Pathology - Paediatric Clinical Chemistry
Sx of osteopenia of prematurity on Xray
fraying, splaying and cupping of long bones
652
Chemical Pathology - Paediatric Clinical Chemistry
Calcium within reference range
Phosphate <1mmol/L
Alk phos >1200 U/l ( 10 x adult ULN)
Vitamin D rarely measured in neonate
Biochemistry of osteopenia
653
Chemical Pathology - Paediatric Clinical Chemistry
What is the biochemistry of osteopenia of newborn?
Calcium within reference range
Phosphate <1mmol/L
Alk phos >1200 U/l ( 10 x adult ULN)
Vitamin D rarely measured in neonate
654
Chemical Pathology - Paediatric Clinical Chemistry
How is osteopenia of newborn Rx?
Phosphate / calcium supplements
| (1 alpha calcidol)
655
Chemical Pathology - Paediatric Clinical Chemistry
Frontal bossing
Bowlegs/knock knees
Muscular hypotonia
Alternative presentation:
Tetany / hypocalcaemic seizure
Hypocalcaemic cardiomyopathy
Rickets
656
Chemical Pathology - Paediatric Clinical Chemistry
What disease can be confused with rickets?
Beware: transient hyperphosphatasaemia of infancy (benign). Very high ALP – distinguishable by electrophoresis
657
Chemical Pathology - Paediatric Clinical Chemistry
Name 3 genetic causes of rickets?
```
Familial Hypophosphataemias
- Low tubular maximum reabsorption of phosphate
- Raised urine phosphoethanolamine
Pseudo vitamin D deficiency II
- Receptor defect
Pseudo vitamin D deficiency I
-Defective renal hydroxylation
```
658
Chemical Pathology - Porphyria
What is porphyria?
Deficiencies in enzymes of the haem biosynthetic pathway
Overproduction of toxic haem precursors
Acute neuro-visceral attacks and/or
Acute or chronic cutaneous symptoms.
Deficiency of enzymes ranges from partial to complete
659
Chemical Pathology - Porphyria
```
Organic heterocyclic compounds
Fe2+in centre
4 pyrrolic (tetrapyrrole) rings around the iron
Carries oxygen
Redox reactions
Erythroid cells and liver cytochrome
Made in all cells
```
Haematology
660
Chemical Pathology - Porphyria
What surrounds iron in haemolytic?
4 pyrrolic (tetrapyrrole) rings
661
Chemical Pathology - Porphyria
Where can the principle site of enzyme deficiency be in porphyria?
Principle site of enzyme deficiency
662
Chemical Pathology - Porphyria
What neurotoxin is produced in the neurovisceral/acute porphyria?
5-aminolaevulinic acid
663
Chemical Pathology - Porphyria
What colourless compounds are raised in porphyria?
Porphyrinogens are raised in porphyria
Unstable and readily oxidised to the corresponding porphyrin by the time urine /faeces reaches lab
664
Chemical Pathology - Porphyria
What happens to prophyrinogens?
Unstable and readily oxidised to the corresponding porphyrin by the time urine /faeces reaches lab
665
Chemical Pathology - Porphyria
Extremely rare form of porphyria
Build-up of ALA, but not PBG
Diagnostic implications
‘ALA Dehydratase or Plumboporphyria’
666
Chemical Pathology - Porphyria
Not a porphyria
X-linked sideroblastic anaemia
ALA Synthase deficiency
667
Chemical Pathology - Porphyria
What enzyme is deficient in Acute Intermittent Porphyria?
HMB Synthase deficiency
668
Chemical Pathology - Porphyria
Inheritance of acute intermittent porphyria?
Autosomal dominant
669
Chemical Pathology - Porphyria
```
Autosomal dominant
Neurovisceral attacks
Abdo pain and vomiting
Tachycardia and hypertension
Constipation, urinary incontinence
Hyponatraemia +/- seizures
Psychological symptoms
Sensory loss / muscle weakness
Arrythmias / cardiac arrest
No skin symptoms: No production of porphyrinogens
```
Acute Intermittent Porphyria
670
Chemical Pathology - Porphyria
Name precipitating factors for acute intermittent porphyrias?
```
ALA synthase inducers
Barbiturates, steroids, ethanol, anticonvulsants
Stress
Infection, surgery
Reduced caloric intake
Endocrine factors
More common in women and premenstrual
```
671
Chemical Pathology - Porphyria
Name ALA synthase inducers for acute intermittent porphyrias?
ALA synthase inducers
| Barbiturates, steroids,
672
Chemical Pathology - Porphyria
How are acute intermittent porphyrias diagnosed?
Increased urinary PBG (and ALA)
PBG gets oxidised to porphobilin
Decreased HMBS activity in erythrocytes
673
Chemical Pathology - Porphyria
Rx of acute intermittent porphyrias?
Avoid attacks
Adequate nutritional intake
Precipitant drugs
Prompt treatment infection/illness
iv carbohydrate
iv haem arginate
674
Chemical Pathology - Porphyria
Which acute porphyrias have skin lesions?
Hereditary coproporphyria
| Variegate porphyria
675
Chemical Pathology - Porphyria
```
Autodomal dominant
Acute neurovisceral attack
Skin lesions
Blistering
Skin fragility
Coproporphyrinogen oxidase
```
Hereditary Coproporphyria (HCP)
676
Chemical Pathology - Porphyria
Autosomal dominant
Acute attacks
Skin lesions
Protoporphyrinogen oxidase
Variegate Porphyria (VP)
677
Chemical Pathology - Porphyria
How can we differentiate the acute porhyrias?
AIP – no skin lesions
HCP & VP – skin lesions
```
Urine PBG – raised in all three
Urine and faeces for porphyrins
Raised HCP or VP, but not AIP
Enzyme activity variable
DNA definitive but large number of mutations
```
678
Chemical Pathology - Porphyria
Skin affected only e.g. blisters, fagility, pigmentation, erosions etc. delay following sun exposure
Non-acute porphyrias
Congenital Erythopoietic porphyria
Porphyria Cutanea Tarda
Erythropoietic protoporphyria
679
Chemical Pathology - Porphyria
List the Non-acute porphyrias
Congenital Erythopoietic porphyria
Porphyria Cutanea Tarda
Erythropoietic protoporphyria
680
Chemical Pathology - Porphyria
Inherited or acquired
Uroporphyrinogen decarboxylase deficiency
Formation of vesicles on sun-exposed areas of skin crusting, superficial scarring, pigmentation
Biochemistry:
Urinary (& plasma) uroporphyrins & coproporphyrins increased
Ferritin often increased
Avoid precipitants (alcohol, hepatic compromise)
Porphyria Cutanea Tarda
681
Chemical Pathology - Porphyria
Sx of Porphyria Cutanea Tarda
Inherited or acquired
Uroporphyrinogen decarboxylase deficiency
Formation of vesicles on sun-exposed areas of skin crusting, superficial scarring, pigmentation
Biochemistry:
Urinary (& plasma) uroporphyrins & coproporphyrins increased
Ferritin often increased
Avoid precipitants (alcohol, hepatic compromise)
682
Chemical Pathology - Porphyria
What enzyme is deficient in porphyria cutanea tarda?
Inherited or acquired
Uroporphyrinogen decarboxylase deficiency
Formation of vesicles on sun-exposed areas of skin crusting, superficial scarring, pigmentation
Biochemistry:
Urinary (& plasma) uroporphyrins & coproporphyrins increased
Ferritin often increased
Avoid precipitants (alcohol, hepatic compromise)
683
Chemical Pathology - Porphyria
Photosensitivity only, no blisters
Only erythroid cells affected, therefore need to measure RBC protoporphyrin
Erythropoietic protoporphyria
684
Chemical Pathology - Porphyria
22 year old female
On holiday, drinking heavily
Abdominal pain, nausea and vomiting
Paranoia
Returned to UK
Tonic/clonic seizures
Blurred vision, flashing lights
Admitted to DGH
Clinical deterioration
Transferred ITU
Developed opthalmoplegia, quadraparesis,
Respiratory failure - Intubated/ventilated
Serum Na 118 mmol/L (135-145)
Urine ALA 207 umol/mmol creatinine (<3.8)
Urine PBG 215 umol/mmol creatinine (<1.5)
Hydroxymethylbilane synthase 11 nmol/mL red cells (20-42
```
Diagnoses
Acute intermittent porphyria
Seizures
Quadraparesis
SIADH
Pulmonary emboli
```
Treatment
High carbohydrate diet
Haem arginate
685
Chemical Pathology - Porphyria
Q1: During acute porphyria, the most useful sample to send is…?
Urine
686
Chemical Pathology - Porphyria
Cutaneous erythema without blisters or bullae, most likely indicates
Erythropoietic protoporphyria
687
Chemical Pathology - Thyroid Disease
What controls the uptake of iodine into the thyroid?
TSH controls uptake of Iodide to thyroid (blocked by perchlorate)
688
Chemical Pathology - Thyroid Disease
Briefly describe the process of thyroxine formation?
TSH controls uptake of Iodide to thyroid (blocked by perchlorate)
Iodide converted to Iodine
Tyrosine residues iodinated (blocked by thionamides)
Iodotyrosines join to form thyroxine
689
Chemical Pathology - Thyroid Disease
```
What controls:
Iodide entry to cell
Iodide to iodine conversion
T3/4 vesicle formation
T3/4 release into capillary lumen?
```
TSH
690
Chemical Pathology - Thyroid Disease
What percentage of T4 is free?
0.03%
691
Chemical Pathology - Thyroid Disease
What percentage of T4 is bound to TBG?
75%
692
Chemical Pathology - Thyroid Disease
What percentage of T4 is bound to TBPA/thyroid binding protein aka Transthyretin
20%
693
Chemical Pathology - Thyroid Disease
What percentage of T4 is bound to albumin?
5%
694
Chemical Pathology - Thyroid Disease
Describe the feedback loop of TSH?
Hypothalamus releases TRH
Acts on pituitary -> release of TSH
TSH acts on thyroid -> production and release thyroxine
Thyroxine has NEGATIVE FEEDBACK on BOTH hypothalamus and pituitary
T4 converted peripherally to T3
695
Chemical Pathology - Thyroid Disease
3 MAIN causes of hypothyroidism?
Hashimoto’s disease
Atrophic
Post Graves’ disease - RAI, surgery, natural history or thionamides.
```
Less common:
Post thyroiditis
Drugs (amiodarone and lithium)
Thyroid agenesis or dysgenesis
Iodide deficiency and dyshormonogenesis
Secondary hypothyroidism, pituitary disease (TSH no utility)
Peripheral thyroid hormone resistance
```
696
Chemical Pathology - Thyroid Disease
List causes of hypothyroidism
Hashimoto’s disease
Atrophic
Post Graves’ disease - RAI, surgery, natural history or thionamides.
```
Less common:
Post thyroiditis
Drugs (amiodarone and lithium)
Thyroid agenesis or dysgenesis
Iodide deficiency and dyshormonogenesis
Secondary hypothyroidism, pituitary disease (TSH no utility)
Peripheral thyroid hormone resistance
```
697
Chemical Pathology - Thyroid Disease
| Sx of hypothyroidism?
Weight gain with decreased REE and poor appetite
cold and dry hands, feels cold
hyponatraemia
normocytic anaemia unless + pernicious anaemia
myxoedema, goitre
subtle in elderly
698
Chemical Pathology - Thyroid Disease
How is hypothyroidism diagnosed?
HIGH TSH
LOW free t4
Check thyroid peroxidase autoantibodies - hashimotos
699
Chemical Pathology - Thyroid Disease
How is hypothyroidism Rx?
```
T4 (levothyroxine), 50-125-200mcg/day titrated to a normal TSH
Heart disease
No EBM for excessive T4
osteopaenia, atrial fibrillation
There is EB that no benefit of T3
```
700
Chemical Pathology - Thyroid Disease
What is Subclinical hypothyroidism?
“compensated hypothyroidism”
An increased TSH is seen, alongside a NORMAL T4
TPO predict later thyroid disease
Unlikely to be cause of symptoms
Is associated with hypercholestrolaemia
701
Chemical Pathology - Thyroid Disease
Neonatal hypothyroidism is tested when?
At birth with Guthrie
702
Chemical Pathology - Thyroid Disease
What is a "sick euthryoid"?
When a euthyroid person becomes ill, T4 may become low.
| A high TSH will be seen (appropriate response)
703
Chemical Pathology - Thyroid Disease
What are the main causes of hyperthyroidism?
```
Graves’ disease 40-60%
Toxic multinodular goitre 30-50%
Single toxic adenoma 5%
Subacute thyroiditis
Postpartum thyroiditis
```
```
LESS COMMON
Silent thyroiditis (immune and amiodarone)
Factitious thyroiditis
TSH induced
Thyroid cancer induced
Trophoblastic tumour and Struma ovarii
```
704
Chemical Pathology - Thyroid Disease
What are the causes of hyperthyroidism?
```
Graves’ disease 40-60%
Toxic multinodular goitre 30-50%
Single toxic adenoma 5%
Subacute thyroiditis
Postpartum thyroiditis
```
```
LESS COMMON
Silent thyroiditis (immune and amiodarone)
Factitious thyroiditis
TSH induced
Thyroid cancer induced
Trophoblastic tumour and Struma ovarii
```
705
Chemical Pathology - Thyroid Disease
List the HIGH uptake causes of hyperthyroidism?
Graves’ disease 40-60%
Toxic multinodular goitre 30-50%
Single toxic adenoma 5%
706
Chemical Pathology - Thyroid Disease
List the LOW uptake causes of hyperthyroidism?
Subacute thyroiditis
| Postpartum thyroiditis
707
Chemical Pathology - Thyroid Disease
How is thryrotoxicosis diagnosed?
Clinical Sx
High T3/4
Low TSH
```
Technitium scan
Thyroid autoantibodies (thyroid microsomal)
```
708
Chemical Pathology - Thyroid Disease
Rx of thyrotoxicosis?
B Block if pulse>100
Definitive
Surgery
Radioactove iodine
Thionamides
709
Chemical Pathology - Thyroid Disease
List thionamides?
What are the SEs?
Carbimazole, propylthiouracil
These prevent iodide->iodine conversion
Several possible moderate side effects including rash
Rarely agranulocytosis (<1%). Warn to stop if sore throat or fever and check FBC. Routine tests of no value
titration or block and replace
710
Chemical Pathology - Thyroid Disease
MoA of thionamides?
Prevent iodide->iodine conversion
711
Haematology - Coagulation
What synthesises of PGI2, vWF, plasminogen activators, thrombomodulin?
The endothelium
712
Haematology - Coagulation
Megakaryocyte lifespan?
10 days
| 1/3 stored in spleen
713
Haematology - Coagulation
Describe the process of platelet adhesion and aggregation?
Adhesion
Adheres to VWF via glp1b
OR
Adheres to collagen via Glp1a
ADP + thromboxane released
Aggregation
Platelets bind via glpIIb/IIIa
Fibrinogen and Ca2+
714
Haematology - Coagulation
How does aspirin reduce platelet aggregation?
Inhibits COX
Reduction of PGG2
Decreased thromboxane production (via TX synthase)
Thomboxane induces platelet aggregation
715
Haematology - Coagulation
Which prostaglandin inhibits platelet aggregation?
Prostacyclin
716
Haematology - Coagulation
What:
Cleaves Fibrinogen
Activates Platelets
Activates procofactors (FV and FVIII)
Activates zymogens (FVII, FXI and FXIII)
Thrombin
717
Haematology - Coagulation
Learn the coagulation cascade?
Yeh yes fekkin learn it
718
Haematology - Coagulation
List physiological anticoagulants?
Antithrombin
Protein C/S
Tissue factor pathway inhibitor
719
```
Haematology - Coagulation
What is seen with:
Site of bleeding
Petechiae
Bleeding after cuts
Haemoarthrosis
Bruising/ecchymosis
Bleeding post surgery
```
With platelet disorders?
```
Site of bleeding - skin/mucus membranes
Petechiae - yes
Bleeding after cuts - yes
Haemoarthrosis - no
Bruising/ecchymosis - small/superficial
Bleeding post surgery - immediate but mild
```
720
Haematology - Coagulation
```
What is seen with:
Site of bleeding
Petechiae
Bleeding after cuts
Haemoarthrosis
Bruising/ecchymosis
Bleeding post surgery
```
With coagulation factor disorders?
Site of bleeding - soft tissue/joint/muscles
Petechiae - no
Bleeding after cuts - no
Haemoarthrosis - Common
Bruising/ecchymosis - large and deep
Bleeding post surgery - delayed (1-2d) and often severe.
721
Haematology - Coagulation
General causes of thrombocytopenia
Decreased Production
Decreased Survival – Immune (ITP)
Increased utilization – DIC
722
Haematology - Coagulation
General causes of defective Platelet function?
Acquired – Drugs – Aspirin, ESRF
| Congenital – Eg. Thrombasthenia.
723
Haematology - Coagulation
A specifc, non-competive inhibitor of adenosine diphosphate- (ADP) induced platelet aggregation, irreversibly inhibiting the binding of ADP to its platelet membrane receptors. Ultimately it inhibits the activation of the GPIIb/IIIa receptor, its binding to fibrinogen and further platelet aggregation.
What drug?
Clopidogrel
724
Haematology - Coagulation
Affects the thromboxane A2 (TXA2) pathway and is the most widely used antiplatelet treatment. Inhibits the cyclo-oxygenase enzyme, reducing the production of prostaglandin and TXA2 from arachidonic acid. TXA2 activates the GPIIb/IIIa binding site on the platelet, allowing fibrinogen to bind.
What drug?
Aspirin
725
Haematology - Coagulation
Inhibits platelet aggregation by blocking the reuptake of adenosine formed from precursors released by red blood cells following microtrauma.
What drug?
Dipyridamole
726
Haematology - Coagulation
List the causes of thrombocytopenia
```
Immune-mediated
Idiopathic
Drug-induced
Connective tissue disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic anemia
```
727
Haematology - Coagulation
Acute ITP is seen in which age group?
Children with preceding infection
| Usually lasts 2-6weeks
728
Haematology - Coagulation
Chronic ITP is seen in which age group?
Adults
Usually spontaneous
Usually no remission
729
Haematology - Coagulation
When is Rx considered for ITP and what is the Rx?
When platelets <50k
| Steroids/IVIG
730
Haematology - Coagulation
List inherited coagulation disorders
Haemophilia A and B
Von Willebrands disease
Other factor deficiencies
Haemophilia (A8 B9!)
731
Haematology - Coagulation
Describe acquired coagulation disorders
Liver disease
Vitamin K deficiency/warfarin overdose
DIC
732
Haematology - Coagulation
| Prolonged aPTT but normal PT.
Gene on X chromosome.
Carrier females, Males suffer
Haemophilia
733
Haematology - Coagulation
```
Haemarthrosis (most common)
Fixed joints
Soft tissue haematomas (e.g., muscle)
Muscle atrophy
Shortened tendons
Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions
```
What illness?
Haemophilia
734
Haematology - Coagulation
Inheritance - autosomal dominant
Incidence - 1/10,000
Clinical features - mucocutaneous bleeding
What disease?
VWD
735
Haematology - Coagulation
Inheritance VWD?
AD
736
Haematology - Coagulation
Classification of VWD?
Types 1-3
Partial qualitative def
Qualitative def
Total quantitative
737
Haematology - Coagulation
Causes of vitamin K deficiency?
Malnutrition Biliary obstruction Malabsorption Antibiotic therapy
738
Haematology - Coagulation
What is DIC?
Systemic coagulation activation
Intravascula fibrin deposition
Thrombosis of small/medium size blood vessels: organ failure
Depletion of platelets and coagulation factors: bleeding
739
Haematology - Coagulation
Rx of DIC?
Treatment of underlying disorder
Anticoagulation with heparin?
Platelet transfusion
Fresh frozen plasma
Coagulation inhibitor concentrate
APC concentrate
740
Haematology - Coagulation
Decreased synthesis of II, VII, IX, X, XI, and fibrinogen
Dietary Vitamin K deficiency (Inadequate intake or malabsortion)
Dysfibrinogenemia
Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)
DIC
Thrombocytoepnia due to hypersplenism
Liver disease
741
Haematology - Coagulation
How are the haemostat defects in liver disease Rx?
Treatment for prolonged PT/PTT
Vitamin K 10 mg o.d x 3 days - usually ineffective
Fresh-frozen plasma infusion
25-30% of plasma volume (1200-1500 ml)
immediate but temporary effect
Treatment for low fibrinogen
Cryoprecipitate (1 unit/10kg body weight)
Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia
Replacement therapy
742
Microbiology - Bone and Joint Infections
What percentage of HAIs are surgical site infections?
15.7%
743
Microbiology - Bone and Joint Infections
What are the main pathogens implicated in surgical site infections?
Staph.aureus (MSSA and MRSA)
E.coli
Pseudomonas aeruginosa
744
Microbiology - Bone and Joint Infections
What is the pathogenesis of surgical site infections?
Contamination of wound at operation
Pathogenicity and innoculum of microorganisms
Host immune response
If surgical site is contaminated with
> 10 5 microorganisms per gram of tissue, risk of SSI is increased.
The dose of contaminating bacteria required to cause infection is much lower if there is foreign material present e.g silk suture
745
Microbiology - Bone and Joint Infections
What are the three levels of surgical site infections?
Superficial incisional- affect skin and subcutaneous tissue
Deep incisional- affect fascial and muscle layers
Organ/space infection- any part of anatomy other than incision
746
Microbiology - Bone and Joint Infections
Name some RFs that increase the likelihood of surgical site infections?
Age
Obesity
Smoking - nicotine delays primary wound healing + peripheral vascular disease
ASA score of 3 or more
Diabetes – two to three fold increased risk. Association with post-op hyperglycaemia. Control blood glucose. HbA1C < 7
Malnutrition
Low serum albumin
Radiotherapy and steroid use. Taper steroids
Rheumatoid arthiritis. Stop disease modifying agents for 4 weeks before and 8 weeks post-op.
747
Microbiology - Bone and Joint Infections
What is the advice regarding pre-operative showering to reduce the chances of surgical site infections?
Microorganisms colonising the skin may contaminate exposed tissues and cause an SSI
There is no difference in SSI incidence when chlorhexidine or detergent/bar soap is used
Patients should be advised to shower or bath using soap on the day of surgery or the day before
748
Microbiology - Bone and Joint Infections
What is the advice regarding hair removal to reduce the chances of surgical site infections?
Micro-abrasions caused by shaving with a razor may lead to multiplication of bacteria
Use electric clippers on the day of surgery with single-use head
Hair should not be removed unless it will interfere with the operation
749
Microbiology - Bone and Joint Infections
A multivariate analysis demonstrated that S.aureus carriage was the most powerful independent risk factor for SSI following cardiothoracic surgery
True or false?
True
S.aureus is carried in the nares of 20-30%
750
Microbiology - Bone and Joint Infections
What is the advice regarding antibiotic prophylaxis to reduce the chances of surgical site infections?
Antibiotic prophylaxis should be given at induction of anaesthesia
Bactericidal concentration of the drug should be established in serum and tissues at time of incision.
Additional doses may be necessary if there has been significant blood loss or if the operation has been prolonged
751
Microbiology - Bone and Joint Infections
What is the advice regarding skin preparation to reduce the chances of surgical site infections?
When skin is incised microorganisms may contaminate tissues and cause an SSI
Prepare skin at surgical site using antiseptic preparation: povidine-iodine or chlorhexidine.
Chlorhexidine in 70% alcohol is used
752
Microbiology - Bone and Joint Infections
Is it better for the patient to be cool, hot or normothermic to prevent surgical site infections?
Mild hypothermia appears to increase the risk of SSIs by causing vasoconstriction, decreased delivery of oxygen to wound space and subsequent impairment of neutrophil function
In theatre suite: Measure patients temperature before inducing anaesthesia. Start forced air warming if temperature is below 36ºC
Warm intravenous fluid. Warm irrigation fluid
753
Microbiology - Bone and Joint Infections
RFs for septic arthritis
Rheumatoid arthritis , osteoarthritis, crystal induced arthritis
Joint prosthesis
Intravenous drug abuse
Diabetes, chronic renal disease, chronic liver disease
Immunosuppression- steroids
Trauma- intra-articular injection, penetrating injury
Organisms adhere to the synovial membrane, bacterial proliferation in the synovial fluid with generation of host inflammatory response.
Joint damage leads to exposure of host derived proteins such as fibronectin to which bacteria adhere
754
Microbiology - Bone and Joint Infections
What bacteria typically cause septic arthritis post surgery?
```
Staph. aureus 46%
- Coagulase negative staphylococci 4%
Streptococci 22%
Streptococcus pyogenes
Streptococcus pneumoniae
Streptococcus agalactiae
Gram negative organisms
-E.coli
- Haemophilus influezae
- Neisseria gonorrhoeae
- Salmonella
Rare- Lyme, brucellosis, mycobacteria, fungi
```
S.aureus has receptors such as fibronectin binding protein that recognise selected host proteins.
Kingella kingae synovial adherence is via bacterial pili
Some strains of Staph. aureus produce the cytotoxin PVL ( Panton-Valentine Leucocidin) which have been associated with fulminant infections.
755
Microbiology - Bone and Joint Infections
Sx of septic arthritis
1-2 week history of red, painful, swollen restricted joint
Monoarticular in 90%
Knee is involved in 50%
Patients with rheumatoid arthritis may show more subtle signs of joint infection
756
Microbiology - Bone and Joint Infections
Ix for septic arthritis?
Blood culture before antibiotics are given
Synovial fluid aspiration for microscopy and culture
ESR,CRP
-Traditionally a synovial count> 50,000 WBC cells/mm3 used to suggest septic arthritis
(Negative culture result does not exclude septic arthritis)
US- confirm effusion and guide needle aspiration
CT- erosive bone change, periarticular soft tissue extension
MRI- joint effusion, articular cartilage destruction, abscess, contiguous osteomyelitis
757
Microbiology - Bone and Joint Infections
What is the management of septic arthritis
Antibiotics- No data on optimum duration of treatment
Upto 6 weeks of antibiotics may be given
OPAT (outpatient parenteral antibiotic team)
Drainage
758
Microbiology - Bone and Joint Infections
Route of infection in vertebral osteomyelitis?
Acute haematogenous
Exogenous- after disc surgery
- implant associated
Localisation
cervical- 10.6%
cervico-thoraco- 0.4%
lumbar 43.1%
759
Microbiology - Bone and Joint Infections
Predominant organism causing vertebral osteomyelitis
S.aureus- 48.3%
760
Microbiology - Bone and Joint Infections
Sx of vertebral osteomyelitis
Symptoms
Back pain- 86%
Fever- 60%
Neurological impairment 34%
761
Microbiology - Bone and Joint Infections
Ix for vertebral osteomyelitis
Diagnosis
MRI: 90% sensitive
Blood cultures
CT/ open biopsy
762
Microbiology - Bone and Joint Infections
Rx of vertebral osteomyelitis
Treatment
Six weeks of treatment
Longer treatment if undrained abscesses/implant associated
763
Microbiology - Bone and Joint Infections
Post-op suction is applied for 30 mins
Antibiotics are instilled through the central lumen followed by 1ml of streptokinase. The suction system was clamped for the next 3.5 hrs.
Antibiotic instilled depended on culture results.
Every week 1l of Hartmanns solution was infused through each drain . Suction fluid was sent for culture
Irrigation was continued for 3 weeks usually
Oral antibiotics were continued for 6 weeks after discharge
After follow up for 101 months, 26 out of 35 patients had no signs of infection
What surgical technique is this, that aims to treat chronic osteomyelitis?
Modified Lautenbach technique
764
Microbiology - Bone and Joint Infections
What is the Papineau technique for chronic osteomyelitis?
Initially described by Papineau in 1973
Complete excision of infected tissue and necrotic bone
Open cancellous bone grafting of the osseous defect.
Split skin grafting for wound closure
Papineau reported a 93 % success rate after treating 180 patients
Panda et al reported a 89% success rate.
765
Microbiology - Bone and Joint Infections
Signs of prosthetic joint infection?
Pain
Patient complains that the joint was ‘never right’
Early failure
Sinus tract
766
Microbiology - Bone and Joint Infections
Causative organisms for prosthetic joint infection
```
Gram positive cocci
-coagulase negative staphylococci
-staphylococus aureus
Streptococci sp
Enterococci sp
```
Aerobic gram negative bacilli
Enterobacteriaceae
Pseudomonas aeruginosa
Anaerobes
Polymicrobial
Culture negative
Fungi
767
Microbiology - Bone and Joint Infections
Ix for prosthetic joint infection
Radiology- loosening
If CRP>13.5 for prosthetic knee joint infection
CRP> 5 for prosthetic hip joint infection
Joint aspiration
If >1700/ml of WCC correlates with knee PJI
If > 4200/ml of WCC correlates with hip PJI
Am J med 2004;117:557-562.
May only get planktonic bacteria in joint fluid, may need to sample bacteria where infection is most likely
768
Microbiology - Bone and Joint Infections
What is single stage revision for prosthetic joint infections?
Remove all foreign material and dead bone
Change gloves, drapes etc
Re-implant new prosthesis with antibiotic impregnated cement and give iv antibiotics .
769
Microbiology - Bone and Joint Infections
What is Endo Klinik single stage revision for prosthetic joint infections?
Aspirate joint to identify pathogen
Excision of infected tissue , synovectomy
Add antibiotics to bone cement according to culture results
Implantation of a cemented hip or knee prosthesis using antibiotic loaded cement
Give 7-10 days of iv antibiotics
Culture drain tips
Success rate is 89% in 2002
The Journal of Arthroplasty Vol 16, No.8 Suppl. 1, 2001;145-149.
770
Microbiology - Bone and Joint Infections
What is two stage revision for prosthetic joint infections?
Remove prosthesis
Take samples for microbiology and histology
Period of iv antibiotics (6weeks). Stop antibiotics for 2 weeks
Re-debride and sample at second stage
Re-implantation with antibiotic impregnated cement
No further antibiotics if samples clear
OPAT
Douglas J et al. Journal of bone and joint surgery 1989;71-A no.6:828-834. (87% success rate)
771
Histopathology - Breast Pathology
Aspirates of breast lumps are coded C1-5, what does each mean?
```
C1 = inadequate
C2 = benign
C3 = atypia, probably benign
C4 = suspicious of malignancy
C5 = malignant
```
772
Histopathology - Breast Pathology
Inflammation and dilation of large breast ducts.
Aetiology unclear.
Usually presents with nipple discharge.
Sometimes causes breast pain, breast mass and nipple retraction.
Cytology of nipple discharge shows proteinaceous material and inflammatory cells only.
Benign condition with no increased risk of malignancy.
What condition?
Duct ectasia
773
Histopathology - Breast Pathology
Sx of duct ectasia?
Usually presents with nipple discharge.
| Sometimes causes breast pain, breast mass and nipple retraction.
774
Histopathology - Breast Pathology
What does cytology of nipple discharge show in duct ectasia?
Cytology of nipple discharge shows proteinaceous material and inflammatory cells only.
Benign condition with no increased risk of malignancy.
775
Histopathology - Breast Pathology
Acute inflammation in the breast.
Often seen in lactating women due to cracked skin and stasis of milk.
May also complicate duct ectasia.
Staphylococci the usual organism.
Presents with a painful red breast.
Drainage & antibiotics usually curative.
Acute mastitis
776
Histopathology - Breast Pathology
Main causative organism for acute mastitis?
Staph A
777
Histopathology - Breast Pathology
Presentation of mastitis?
Presents with a painful red breast.
778
Histopathology - Breast Pathology
What is fat necrosis?
An inflammatory reaction to damaged adipose tissue.
Caused by trauma, surgery, radiotherapy.
Presents with a breast mass.
Benign condition.
779
Histopathology - Breast Pathology
What is fibrocystic disease?
A group of alterations in the breast which reflect normal, albeit exaggerated, responses to hormonal influences.
Very common.
Presents with breast lumpiness.
No increased risk for subsequent breast carcinoma
780
Histopathology - Breast Pathology
A benign fibroepithelial neoplasm of the breast.
Fibroadenoma
781
Histopathology - Breast Pathology
Presents as a circumscribed mobile breast lump in young women aged 20-30.
Simple “shelling out” curative.
Fibroadenoma
782
Histopathology - Breast Pathology
A group of potentially aggressive fibroepithelial neoplasms of the breast.
Uncommon tumours.
Present as enlarging masses in women aged over 50.
Some may arise within pre-existing fibroadenomas.
Vast majority behave in a benign fashion but a small proportion can behave more aggressively.
Phyllodes tumours
783
Histopathology - Breast Pathology
A benign papillary tumour arising within the duct system of the breast.
Arise within small terminal ductules (peripheral papillomas) or larger lactiferous ducts (central papillomas).
Common.
Seen mostly in women aged 40-60.
Central papillomas present with nipple discharge.
Peripheral papillomas may remain clinically silent if small.
Excision of involved duct is curative
Intraductal papilloma
784
Histopathology - Breast Pathology
How do papillomas present?
Common.
Seen mostly in women aged 40-60.
Central papillomas present with nipple discharge.
Peripheral papillomas may remain clinically silent if small.
Excision of involved duct is curative
785
Histopathology - Breast Pathology
What is a radial scar?
A benign sclerosing lesion characterised by a central zone of scarring surrounded by a radiating zone of proliferating glandular tissue.
Range in size from tiny microscopic lesions to large clinically apparent masses.
Lesions >1 cm are sometimes called “complex sclerosing lesions”.
786
Histopathology - Breast Pathology
A benign sclerosing lesion characterised by a central zone of scarring surrounded by a radiating zone of proliferating glandular tissue.
Range in size from tiny microscopic lesions to large clinically apparent masses.
Lesions >1 cm are sometimes called “complex sclerosing lesions”.
Reasonably common lesions.
Thought to represent an exuberant reparative phenomenon in response to areas of tissue damage in the breast.
Usually present as stellate masses on screening mammograms which may closely a carcinoma.
Excision is curative.
Radial scar
787
Histopathology - Breast Pathology
What lesion resembles a carcinoma on mammograms, presenting as a stellate lesion?
Radial scar
Reasonably common lesions.
Thought to represent an exuberant reparative phenomenon in response to areas of tissue damage in the breast.
Usually present as stellate masses on screening mammograms which may closely a carcinoma.
Excision is curative.
788
Histopathology - Breast Pathology
A diverse group of intraductal proliferative lesions of the breast associated with an increased risk, of greatly different magnitudes, for subsequent development of invasive breast carcinoma.
Microscopic lesions which usually produce no symptoms.
Diagnosed in breast tissue removed for other reasons or on screening mammograms if they calcify.
Proliferative breast diseases
789
Histopathology - Breast Pathology
List proliferative breast diseases?
Usual epithelial hyperplasia
Flat epithelial atypia/Atypical ductal carcinoma
In situ lobular neoplasia
790
Histopathology - Breast Pathology
A neoplastic intraductal epithelial proliferation in the breast with an inherent, but not inevitable, risk of progression to invasive breast carcinoma.
Common.
Incidence has markedly increased since the introduction of breast screening programmes.
Ductal carcinoma in situ (DCIS)
791
Histopathology - Breast Pathology
85% are detected on mammography as areas of microcalcification.
10% produce clinical findings such as a lump, nipple discharge, or eczematous change of the nipple (Paget’s disease of the nipple).
5% are diagnosed incidentally in breast specimens removed for other reasons.
Subclassified histologically into low, intermediate and high grade.
DCIS
792
Histopathology - Breast Pathology
How does DCIS present?
85% are detected on mammography as areas of microcalcification.
10% produce clinical findings such as a lump, nipple discharge, or eczematous change of the nipple (Paget’s disease of the nipple).
5% are diagnosed incidentally in breast specimens removed for other reasons.
Subclassified histologically into low, intermediate and high grade.
793
Histopathology - Breast Pathology
Rx of DCIS
Treatment is surgical excision.
Complete excision with clear margins is curative.
Recurrence is more likely with extensive disease and high grade DCIS.
794
Histopathology - Breast Pathology
Lifetime risk of invasive breast cancer?
The most common cancer in women with a lifetime risk of 1 in 8.
Incidence rates rise rapidly with increasing age, such that most cases occur in older women.
795
Histopathology - Breast Pathology
RFs for invasive breast cancer?
Early menarche, late menopause, increased weight, high alcohol consumption, oral contraceptive use, and a positive family history are all associated with increased risk.
796
Histopathology - Breast Pathology
Recently described type of carcinoma discovered following genetic analysis of breast carcinomas.
Histologically characterised by sheets of markedly atypical cells with a prominent lymphocytic infiltrate. Central necrosis is common.
Immunohistochemically characterised by positivity for “basal” cytokeratins CK5/6 and CK14.
Often associated with BRCA mutations.
Seem to have particular propensity to vascular invasion and distant metastatic spread.
What type of breast carcinoma?
Basal-like carcinoma
797
Histopathology - Breast Pathology
What 3 aspects are breast carcinomas graded by?
All invasive breast cancers are graded histologically by assessing 1) tubule formation 2) nuclear pleomorphism,, and 3)mitotic activity.
Each parameter is scored from 1-3 and the three values are added together to produce total scores from 3-9.
3-5 points = grade 1 (well differentiated).
6-7 points = grade 2 (moderately differentiated).
8-9 points = grade 3 (poorly differentiated).
798
Histopathology - Breast Pathology
What receptors occur in breast cancers?
What receptors do low and high grade tend to have?
All invasive breast carcinomas are assessed for oestrogen receptor (ER), progesterone receptor (PR) and Her2 status.
Low grade tumours tend to be ER/PR positive and Her2 negative.
High grade tumours tend to be ER/PR negative and Her2 positive.
Basal-like carcinomas are often ER/PR/Her2 negative (“triple negative”).
799
Histopathology - Breast Pathology
What receptor status do basal-like carcinomas tend to have?
All invasive breast carcinomas are assessed for oestrogen receptor (ER), progesterone receptor (PR) and Her2 status.
Low grade tumours tend to be ER/PR positive and Her2 negative.
High grade tumours tend to be ER/PR negative and Her2 positive.
Basal-like carcinomas are often ER/PR/Her2 negative (“triple negative”).
800
Histopathology - Breast Pathology
Most important prognostic factor for breast cancers?
The single most important prognostic factor is the status of the axillary lymph nodes.
Other important factors include tumour size, histological type, and histological grade.
801
Histopathology - Breast Pathology Histopathology - Breast Pathology
How often are women screened for breast cancer, and at what ages does this occur between?
The aim of screening is to pick up DCIS or early invasive carcinomas.
Women aged 47-73 are invited for screening every three years.
The screening test is a mammogram which looks for abnormal areas of calcification or a mass within the breast.
802
Histopathology - Breast Pathology
What percentage of women have abnormal mammograms at screening?
About 5% of women have an abnormal mammogram and are recalled to an assessment clinic for further investigation.
This may include more mammograms or an ultrasound followed by sampling of the abnormal area, usually by core biopsy.
803
Histopathology - Breast Pathology
Core biopsies taken from the breast as part of the screening programme are given a B code from 1-5.
What does B1-5 correspond to?
```
B1 = normal breast tissue.
B2 = benign abnormality.
B3 = lesion of uncertain malignant potential.
B4 = suspicious of malignancy.
B5 = malignant (B5a = DCIS, B5b = invasive carcinoma).
```
804
Histopathology - Breast Pathology
Refers to enlargement of the male breast.
Pubertal boys and older men aged over 50.
Idiopathic or associated with drugs (both therapeutic and recreational).
Histologically the breast ducts show epithelial hyperplasia with typical finger-like projections extending into the duct lumen. The periductal stromal is often cellular and oedematous.
Benign, no risk of malignancy.
Gynaecomastia
805
Histopathology - Breast Pathology
Median age at diagnosis for male breast cancer?
Carcinoma of the male breast is rare (0.2% of all cancers).
Median age at diagnosis 65 years old.
Most present with a palpable lump.
Histologically the tumours show similar features to female breast cancers.
806
Histopathology - Endocrine Pathology
Hypothalamic factor causing release of TSH
TRH
807
Histopathology - Endocrine Pathology
Hypothalamic factor causing release of ACTH
CRH
808
Histopathology - Endocrine Pathology
Hypothalamic factor causing release of GH
GHRH
809
Histopathology - Endocrine Pathology
Hypothalamic factor reducing release of GH
Somatostatin
810
Histopathology - Endocrine Pathology
Hypothalamic factor causing release of FSH/LH
GnRH
811
Histopathology - Endocrine Pathology
Hypothalamic factor reducing release of prolactin
Dopamine
812
Histopathology - Endocrine Pathology
What normally causes hyperpituitarism?
Usually due to functional adenoma
Originally classified on the morphological character of the predominant cell type e.g acidophil, basophil or chromophobe adenomas.
Now classified on the basis of the hormones produced - detected by immunohistochemistry
813
Histopathology - Endocrine Pathology
Clinical effects of functioning pituitary adenomas
Sx of prolactinoma
Amenorrhea, galactorrhea, loss of libido, infertility
| Usually diagnosed earlier in females of reproductive age
814
Histopathology - Endocrine Pathology
Sx of growth hormone adenoma (aka acromegaly)
Prepubertal children - gigantism
Adults - acromegaly
Diabetes mellitus, muscle weakness, hypertension, congestive cardiac failure
815
Histopathology - Endocrine Pathology
Sx of corticotroph cell adenomas
Cushing’s syndrome
816
Histopathology - Endocrine Pathology
What are the main causes of hypopituitarism?
Most cases caused by:
Nonsecretory pituitary adenomas (ie non-functional)
Ischaemic necrosis
- Most commonly post-partum (Sheehan’s syndrome)
- DIC, sickle cell anaemia, elevated intracranial pressure, shock
Ablation of pituitary by surgery or irradiation
817
Histopathology - Endocrine Pathology
Clinical features of hypopituitarism?
Children - growth failure (pituitary dwarfism)
Gonadotrophin deficiency - amenorrhea and infertility in women. Decreased libido and impotence in men
TSH and ACTH deficiency - hypothyroidism and hypoadrenalism
Prolactin deficiency - failure of post-partum lactation
818
Histopathology - Endocrine Pathology
Name the two posterior pituitary syndromes?
Posterior pituitary releases two peptides - antidiuretic hormone (ADH) and oxytocin
Clinically important posterior pituitary syndromes involve ADH
diabetes insipidus
Inappropriately high ADH
819
Histopathology - Endocrine Pathology
Aside from T3/4, what else does the thyroid gland synthesise?
In response to TSH from anterior pituitary follicular epithelial cells pinocytose colloid and convert thyroglobulin into T4 and T3
T4 and T3 released into circulation
Effect is to increase the basal metabolic rate
Thyroid also contains a population of parafollicular or ‘C’ cells that synthesize calcitonin - promotes absorption of calcium by the skeletal system
820
Histopathology - Endocrine Pathology
Most common cause of non-toxic goitre?
Goitre is enlargement of the thyroid
Common if there is impaired synthesis of thyroid hormone - most often due to iodine deficiency
Endemic in areas where iodine in the soil and water is low (‘Derbyshire neck’)
May be seen at puberty particularly in females
May be due to ingestion of substances that interfere with thyroid hormone synthesis e.g. brassicas
May be due to hereditary enzyme defects
821
Histopathology - Endocrine Pathology
What is a multi nodular goitre?
With time simple thyroid enlargement may be transformed to a multinodular pattern
May reach massive size
May lead to mechanical effects including dysphagia and airways obstruction
A hyperfunctioning nodule may develop leading to hyperthyroidism
822
Histopathology - Endocrine Pathology
Hypermetabolic state caused by elevated circulating levels of free T3 and T4
Thyrotoxicosis
823
Histopathology - Endocrine Pathology
Primary causes of Thyrotoxicosis
```
Primary
Grave’s disease
Hyperfunctioning multinodular goitre
Hyperfunctioning adenoma
Thyroiditis
Secondary
TSH secreting pituitary adenoma (rare)
Not associated with thyroid disease
Struma ovarii (ovarian teratoma with ectopic thyroid)
Factitious thyrotoxicosis (exogenous thyroid intake)
```
824
Histopathology - Endocrine Pathology
Secondary causes of Thyrotoxicosis
```
Primary
Grave’s disease
Hyperfunctioning multinodular goitre
Hyperfunctioning adenoma
Thyroiditis
Secondary
TSH secreting pituitary adenoma (rare)
Not associated with thyroid disease
Struma ovarii (ovarian teratoma with ectopic thyroid)
Factitious thyrotoxicosis (exogenous thyroid intake)
```
825
Histopathology - Endocrine Pathology
Tertiary causes of Thyrotoxicosis
```
Primary
Grave’s disease
Hyperfunctioning multinodular goitre
Hyperfunctioning adenoma
Thyroiditis
Secondary
TSH secreting pituitary adenoma (rare)
Not associated with thyroid disease
Struma ovarii (ovarian teratoma with ectopic thyroid)
Factitious thyrotoxicosis (exogenous thyroid intake)
```
826
Histopathology - Endocrine Pathology
Most common cause of endogenous hyperthyroidism
Triad of:
Thyrotoxicosis
Infiltrative ophthalmopathy with exophthalmos in up to 40%
Infiltrative dermopathy (pretibibial myxoedema) in a minority of cases
Primarily younger adults. F:M, 7:1
Graves
827
Histopathology - Endocrine Pathology
Triad of Sx in graves
Most common cause of endogenous hyperthyroidism
Triad of:
Thyrotoxicosis
Infiltrative ophthalmopathy with exophthalmos in up to 40%
Infiltrative dermopathy (pretibibial myxoedema) in a minority of cases
Primarily younger adults. F:M, 7:1
828
Histopathology - Endocrine Pathology
Antibodies possible in graves
Autoimmune disorder
Variety of antibodies including antibodies to TSH receptor and thyroglobulin
Antibodies to TSH receptor most important in pathogenesis
May stimulate release of thyroid hormones and increased proliferation of epithelium
Associated with other autoimmune diseases such as SLE, pernicious anaemia, type 1 diabetes and Addison’s disease
829
Histopathology - Endocrine Pathology
Primary causes of hypothyroidism?
Primary
Postablative (after surgery or radioiodine therapy)
Autoimmune - Hashimoto’s thyroiditis
Iodine deficiency
Congenital biosynthetic defect
Secondary
Pituitary or hypothalamic failure (uncommon)
830
Histopathology - Endocrine Pathology
Secondary causes of hypothyroidism
Primary
Postablative (after surgery or radioiodine therapy)
Autoimmune - Hashimoto’s thyroiditis
Iodine deficiency
Congenital biosynthetic defect
Secondary
Pituitary or hypothalamic failure (uncommon)
831
Histopathology - Endocrine Pathology
Most common cause of hypothyroidism?
What age does it typically affect?
```
Other end of the spectrum of autoimmune thyroid disease from Grave’s disease
Common cause of hypothyroidism
Most common from 45 - 65 years
F:M 15:1
Presents with painless enlargement
```
832
Histopathology - Endocrine Pathology
What are the discerning features of neoplastic thyroid nodules, as opposed to benign causes?
Solitary nodules more often neoplastic than multiple nodules
Solid nodules more likely to be neoplastic than cystic nodules
Nodules in younger patients more likely to be neoplastic than in older patients
Nodules in males more likely to be neoplastic than those in females
Nodules that do not take up radioactive iodine (cold nodules) more commonly neoplastic than ‘hot’ nodules
Ultimately it is the morphology that provides the answer
Fine needle aspiration cytology
Histology
833
Histopathology - Endocrine Pathology
2 most common types of thyroid carcinomas
```
<1% of cancer deaths
Most cases in adults
Papillary (75-85%)
Follicular (10-20%)
Medullary (5%)
Anaplastic (<5%)
```
834
Histopathology - Endocrine Pathology
What nuclear features suggest papillary carcinomas?
```
May occur at any age
May have papillary architecture
BUT diagnosis is based on nuclear features
Optically clear nuclei
Intranuclear inclusions
May be psammoma bodies
```
835
Histopathology - Endocrine Pathology
Optically clear nuclei
Intranuclear inclusions
May be psammoma bodies
Papillary carcinomas
836
Histopathology - Endocrine Pathology
Presentation of papillary carcinomas
Nonfunctional
Present as painless mass in neck
May present with metastasis in cervical lymph node
10 year survival up to 90%
837
Histopathology - Endocrine Pathology
Where do follicular carcinomas tend to metastasise?
Peak incidence in middle age
Follicular morphology
May be well demarcated with minimal invasion or clearly infiltrative
Usually metastasise via bloodstream to lungs bone and liver
838
Histopathology - Endocrine Pathology
Neuroendocrine neoplasm derived from parafollicular C cells
80% sporadic - adults 5-6th decade
20% familial - MEN - younger patients
Medullary carcinoma
839
Histopathology - Endocrine Pathology
Occur in elderly patients
Very aggressive
Metastases common
Most cases death within one year due to local invasion
Anaplastic carcinoma
840
Histopathology - Endocrine Pathology
Effects of PTH
PTH
Activates osteoclasts
Increases renal tubular reabsorption of calcium
Increases conversion of vitamin D to its active form
Increases urinary phosphate excretion
Increases intestinal calcium absorption
841
Histopathology - Endocrine Pathology
Main causes of hyperparathyroidism
80-90% - solitary adenoma
10-20% hyperplasia of all 4 glands
Sporadic or component of MEN type 1
<1% carcinoma
842
Histopathology - Endocrine Pathology
Sx of primary hyperparathyroidism?
Bone resorption with thinning of cortex and cyst formation - osteitis fibrosa cystica - may lead to fractures
Renal stones and obstructive uropathy
GI disturbances - constipation, pancreatitis and gallstones
CNS alterations - depression, lethargy and fits
Neuromuscular abnormalities - weakness
Polyuria and polydipsia
843
Histopathology - Endocrine Pathology
How is secondary hyperparathyroidism caused?
Caused by any condition associated with chronic depression of serum calcium
Renal failure is by far the most common cause
Parathyroid glands are enlarged - may be asymmetrical
Leads to bone changes as with primary disease
844
Histopathology - Endocrine Pathology
Sx of hypoparathyroidism?
```
Clinical manifestations
Neuromuscular irritability - tingling, muscle spasms, tetany
Cardiac arrhythmias
Fits
Cataracts
```
845
Histopathology - Endocrine Pathology
Causes of Hypoparathyroidism
Surgical ablation
Congenital absence
Autoimmune
846
Histopathology - Endocrine Pathology
Function of zona glomerulosa?
Secretes aldosterone
847
Histopathology - Endocrine Pathology
Function of zona fasciculata?
Secretes glucocorticoids
848
Histopathology - Endocrine Pathology
Function of zona reticularis?
secretes androgens and glucocorticoids
849
Histopathology - Endocrine Pathology
Function of medulla
Medulla – secretes noradrenaline and adrenaline
850
Histopathology - Endocrine Pathology
Sx of cushings syndrome
```
Hypertension and weight gain
Truncal obesity
‘moon’ facies
‘buffalo hump’
Cutaneous striae
```
851
Histopathology - Endocrine Pathology
Most common cause of cushings disease?
>50% due to primary hypothalamic-pituitary disease with increased ACTH – Cushing’s disease
Most associated with ACTH-producing adenoma in the pituitary
Some have hyperplasia of ACTH secreting cells in pituitary
Adrenal glands show nodular cortical hyperplasia
852
Histopathology - Endocrine Pathology
What percentage of cushings disease is adrenal?
30% of cases – primary adrenal
Most cases are due to a solitary neoplasm
Adenoma
Carcinoma
Less commonly due to bilateral hyperplasia
853
Histopathology - Endocrine Pathology
Which type of carcinoma can cause a cushings syndrome?
Remaining cases due to secretion of ectopic ACTH by non-endocrine tumours
Most commonly small cell carcinoma of the lung
Adrenals show bilateral hyperplasia
854
Histopathology - Endocrine Pathology
Causes of hyperaldosteronism
35 % aldosterone secreting adenoma – Conn’s syndrome
60 % bilateral adrenal hyperplasia
Clinical manifestations are hypertension and hypokalaemia
Accounts for <1% of causes of hypertension but important to recognise as surgically correctable
855
Histopathology - Endocrine Pathology
Group of autosomal recessive disorders
Hereditary defects in enzymes involved in cortisol biosynthesis
Decreased cortisol results in increased ACTH, adrenal stimulation and increased androgen synthesis
May present in childhood or less commonly in adults
Congenital adrenal hyperplasias
856
Histopathology - Endocrine Pathology
Secondary causes of adrenal insufficiency
Secondary to reduced ACTH
Non-functional pituitary adenomas
Other lesions of pituitary or hypothalamus including infarction
857
Histopathology - Endocrine Pathology
Acute causes of adrenal insufficiency
Acute
Sudden withdrawal of corticosteroid therapy
Haemorrhage (neonates)
Sepsis with DIC (Waterhouse-Friderichson syndrome)
Chronic (Addison’s disease)
Autoimmune (75-90%)
TB
HIV
Metastatic tumour (lung and breast particularly)
Rarely amyloid, fungal infections, haemochromatosis, sarcoidosis
858
Histopathology - Endocrine Pathology
Chronic causes of adrenal insufficiency
Acute
Sudden withdrawal of corticosteroid therapy
Haemorrhage (neonates)
Sepsis with DIC (Waterhouse-Friderichson syndrome)
Chronic (Addison’s disease)
Autoimmune (75-90%)
TB
HIV
Metastatic tumour (lung and breast particularly)
Rarely amyloid, fungal infections, haemochromatosis, sarcoidosis
859
Histopathology - Endocrine Pathology
Antibody in addisons commonly
auto-antibodies against 21-hydroxylase
860
Histopathology - Endocrine Pathology
Secrete catecholamines and give rise to a surgically correctable form of hypertension
Rule of 10s
10% arise in association with a familial syndrome inc. MEN 2A and 2B, von Hippel-Lindau disease and Sturge-Weber syndrome
10% are bilateral
10% are malignant
In addition 10% of catecholamine-secreting tumours arise outside the adrenal (paragangliomas)
Phaeochromocytoma
861
Histopathology - Endocrine Pathology
What is the "rule of tens" with phaeochromocytomas
Secrete catecholamines and give rise to a surgically correctable form of hypertension
Rule of 10s
10% arise in association with a familial syndrome inc. MEN 2A and 2B, von Hippel-Lindau disease and Sturge-Weber syndrome
10% are bilateral
10% are malignant
In addition 10% of catecholamine-secreting tumours arise outside the adrenal (paragangliomas)
862
Histopathology - Immune-related Multisystem Disorders
Sx of SLE
```
Skin
Oral ulcers
Joints
Neurological
Serositis
Renal
Haemotogical
Immunological
```
863
Histopathology - Immune-related Multisystem Disorders
What sort of antibodies are present in SLE
ANA:
Anti-dsDNA
Anti-smith (against ribonucleoproteins)
Anti-histone (drug related e.g. hydralazine)
864
Histopathology - Immune-related Multisystem Disorders
What is seen on renal biopsy, in SLE?
Thickened pink glomerular capillary loops (‘wire loops’) due to immune complex deposition
=
Deposits of IgG and complement in the basement membrane
865
Histopathology - Immune-related Multisystem Disorders
What is seen on skin biopsy, in SLE?
Lymphocyte infiltration in the upper dermis; vacuolization of the basal layer of epidermis; RBCs extravasated into the upper dermis (which are the reasons for the rash)
866
Histopathology - Immune-related Multisystem Disorders
What are Libman-sacks, seen in SLE
Strands of fibrin, neutrophils, lymphocytes, histiocytes
867
Histopathology - Immune-related Multisystem Disorders
What are the antibodies found in diffuse scleroderma/systemic sclerosis?
```
Diffuse form: Antibodies to DNA topoisomerase (Scl70)
Limited form: Anticentromere antibody
Calcinosis
Raynauds
Esophageal dysmotility
Sclerodactyly
Telagiectasia
```
868
Histopathology - Immune-related Multisystem Disorders
What are the antibodies found in limited scleroderma/systemic sclerosis?
```
Diffuse form: Antibodies to DNA topoisomerase (Scl70)
Limited form: Anticentromere antibody
Calcinosis
Raynauds
Esophageal dysmotility
Sclerodactyly
Telagiectasia
```
869
Histopathology - Immune-related Multisystem Disorders
What are the Sx of limited scleroderma / Syst sclerosis
```
Limited form: Anticentromere antibody
Calcinosis
Raynauds
Esophageal dysmotility
Sclerodactyly
Telagiectasia
```
870
Histopathology - Immune-related Multisystem Disorders
What is seen on skin biopsy in scleroderma?
‘Onion skin’ intimal thickening of small arteries
871
Histopathology - Immune-related Multisystem Disorders
Gottron’s papules
Dermatomyositis
872
Histopathology - Immune-related Multisystem Disorders
Sx of sarcoid?
Skin: Lupus pernio, erythema nodosum
CNS: Meningitis, cranial nerve lesions
Eyes: Uveitis, keratoconjunctivitis
Parotids: Bilateral enlargement
Lungs: BHL, fibrosis, lymphocytosis (CD4+ in BAL)
Liver: Hepatitis, cholestasis & cirrhosis
873
Histopathology - Immune-related Multisystem Disorders
What is seen on skin biopsy of sarcoid?
Non-necrotizing granulomas: histiocytes (epithelioid cells), multinucleated giant cells of Langhans (peripheral nuclei) and lymphocytes.
874
Histopathology - Immune-related Multisystem Disorders
What changes are seen chem-path-wise in sarcoid?
Hypergammaglobulinaemia
Raised ACE
Hypercalcaemia
Vit D hydroxylation by activated macrophages
875
Histopathology - Immune-related Multisystem Disorders
What is seen on small artery biopsy with temporal arteritis?
Chronic lymphocytic inflammation in the media, giant cells, narrowing of the lumen
876
Histopathology - Immune-related Multisystem Disorders
```
Fever
Erythema of palms & soles, desquamation
Conjunctivitis
Lymphadenopathy
Coronary arteries may be affected (MI)
otherwise disease is self limiting
```
Kawasaki’s disease
877
Histopathology - Immune-related Multisystem Disorders
```
Necrotising arteritis
Polymorphs, lymphocytes, eosinophils
Arteritis is focal and sharply demarcated
Heals by fibrosis
More often renal and mesenteric arteries
```
Nodular appearance on angiography (small aneurysms)
Polyarteritis Nodosa
878
Histopathology - Immune-related Multisystem Disorders
What antibody is seen in Granulomatosis with polyangiitis?
C-ANCA (cytoplasmic ANCA) directed against proteinase 3
879
Histopathology - Immune-related Multisystem Disorders
Churg-Strauss
(Eosinophilic Granulomatosis with polyangiitis) antbiody
P-ANCA (perinuclear ANCA) directed against myeloperoxidase
880
Histopathology - Immune-related Multisystem Disorders
Which antibodies are seen in charge-strauss and Granulomatosis with polyangiitis?
Churg: P-ANCA (perinuclear ANCA) directed against myeloperoxidase
Granulomatosis with polyangiitis - C-ANCA (cytoplasmic ANCA) directed against proteinase 3
881
Histopathology - Gynaecological Pathology
What infections of the female genital tract cause discomfort but no serious complications?
Candida: Diabetes mellitus, oral contraceptives and pregnancy enhance development of infection
Tichomonas vaginalis: protozoan
Gardenerella: gram negative bacillus causes vaginitis
882
Histopathology - Gynaecological Pathology
What infections of the female genital tract have serious complications?
```
Have serious complications:
Chlamydia: major cause of infertility
Gonorrhoea: major cause of infertility
Mycoplasma: causes spontaneous abortion and chorioamnionitis
HPV: implicated in cancer
```
883
Histopathology - Gynaecological Pathology
What bacteria cause Pelvic inflammatory disease (PID)?
Gonococci, chlamydia, enteric bacteria
usually starts from the lower genital tract and spreads upward via mucosal surface
Staph, stept, coliform bacteria and clostridium perfringens
secondary to abortion
usually start from the uterus and spread by lymphatics and blood vessels upwards
deep tissue layer involvement
884
Histopathology - Gynaecological Pathology
Complications of PID
Peritonitis
Intestinal obstruction due to adhesions
Bacteremia
Infertility
885
Histopathology - Gynaecological Pathology
What is salpingitis?
What are the complications?
```
Usually direct ascent from the vagina
Depending on severity and treatment may result in:
Resolution
Complications:
Plical fusion
Adhesions to ovary
Tubo-ovarian abscess
Peritonitis
Hydrosalpinx
Infertility
Ectopic pregnancy
```
886
Histopathology - Gynaecological Pathology
Types of ectopic pregnancy?
Tubal >95%
Ovarian
Peritoneal
887
Histopathology - Gynaecological Pathology
2nd most common cancer affecting women worldwide
Cervical cancer
888
Histopathology - Gynaecological Pathology
Median age of cervical cancer?
45-50
RFs:
```
Human Papilloma Virus -present in 95%
Many sexual partners
Sexually active early
Smoking
Immunosuppressive disorders
```
889
Histopathology - Gynaecological Pathology
Risk factors for cervical cancer
```
Human Papilloma Virus -present in 95%
Many sexual partners
Sexually active early
Smoking
Immunosuppressive disorders
```
890
Histopathology - Gynaecological Pathology
Most common low risk HPV subtypes
Most common types: 6, 11
891
Histopathology - Gynaecological Pathology
Epithelial cells have undergone some phenotypic and genetic changes which are premalignant and preinvasive
Basal membrane immediately deep to the surface epithelium is intact
Cervical intraepithelial neoplasia(CIN)
892
Histopathology - Gynaecological Pathology
Name the two types of cervical carcinoma
Squamous cell carcinoma
| Adenocarcinoma (20% of all invasive cases)
893
Histopathology - Gynaecological Pathology
How does HPV transform cells?
Two proteins E6 and E7 encoded by the virus have transforming genes.
E6 and E7 bind to and inactivate two tumour suppressor genes:
Retinoblastoma gene (Rb) (E7)
P53 (E6)
Both effects interfere with apoptosis and increase unscheduled cellular proliferation both of which contribute to oncogenesis.
Infection is either latent or productive.
894
Histopathology - Gynaecological Pathology
Which two proteins on HPV have transforming capabilities?
E6 + E7
895
Histopathology - Gynaecological Pathology
Which two tumour suppressor genes are inactivated by HPV in cervical cancer
Two proteins E6 and E7 encoded by the virus have transforming genes.
E6 and E7 bind to and inactivate two tumour suppressor genes:
Retinoblastoma gene (Rb) (E7)
P53 (E6)
Both effects interfere with apoptosis and increase unscheduled cellular proliferation both of which contribute to oncogenesis.
Infection is either latent or productive.
896
Histopathology - Gynaecological Pathology
What is non productive or latent infection?
HPV DNA continues to reside in the basal cells
Infectious virions are not produced
Replication of viral DNA is coupled to replication of the epithelial cells occurring in concert with replication of the host DNA
Complete viral particles are not produced
The cellular effects of HPV infection are not seen
Infection can only be identified by molecular methods
897
Histopathology - Gynaecological Pathology
At what age does the cervical screening programme commence?
25
3 yrly up to age 50 -> becomes 5 yrly
898
Histopathology - Gynaecological Pathology
Can >65yos be screened for cervical cancer?
Only screen those who have not been screened since age 50 or have had recent abnormal tests
899
Histopathology - Gynaecological Pathology
A nucleic acid solution hybridization assay with signal amplification that uses long synthetic RNA probes complementary to the DNA sequence of:
5 low-risk HPV types ( types 6, 11, 42, 43 and 44)
13 high risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68).
Hybrid Capture II (HC2) HPV DNA Test
900
Histopathology - Gynaecological Pathology
What 2 HPV vaccines exist?
Quadrivalent 6/11/16/18
| Bivalent - 16/18
901
Histopathology - Gynaecological Pathology
```
Smooth muscle tumour of myometrium
Commonest uterine tumour
20% of women >35yrs
Lay term is fibroid
Usually multiple
May be intramural, submucosal or
subserosal
```
Leiomyoma
902
Histopathology - Gynaecological Pathology
What is a leiomyosarcoma?
```
Malignant counterpart of leiomyoma - rare
Usually solitary
Usually postmenopausal
5yr survival 20-30%
Local invasion and blood stream spread
```
903
Histopathology - Gynaecological Pathology
Causes/stimulants of endometrial hyperplasia?
```
State: Persistent Estrogen,
Perimenopausal
Persistent anovulation
Polycystic ovary (PCO)
Granulosa cell tumours ovary
Estrogen therapy (alone)
```
904
Histopathology - Gynaecological Pathology
Most common gynaecological malignancy in developed countries, causing 6% of new cancer cases in women.
Endometrial carcinoma
905
Histopathology - Gynaecological Pathology
RFs for endometrial carcinoma
```
Risk factors:
Nulliparity
Obesity
Diabetes mellitus
Excessive oestrogen stimulation
```
906
Histopathology - Gynaecological Pathology
What are the two types of endometrial carcinoma?
Type I: 80-85%
Endometrioid, mucinous and secretory adenocarcinomas
Younger age
Are oestrogen dependent
Often associated with atypical endometrial hyperplasia
Low grade tumours, superficially invasive
Type II: 10-15%
```
Serous and clear cell carcinomas
Older, postmenopausal
Less oestrogen dependent
Arise in atrophic endometrium
High grade, deeper invasion, higher stage
```
907
Histopathology - Gynaecological Pathology
Which type of endometrial carcinoma is more prevalent?
Type I: 80-85%
Endometrioid, mucinous and secretory adenocarcinomas
Younger age
Are oestrogen dependent
Often associated with atypical endometrial hyperplasia
Low grade tumours, superficially invasive
Type II: 10-15%
```
Serous and clear cell carcinomas
Older, postmenopausal
Less oestrogen dependent
Arise in atrophic endometrium
High grade, deeper invasion, higher stage
```
908
Histopathology - Gynaecological Pathology
Which type of endometrial carcinoma is oestrogen dependent?
Type I: 80-85%
Endometrioid, mucinous and secretory adenocarcinomas
Younger age
Are oestrogen dependent
Often associated with atypical endometrial hyperplasia
Low grade tumours, superficially invasive
Type II: 10-15%
```
Serous and clear cell carcinomas
Older, postmenopausal
Less oestrogen dependent
Arise in atrophic endometrium
High grade, deeper invasion, higher stage
```
909
Histopathology - Gynaecological Pathology
Which type of endometrial carcinoma affects younger patients?
Type I: 80-85%
Endometrioid, mucinous and secretory adenocarcinomas
Younger age
Are oestrogen dependent
Often associated with atypical endometrial hyperplasia
Low grade tumours, superficially invasive
Type II: 10-15%
```
Serous and clear cell carcinomas
Older, postmenopausal
Less oestrogen dependent
Arise in atrophic endometrium
High grade, deeper invasion, higher stage
```
910
Histopathology - Gynaecological Pathology
Which gene mutations are implicated in type 1 endometrial carcinomas?
PTEN (10q23; 37-61%)
PI3KCA (39%) (mainly codons 9 and 20)
K-ras (10-30%)
CTNNB1 (14%-44%)
FGFR2 (16%)
P53 (10%)
911
Histopathology - Gynaecological Pathology
Which gene mutations are implicated in type 2 endometrial carcinomas?
Endometrial serous carcinoma
P53 mutations in 90%
PI3KCA mutations in 15% Her-2 amplification
Clear cell carcinoma
PTEN mutation
CTNNB1 mutation
Her-2 amplification
912
Histopathology - Gynaecological Pathology
What are the 4 stages for endometrial carcinoma?
Stage 1 – confined to uterus
Stage 2 – spread to cervix
Stage 3 – spread to adnexae, vagina, local lymph nodes (pelvic or para-aortic)
Stage 4 – other pelvic organs distant spread inc any other distant lymph node groups
913
Histopathology - Gynaecological Pathology
How are endometrial carcinomas graded?
1. Pattern: glands vs solid areas
| 2. Degree of cytological atypia
914
Histopathology - Gynaecological Pathology
```
A spectrum of tumours and tumour like conditions characterised by proliferation of of pregnancy associated trophoblastic tissue.
Includes:
Complete and partial mole
Invasive mole
Choriocarcinoma
```
Gestational trophoblastic disease
915
Histopathology - Gynaecological Pathology
How do most complete and partial moles present?
1 in 1000 pregnancies
Most present with spontaneous abortion
Curettage due to abnormal ultrasound
Excessive level of HCG hormone
None of partial and only 2.5% of complete moles progress to malignancy
10% of complete moles develop into invasive moles – locally destructive
Complete moles may persist or recur
Chromosomal abnormalities play an important role in development of moles.
916
Histopathology - Gynaecological Pathology
```
1 in 20,000 to 30,000 pregnancies
Rapidly invasive, widely metastasising (lung, vagina, brain, liver, kidney)
Responds well to chemotherapy
50% arise in moles
25% arise in previous abortion
22% arise in normal pregnancy
```
Choriocarcinoma
917
Histopathology - Gynaecological Pathology
Definition of endometriosis?
Presence of endometrial glands and stroma outside the uterus
Common – 10% of premenopausal women
Origin:
Metaplasia of pelvic peritoneum
Implantation of endometrium, retrograde menstruation
Ectopic endometrial tissue is functional and bleeds at time of menstruation -> pain, scarring and infertility
Can develop hyperplasia and malignancy
918
Histopathology - Gynaecological Pathology
Ectopic endometrial tissue deep within the myometrium
Cause of dysmenorrhoea
Adenomyosis
919
Histopathology - Gynaecological Pathology
Name two non neoplastic functional cysts:
Follicular and luteal cysts
| Endometriotic cyst
920
Histopathology - Gynaecological Pathology
Worldwide is the 6th most common cancer in women
2nd commonest female cancer causing death in women
More common in industrialised countries where parity is lower
Rate increases exponentially with age
Mean age 60yrs
4000 deaths/year in UK
Difficult to diagnosis at an early stage
Associated with nulliparity, early menarche, late menopause
Decreased risk after pregnancy, oral contraceptive use
1% cases have genetic basis
Ovarian cancer
921
Histopathology - Gynaecological Pathology
RFs for ovarian cancer?
The majority of women with ovarian cancer have no known risk factors
Most significant risk factor is genetic predisposition
Family history of ovarian and breast cancers
Infertility
Endometriosis
Hormone replacement therapy
Inflammation: Pelvic inflammation exposes the lining of the ovary to toxic mediators and makes cells quickly turnover. Both may be mutagenic.
922
Histopathology - Gynaecological Pathology
In what age groups do germ cell ovarian tumours typically occur?
Germ cell tumours have bimodal distribution; one peak 15-21 year olds and one peak at 65-69.
923
Histopathology - Gynaecological Pathology
Low grade, relatively indolent, arise from well characterised precursors (BOT) and endometriosis
Usually present as large stage I tumours
Mutations in K-ras, BRAF, PI3KCA and HER2, PTEN and beta–catenin
Usually have precursors
Include low grade serous, low grade endometrioid, mucinous and tentatively CCC.
Which type of ovarian tumour?
Type I ovarian tumours (20%)
924
Histopathology - Gynaecological Pathology
High grade mostly of serous type
Aggressive
More than 75% have p53 mutations
No precursor lesions
Which type of ovarian tumour?
Type II ovarian carcinoma
925
Histopathology - Gynaecological Pathology
Name benign tumours of the ovaries?
Serous Cystadenomas
Cystadenofibromas
Mucinous cystadenomas
Brenner tumour
926
Histopathology - Gynaecological Pathology
Most common type of benign ovarian tumour
Usually cystic – unilocular
30-50% are bilateral
Benign tumours are lined by bland epithelium
Borderline tumours - more complex atypical epithelial lining with papillae but no invasion (90% 5yr, 70% 15 yr survival)
Malignant tumours are invasive (15% 5yr survival)
Serous Cystadenomas
927
Histopathology - Gynaecological Pathology
Clear cell ovarian carcinoma is associated strongly with which other gynaecological condition?
Endometriosis
928
Histopathology - Gynaecological Pathology
Benign
Solid or cystic
May show many lines of differentiation but all mature adult type tissues
Teeth and hair very common
Mature teratoma (Dermoid)
929
Histopathology - Gynaecological Pathology
Secondary ovarian tumours
bilateral metastases composed of mucin producing signet ring cells
most often of gastric origin or breast
Krukenberg tumours:
930
Histopathology - Gynaecological Pathology
What tumour frequently metastasises to the ovaries?
Metastatic colorectal carcinoma:
Ovaries, an anatomic site prone to involvement by metastatic colorectal adenocarcinoma.
4-10% of CRC go to ovary
Ovarian lesions are identified prior to the primary tumor in 14-32% of cases
931
Histopathology - Gynaecological Pathology
What 3 familial syndromes, all transmitted in an autosomal dominant fashion, can cause hereditary ovarian cancer?
Up to 10% of epithelial ovarian cancer cases are familial
10% of women with ovarian carcinoma are carries of a breast/ovarian ca susceptibility gene
3 familial syndromes: All are transmitted in an autosomal dominant fashion:
familial breast-ovarian cancer syndrome
site-specific ovarian cancer
cancer family syndrome (Lynch type II)
____________________
Familial breast-ovarian cancer and site-specific ovarian cancer syndromes both associated with mutations of the BRCA1 suppressor gene; account for 90% of familial ovarian cancers
Hereditary ovarian cancer occurs at a younger age than sporadic
Carriers have 15 fold increase risk of ovarian carcinoma to non-carriers Multiple cases of early onset breast cancer
932
Histopathology - Cardiovascular Disease
Most common cause of death in males <75
Coronary heart disease
933
Histopathology - Cardiovascular Disease
Define atherosclerosis
An arteriosclerosis characterized by atheromatous deposits in and fibrosis of the inner layer of the arteries
934
Histopathology - Cardiovascular Disease
Stage 1/3 atherosclerosis?
1. Smooth damaged endothelium
2. Platelet adhesion, deposits of cholesterol, proliferation of the endothelium, fibrous cap formation
3. Plaque enlarges, blocking artery, fatty core
935
Histopathology - Cardiovascular Disease
Stage 2/3 atherosclerosis?
1. Smooth damaged endothelium
2. Platelet adhesion, deposits of cholesterol, proliferation of the endothelium, fibrous cap formation
3. Plaque enlarges, blocking artery, fatty core
936
Histopathology - Cardiovascular Disease
Stage 3/3 atherosclerosis?
1. Smooth damaged endothelium
2. Platelet adhesion, deposits of cholesterol, proliferation of the endothelium, fibrous cap formation
3. Plaque enlarges, blocking artery, fatty core
937
Histopathology - Cardiovascular Disease
Cardiovascular RFs
```
Age
Gender
Genetics
Hyperlipidaemia
Hypertension
Smoking
Diabetes Mellitus
```
938
Histopathology - Cardiovascular Disease
CV RFs have a MULTIPLICATIVE EFFECT
T/F
T
Risk factors have a MULTIPLICATIVE EFFECT
2 risk factors increase the risk fourfold
3 risk factors increase the risk sevenfold
939
Histopathology - Cardiovascular Disease
What effect does menopause have on CV risk?
Premenopausal women protected (HRT no protection)
| Postmenopausal risk increases (older ages greater than men)
940
Histopathology - Cardiovascular Disease
What is the most significant independent cardiovascular RF?
Genetics
```
Family history most significant independent risk factor
Some mendelian disorders (eg Familial Hypercholesterolaemia)
Most multifactorial (genetic polymorphisms -> clustered risk factors HT, DM)
```
941
Histopathology - Cardiovascular Disease
What do statins inhibit?
LDL – bad HDL – good
Diet rich in cholesterol/saturated fat – bad
Statins inhibit HMG-CoA reductase rate limiting enzyme in liver cholesterol synthesis - good
942
Histopathology - Cardiovascular Disease
Hypertension increases the risk of IHD by
Hypertension (Ht)
Systolic & Diastolic important
Ht alone increases risk of IHD by 60%
943
Histopathology - Cardiovascular Disease
DM increases risk of IHD by how much?
Diabetes mellitus (Dm)
Induces hypercholestrolaemia
Increases risk of atherosclerosis
2 x risk IHD in DM if all other factors equal
944
Histopathology - Cardiovascular Disease
Do you have to have CV RFs to suffer from CV events?
NEY
20% cardiovascular events occur in absence of Ht, Hyperlipidaemia,smoking, Dm
75% events in healthy women occur with LDL below risk level
Other risk factors must be involved
945
Histopathology - Cardiovascular Disease
What other [aside from specific CV RFS] increase risk of IHD?
```
Inflammation
Hyperhomocyteinaemia
Metabolic syndrome
Lipoprotein (a)
Haemostasis (procoagulation)
Lack of exercise
Stress
Obesity (Ht, Dm, low HDL)
```
946
Histopathology - Cardiovascular Disease
What is the "fatty streak" and by what age can this been seen?
```
Earliest lesion
Lipid filled foamy macrophages
No flow disturbance
In virtually all children >10yrs
Relationship to plaques uncertain
Same sites as plaques
```
947
Histopathology - Cardiovascular Disease
At what percentage occlusion does critical stenosis occur?
Stenosis
```
Critical stenosis – demand > supply
Occurs at ~70% occlusion
(or diameter <1mm)
Causes “stable” angina
Can lead to Chronic Ischaemic Heart Disease
Acute plaque rupture can occur
```
948
Histopathology - Cardiovascular Disease
| What is a "vulnerable plaque"?
Lots foam cells or extracellular lipid
Thin fibrous cap
Few smooth muscle cells
Clusters inflammatory cells
Adrenalin increases blood pressure & causes vasoconstriction
Increases physical stress on plaque
Hence emotional stress increases risk of sudden death
Circadian periodicity to sudden death (6am-noon)
949
Histopathology - Cardiovascular Disease
IHD presentation? IE what diseases/syndromes does IHD encompass
Angina pectoris
Myocardial infarction
Chronic IHD with heart failure
Sudden cardiac death.
950
Histopathology - Cardiovascular Disease
IHD pathogenesis
Predominant cause is insufficient coronary perfusion relative to myocardial demand due to chronic progressive atherosclerotic narrowing of epicardial coronary arteries and variable degrees of superimposed plaque change, thrombosis and vasospasm
951
Histopathology - Cardiovascular Disease
What percentage of stenosis is generally needed to precipitate symptoms on exercise?
>90% have atherosclerosis of 1 or more epicardial coronary arteries
75% stenosis or more generally needed to cause symptoms precipitated by exercise
Vasodilation cannot compensate above this level of stenosis
90% stenosis can lead to pain at rest
952
Histopathology - Cardiovascular Disease
In which arteries to do plaques typically arise?
Plaques mainly in first few cm of LAD or LCX
| Entire length RCA
953
Histopathology - Cardiovascular Disease
Transient ischaemia not producing myocyte necrosis
Stable, Prinzmetal,Unstable
Stable comes on with exertion, relieved by rest, no plaque disruption
Prinzmetal Uncommon, due to artery spasm
Angina Pectoris
954
Histopathology - Cardiovascular Disease
```
Unstable more frequent, longer, onset with less exertion or at rest
Disruption of plaque
Superimposed thrombus
Possible embolisation or vasospasm
Warning of impending infarction
```
Angina Pectoris(unstable)
955
Histopathology - Cardiovascular Disease
Death of cardiac muscle due to prolonged ischaemia
Incidence 5/1000 per year UK (ST elevation)
1.5 million MIs per year USA
10% less than 40yrs
45% less than 65yrs
Blacks & whites equal
Men greater risk than women throughout life
IHD most common cause death postmenopausal women
Myocardial Infarction(MI)
956
Histopathology - Cardiovascular Disease
Describe the gross morphology seen in an MI at:
1-18hr
```
1-18 - none
24h - Pale, Oedema + inflammation
3-4days - Haemorrhage - Necrosis, granulation
1-3w - Thin/yellow - Granuation tissue
3-6w - Tough white - Dense fibrosis
```
Under 6 hours – normal by histology (CK-MB also normal)
6–24 hrs loss of nuclei, homogenous cytoplasm necrotic cell death
1-4 days – infiltration of polymorphs then macrophages (clear up debris)
5-10 days removal of debris
1-2 weeks granulation tissue, new blood vessels, myofibroblasts, collagen synthesis
Weeks-months strengthening, decellularising scar
957
Histopathology - Cardiovascular Disease
Describe the gross morphology seen in an MI at:
24hr
```
1-18 - none
24h - Pale, Oedema + inflammation
3-4days - Haemorrhage - Necrosis, granulation
1-3w - Thin/yellow - Granuation tissue
3-6w - Tough white - Dense fibrosis
```
Under 6 hours – normal by histology (CK-MB also normal)
6–24 hrs loss of nuclei, homogenous cytoplasm necrotic cell death
1-4 days – infiltration of polymorphs then macrophages (clear up debris)
5-10 days removal of debris
1-2 weeks granulation tissue, new blood vessels, myofibroblasts, collagen synthesis
Weeks-months strengthening, decellularising scar
958
Histopathology - Cardiovascular Disease
Describe the gross morphology seen in an MI at:
3-4days
```
1-18 - none
24h - Pale, Oedema + inflammation
3-4days - Haemorrhage - Necrosis, granulation
1-3w - Thin/yellow - Granuation tissue
3-6w - Tough white - Dense fibrosis
```
Under 6 hours – normal by histology (CK-MB also normal)
6–24 hrs loss of nuclei, homogenous cytoplasm necrotic cell death
1-4 days – infiltration of polymorphs then macrophages (clear up debris)
5-10 days removal of debris
1-2 weeks granulation tissue, new blood vessels, myofibroblasts, collagen synthesis
Weeks-months strengthening, decellularising scar
959
Histopathology - Cardiovascular Disease
Describe the gross morphology seen in an MI at:
1-3weeks
```
1-18 - none
24h - Pale, Oedema + inflammation
3-4days - Haemorrhage - Necrosis, granulation
1-3w - Thin/yellow - Granuation tissue
3-6w - Tough white - Dense fibrosis
```
Under 6 hours – normal by histology (CK-MB also normal)
6–24 hrs loss of nuclei, homogenous cytoplasm necrotic cell death
1-4 days – infiltration of polymorphs then macrophages (clear up debris)
5-10 days removal of debris
1-2 weeks granulation tissue, new blood vessels, myofibroblasts, collagen synthesis
Weeks-months strengthening, decellularising scar
960
Histopathology - Cardiovascular Disease
Describe the gross morphology seen in an MI at:
3-6 weeks
```
1-18 - none
24h - Pale, Oedema + inflammation
3-4days - Haemorrhage - Necrosis, granulation
1-3w - Thin/yellow - Granuation tissue
3-6w - Tough white - Dense fibrosis
```
Under 6 hours – normal by histology (CK-MB also normal)
6–24 hrs loss of nuclei, homogenous cytoplasm necrotic cell death
1-4 days – infiltration of polymorphs then macrophages (clear up debris)
5-10 days removal of debris
1-2 weeks granulation tissue, new blood vessels, myofibroblasts, collagen synthesis
Weeks-months strengthening, decellularising scar
961
Histopathology - Cardiovascular Disease
Describe the temporary sequence in cells infiltrating after an MI?
Neutrophils -> macrophages -> angioplasty -> fibroblasts and collagen
962
Histopathology - Cardiovascular Disease
What day post MI would you histologically see:
Coagulation necrosis, loss nuclei & striations, neutrophils +++
1-3 days
963
Histopathology - Cardiovascular Disease
What day post MI would you histologically see:
Granulation tissue, macrophages
10-14 days
964
Histopathology - Cardiovascular Disease
Briefly, what is "Reperfusion injury"
Clinical importance uncertain
Due to oxidative stress, Ca overload, inflammation
Arrhythmias common
Biochemical abnormalities last days -> weeks
Thought to cause “stunned myocardium” – reversible cardiac failure lasting several days
965
Histopathology - Cardiovascular Disease
List the complications of an MI?
Contractile dysfunction – 40% infarct-> cardiogenic shock with 70% mortality rate
Arrhythmia due to myocardial irritability & conduction disturbance
Myocardial rupture - free wall most common, septum less common, papillary muscle least common.
(At mean 4-5days, range 1-10 days)
Pericarditis (Dressler syndrome) 2nd or 3rd day
RV infarction
Infarct extension – new necrosis adjacent to old
Infarct expansion – necrotic muscle stretches ->mural thrombus
Mural thrombus
Ventricular aneurysm, late -> thrombus, heart failure, arrhythmia, do not rupture
Papillary muscle rupture
Chronic Ischaemic Heart Disease (Chronic IHD) = progressive late heart failure
966
Histopathology - Cardiovascular Disease
Total mortality MI in one year?
Total mortality = 30% in one year
| 3-4% mortality per year after first
967
Histopathology - Cardiovascular Disease
What is chronic IHD?
Progressive heart failure due to ischaemic myocardial damage
May not be prior infarction
Can arise with severe obstructive coronary artery disease
Enlarged heavy heart, hypertrophied, dilated LV
Atherosclerosis
Maybe mural thrombi
Fibrosis (microscopic)
968
Histopathology - Cardiovascular Disease
What is SCD / sudden cardiac death?
“Unexpected death from cardiac causes in individuals without symptomatic heart disease or early (1hr) after onset of symptoms”
Usually due to lethal arrhythmia
Usually on background of IHD (90%)
300,000 - 400,000 per annum in USA
Acute myocardial ischaemia is usual trigger
Usually causes electrical instability at sites distant from conduction system often near scars from old MIs
Other conditions also associated eg Aortic stenosis, mitral valve prolapse, pulmonary hypertension
Marked atherosclerosis (>75% stenosis) in one or more vessels usually >90%
10% non atherosclerotic cause
(long QT etc)
½ have plaque rupture.
25% have MI changes but conflicting data on role of MI
Felt to be ischaemia induced electrical instability
Some cases heritable
969
Histopathology - Cardiovascular Disease
List the causes of cardiac failure?
```
Causes
Ischaemic heart disease
Valve disease
Hypertension
Myocarditis
Cardiomyopathy
Left sided heart failure (Right)
```
970
Histopathology - Cardiovascular Disease
Complications of cardiac failure?
Sudden DeathArrhythmias Systemic emboliPulmonary oedema with superimposed infection
971
Histopathology - Cardiovascular Disease
Gross and microscopic pathology in HF?
Dilated heart, Scarring & thinning of the walls
Microscopy: fibrosis and replacement of ventricular myocardium,
972
Histopathology - Cardiovascular Disease
Cardiomyopathy put VERY simply is:
too ___
too ___
too ___
```
Too thin
Too thick
Too stiff
IE
Dilated cardiomyopathy
Hypertrophic cardiomyopathy
Restrictive cardiomyopathy
```
973
Histopathology - Cardiovascular Disease
What is dilated cardiomyopathy?
Progressive loss of myocytes
Dilated heart
Causes:
Idiopathic
Infective – viral myocarditis
Toxic: alcohol, chemotherapy (adriamycin, daunorubicin), cobalt, iron
Hormonal – hyper-, hypo- thyroid, diabetes, peri-partum (?)
Genetic – haemochromatosis, Fabry’s, McArdle’s
Immunological – myocarditis incl. Viral (hypersensitivity component)
974
Histopathology - Cardiovascular Disease
What are the causes of dilated cardiomyopathy?
Progressive loss of myocytes
Dilated heart
Causes:
Idiopathic
Infective – viral myocarditis
Toxic: alcohol, chemotherapy (adriamycin, daunorubicin), cobalt, iron
Hormonal – hyper-, hypo- thyroid, diabetes, peri-partum (?)
Genetic – haemochromatosis, Fabry’s, McArdle’s
Immunological – myocarditis incl. Viral (hypersensitivity component)
975
Histopathology - Cardiovascular Disease
What is hypertrophic cardiomyopathy?
What thickens, narrowing the left ventricular outflow tract?
Left ventricular hypertrophy
Familial in 50% (autosomal dominant, variable penetrance)
Beta-myosin heavy chain
Thickening of septum narrows left ventricular outflow tract
976
Histopathology - Cardiovascular Disease
What is restrictive cardiomyopathy? What causes it?
Impaired ventricular compliance
Idiopathic or secondary to myocardial disease eg amyloid, sarcoidosis
Normal size heart – big atria
977
Histopathology - Cardiovascular Disease
What valve does rheumatic heart disease typically affect?
Sequelae of earlier rheumatic fever
Predominantly left-sided valves (almost always mitral)
Mitral > Aortic > Tricuspid > Pulmonic
Mitral alone 48%, Mitral + aortic 42%
Thickening of valve leaflet, especially along lines of closure
Fusion of commissures
Thickening, shortening and fusion of chordae tendineae
978
Histopathology - Cardiovascular Disease
What is the pathogenesis of rheumatic valvular disease?
Sequelae of earlier rheumatic fever
Predominantly left-sided valves (almost always mitral)
Mitral > Aortic > Tricuspid > Pulmonic
Mitral alone 48%, Mitral + aortic 42%
Thickening of valve leaflet, especially along lines of closure
Fusion of commissures
Thickening, shortening and fusion of chordae tendineae
979
Histopathology - Cardiovascular Disease
```
Commonest cause aortic stenosis
70s or 80s
Calcium deposits outflow side cusp
Impairs opening
Orifice compromised
Outflow tract obstruction
```
Calcific aortic stenosis
980
Histopathology - Cardiovascular Disease
What are the causes of aortic regurgitation?
```
Causes
Rigidity - rheumatic, degenerative
Destruction - microbial endocarditis
Disease of aortic valve ring
dilatationvalve insufficient to cover increased area
Marfan's Syndrome
Dissecting aneurysm
Syphilitic aortitis
Ankylosing spondylitis
```
981
Histopathology - Cardiovascular Disease
What is the difference between a true aneurysm and a false one?
```
True - all layers wall
False – extravascular haematoma
Causes: Weak wall
Congenital eg Marfans
Atherosclerosis
Hypertension
```
982
Histopathology - Cardiovascular Disease
What are the causes of aneurysms?
```
True - all layers wall
False – extravascular haematoma
Causes: Weak wall
Congenital eg Marfans
Atherosclerosis
Hypertension
```
983
Microbiology - CNS infections
What are the four routes of entry for CNS infections?
Four routes of entry:
a) haematogenous spread
b) direct implantation
c) local extension
d) PNS into CNS
984
Microbiology - CNS infections
What species can cause myelitis?
Poliovirus
985
Microbiology - CNS infections
What can cause both CNS/PNS infections, with Sx of paralysis, rigidity or flaccidity?
Clostrodium botulinum+tetani
986
Microbiology - CNS infections
Main causative agents for encephalitis?
Rabies virus, arboviruses, Trypanosoma species
Prions Amoeba
987
Microbiology - CNS infections
Inflammatory process of
meninges and CSF
Meningitis
988
Microbiology - CNS infections
3 classifications of meningitis?
Acute, chronic, aseptic
989
Microbiology - CNS infections
Sx meningitis?
```
Vomiting
Fever
Headache
Neck stiffness
Light aversion
Drowsiness
Joint pain
Fitting
```
990
Microbiology - CNS infections
List the main pathogens causing acute meningitis?
```
Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae
Listeria monocytogenes
Group B Streptococcus
Escherichia coli
Mycobacterium tuberculosis
Staphylococcus aureus
Treponema pallidum
Cryptococcus neoformans
Candida
Coccidioides immitis,
Histoplasma capsulatum,
Blastomyces dermatitidis
```
991
Microbiology - CNS infections
Main meningitis infectious cause of childhood death?
N.meningitidis
Infectious cause of childhood death in all countries.
Transmission is person-to-person, from asymptomatic carriers.
Pathogenic strains are found in only 1% of carriers.
Through nasopharyngeal mucosa in a susceptible individual.
Cause infections in less than 10 days.
992
Microbiology - CNS infections
If a child doesn't have a non-blanching rash, does this rule out meningitis?
NO!!!
A nonblanching rash (petechial or purpuric) develops in 80% of children.
A maculopapular rash remains in 13% of children, and no rash occurs in 7%.
993
Microbiology - CNS infections
Is there any association between meningitis and septicaemia?
50% of cases have meningitis
7-10% have septicemia
40% have septicemia AND meningitis
The clinical difference between septicemia and meningitis is important.
WHY?
994
Microbiology - CNS infections
CT scan - enhancement in the basal cistern and
meninges, with dilatation
of the ventricles.
tuberculous meningitis
995
Microbiology - CNS infections
Incidence: 544 per 100,000 population in Africa.
More common in patients who are immunosuppressed.
Mortality was 5.5 deaths per 100,000 persons.
Involves the meninges and basal cisterns of the brain and spinal cord.
Can result in granulomas, abscesses, or cerebritis
Tuberculous Chronic Meningitis
996
Microbiology - CNS infections
Most common CNS infection?
Aseptic meningitis is the most common infection of the CNS.
Patients with aseptic meningitis have headache, stiff neck, and photophobia.
A nonspecific rash can accompany these symptoms.
Coxsackievirus group B and echoviruses are responsible for 80-90% cases in which a causative organism of aseptic meningitis is identified.
It most frequently occurs in children younger than 1 year.
The clinical course of aseptic meningitis is self-limited and resolves in 1-2 weeks.
997
Microbiology - CNS infections
Most common causative agents of aseptic meningitis?
Aseptic meningitis is the most common infection of the CNS.
Patients with aseptic meningitis have headache, stiff neck, and photophobia.
A nonspecific rash can accompany these symptoms.
Coxsackievirus group B and echoviruses are responsible for 80-90% cases in which a causative organism of aseptic meningitis is identified.
It most frequently occurs in children younger than 1 year.
The clinical course of aseptic meningitis is self-limited and resolves in 1-2 weeks.
998
Microbiology - CNS infections
Main cause bacterial encephalitis?
Listeria monocytogenes
999
Microbiology - CNS infections
An obligate intracellular protozoal parasite
Via the oral, transplacental route or organ transplantation.
Severe infection in immunocompromised
patients.
Affected organs include the gray and
white matter of the brain, retinas,
alveolar lining of the lungs, heart,
and skeletal muscle.
Toxoplasma gondii
AKA toxoplasmosis
1000
Microbiology - CNS infections
What infections can lead to brain abscess formation?
Arises post:
otitis media/mastoiditis/paranasal sinuses/endocarditis/haematogenously
1001
Microbiology - CNS infections
What species cause brain abscesses?
Streptococci (both aerobic and anaerobic)
Staphylococci,
Gram-negative organisms. (particularly in neonates)
Mycobacterium tuberculosis
fungi
parasites
Actinomyces and Nocardia species
1002
Microbiology - CNS infections
Most common spinal infection?
How does infection occur/spread?
Pyogenic vertebral osteomyelitis common form of vertebral infection.
Direct open spinal trauma, from infections in adjacent structures, from hematogenous spread of bacteria to a vertebra.
Left untreated, it can lead to permanent neurologic deficits, significant spinal deformity, or death.
1003
Microbiology - CNS infections
Spinal infection RFs?
```
Advanced age
Intravenous drug use
Long-term systemic steroids
Diabetes mellitus
Organ transplantation
Malnutrition
Cancer
```
1004
Microbiology - CNS infections
Describe appearance, protein levels, glucose levels when differentiating between purulent, aseptic and TB meningitis?
```
Condition
Appearance
Cells x 106/l
Gram stain or antigen tests
Protein g/l
Glucose mmol/l
Main differential diagnosis
Normal
Clear
0-5 leukocytes
Negative results
0.15-0.4
```
```
2.2-3.3, 60% blood glucose level
Purulent meningitis
Turbid
100-2000 polymorphs
Positive results
0.5-3.0
0-2.2
Bacterial meningitis,
? Meningococcus ? Pneumococcus
? Listeria
Aseptic meningitis
Clear or slightly turbid
15-500 lymphocytes
Negative results
0.5-1.0
Normal
Viral meningitis, partially antibiotic treated bacterial meningitis, encephalitis, brain abscess, TB/fungal meningitis
Tuberculous meningitis
Clear or slightly turbid
30-500 lymphocytes or some polymorphs
Negative results (scanty acid fast bacilli)
1.0-6.0
0-2.2
TB meningitis, brain abscess, Cryptococcal meningitis
```
1005
Microbiology - CNS infections
Generic meningitis therapy?
Ceftriaxone 2g iv bd
If >50yrs or immunocompromised add:
Amoxicillin 2g iv 4hourly
1006
Microbiology - CNS infections
Generic meningo-encephalitis therapy?
Aciclovir 10mg/kg iv tds
Ceftriaxone 2g iv bd
If >50yrs or immunocompromised add:
Amoxicillin 2g iv 4hourly
1007
Microbiology - GI infections
Common REPORTABLE GI infections
Reportable: Campylobacter, Salmonella, Shigella, E.Coli 0157, Listeria, Norovirus
1008
Microbiology - GI infections
GI infection + secretory diarrhoea
No fever or LOW GRADE fever, no WBCs in stool sample.
What organisms?
```
EHEC - haemorrhage
ETEC - toxi
EPEC - pathogenic
EAggEC
Vibrio cholerae
```
1009
Microbiology - GI infections
FEVER + WBC in stool (neutrophils)
aka "inflammatory diarrhoea"
What organisms?
Campylobacter jejune
Shigella
Non-typhoidal salmonella serotypes
EIEC - Enteroinvasive Escherichia coli
1010
Microbiology - GI infections
FEVER + WBC in stool (mononuclear cells)
aka "enteric fever"
What organisms?
Typhoidal salmonella phenotypes
Enteropathogenic yersinia
Brucella app
1011
Microbiology - GI infections
1-10 days incubation
2-20 duration
Poultry
What GI bacteria?
Campylobacter
1012
Microbiology - GI infections
1-5 days incubation
1-4 duration
HUS, verotoxin
What GI bacteria?
E.coli 0157
1013
Microbiology - GI infections
12-96hr incubation
5-7day duration
Small infective dose, outbreaks
What GI bacteria?
Shigella
1014
Microbiology - GI infections
8-48hr incubation
4-7 day duration
Rare cause systemic dx
Poultry + lizards
What GI bacteria?
Salmonella (non typhoidal)
1015
Microbiology - GI infections
24-72h incubation
2-10 day duration
Shellfish
What GI bacteria?
Vibrio parahaemolyticus
1016
Microbiology - GI infections
1-5 days incubation
Variable duration
Ricewater, endemic
What GI bacteria?
Vibrio cholera
1017
Microbiology - GI infections
1-6h incubation
<1 day duration
Heat stable emetic toxin (rice)
What GI bacteria?
Bacillus cereus
1018
Microbiology - GI infections
2-7h incubation
<1day duration
Preformed toxin
What GI bacteria?
Staph aureus
1019
Microbiology - GI infections
Briefly, how does cholera toxin cause a secretory diarrhoea?
Binds to epithelial cell membrane
Presents subunit A
Subunit A enters cell
Activates G protein -> GTPase activated -> adenylate cyclase activated
cAMP: opens Cl channel at the apical membrane of enterocytes
>> efflux of Cl to lumen; loss of H2O and electrolytes
1020
Microbiology - GI infections
What do super antigens bind to?
What do they cause release of?
Superantigens bind directly to
T-cell receptors and
MHC molecules;
outside the peptide binding site
>> massive cytokine production by CD4 cells ie systemic toxicity and suppression of adaptive response
1021
Microbiology - GI infections
1/3 population chronic carriers, 1/3 transient
Spread by skin lesions on food handlers
Catalase, coagulase positive Gram positive coccus
Appears in tetrads, clusters on Gram stain
Yellow colonies on blood agar
Which "food poisoning" bacteria?
Staphylococcus aureus : food poisoning
1022
Microbiology - GI infections
What does S.Aureus produce, causing prominent vomiting and watery, non bloody diarrhoea?
What cytokines are released as a result
Produces enterotoxin, an exotoxin that can act as a superantigen in the GI tract, releasing IL1 and IL2
1023
Microbiology - GI infections
Gram positive rods: spore forming
Spores germinate in reheated fried rice
Bacillus cereus : food poisoning
1024
Microbiology - GI infections
```
Gram positive rod-spores
Heat stable emetic toxin
-not destroyed by reheating
Heat labile diarrhoeal toxin
-food is not cooked to a high enough temperature
```
and
watery non bloody diarrhoea; self limited
Rare cause of bacteremia in vulnerable population
Can cause cerebral abscesses
Bacillus cereus
1025
Microbiology - GI infections
Source : canned or vacuum packed food (honey / infants)
Ingestion of preformed toxin (inactivated by cooking)
Blocks Ach release from peripheral nerve synapses
Treatment with antitoxin
Clostridium botulinum : botulism
1026
Microbiology - GI infections
Source : reheated food (meat)
Normal flora of colon but not small bowel, where the enterotoxin acts (superantigen)
Incubation 8-16hrs
Watery diarrhoea, cramps,little vomiting lasting 24hrs
Clostridium pefringens : food poisoning
1027
Microbiology - GI infections
3%, 30% of hospitalised patients
Antibiotic related colitis (any but.. mainly cephalosporins, cipro and clindamycin
Clostiridium difficile : Pseudomembranous colitis
1028
Microbiology - GI infections
Treatment of C.dif?
Infection control
Treatment : (PO) metronidazole, vancomycin, stop antibiotics where possible
1029
Microbiology - GI infections
Outbreaks of febrile gastroenteritis
ß haemolytic, aesculin positive with tumbling motility
Source : refrigerated food (“cold enhancement”),i.e. unpasteurised dairy, vegetables
Grows at 4 ºC GI watery diarrhoea, cramps, headache, fever, little vomiting
Perinatal infection, immunocompromised patients
Treatment : ampicillin
Listeria monocytogenes
1030
Microbiology - GI infections
Facultative anaerobes, glucose/lactose fermenters (LF),
oxidase negative
Enterobacteriacae
1031
Microbiology - GI infections
Traveller’s diarrhoea
Source: food/water contaminated with human faeces
Enterotoxins :
-Heat labile stimulates adenyl cyclase and cAMP
-Heat stable stimulates guanylate cyclase
-Act on the jejeunum, ileum not on colon
Escherichia coli
1032
Microbiology - GI infections
How does Escherichia coli cause watery diarrhoea?
Traveller’s diarrhoea
Source: food/water contaminated with human faeces
Enterotoxins :
-Heat labile stimulates adenyl cyclase and cAMP
-Heat stable stimulates guanylate cyclase
-Act on the jejeunum, ileum not on colon
1033
Microbiology - GI infections
Outbreaks of febrile gastroenteritis
ß haemolytic, aesculin positive with tumbling motility
Source : refrigerated food (“cold enhancement”),i.e. unpasteurised dairy, vegetables
Grows at 4 ºC GI watery diarrhoea, cramps, headache, fever, little vomiting
Perinatal infection, immunocompromised patients
Treatment : ampicillin
Listeria monocytogenes
1034
Microbiology - GI infections
Which class, out of ETEC, EPEC and EIEC causes travellers diarrhoea?
ETEC; toxigenic, main cause of traveller’s diarrhoea
1035
Microbiology - GI infections
Which class, out of ETEC, EPEC and EIEC causes infantile diarrhoea?
EPEC; pathogenic, infantile diarrhoea
1036
Microbiology - GI infections
Which class, out of ETEC, EPEC and EIEC causes dysentery?
EIEC; invasive, dysentery
1037
Microbiology - GI infections
Which class, out of ETEC, EPEC and EIEC causes haemorrhagic dysentery?
EHEC; haemorrhagic O157:H7 EHEC: shiga- like verocytotoxin causes HUS
1038
Microbiology - GI infections
Non lactose fermenters,
H2S producers,
TSI agar,
XLD agar,selenite F broth
Antigens:
- cell wall O (groups A-I)
- flagellar H
- capsular Vi (virulence, antiphagocytic)
Three species :
- S. typhi (and paratyphi) -S.enteritidis
- S.cholerasuis
Salmonella
1039
Microbiology - GI infections
Name the three species of salmonella?
Non lactose fermenters,
H2S producers,
TSI agar,
XLD agar,selenite F broth
Antigens:
- cell wall O (groups A-I)
- flagellar H
- capsular Vi (virulence, antiphagocytic)
Three species :
- S. typhi (and paratyphi) -S.enteritidis
- S.cholerasuis
1040
Microbiology - GI infections
Name the salmonellae antigens?
O H V
Non lactose fermenters,
H2S producers,
TSI agar,
XLD agar,selenite F broth
Antigens:
- cell wall O (groups A-I)
- flagellar H
- capsular Vi (virulence, antiphagocytic)
Three species :
- S. typhi (and paratyphi) -S.enteritidis
- S.cholerasuis
1041
Microbiology - GI infections
transmitted from poultry, eggs, meat
invasion of epi- and sub-epithelial, tissue of small and large bowel
bacteraemia infrequent
self limited non bloody diarrhoea ,usually no treatment
Stool positivity
Which salmonella?
S.enteritidis
AKA
Enterocolitis
1042
Microbiology - GI infections
```
Transmitted only by humans
multiplies in Payer’s patches,
spreads ERS
bacteraemia, 3% carriers
.
Slow onset, fever and constipation,
splenomegaly,rose spots,
anaemia, leucopaenia,
bradycardia, haemorrhage and
perforation
Blood culture positive
Treatment : ceftriaxone
```
Which salmonella?
S.typhi
AKA
Typhoid (enteric) fever
1043
Microbiology - GI infections
Non lactose fermenters, non H2S producers, non motile
Antigens:
-cell wall O antigens,
-polysaccharide (groups A-D) : S.sonnei, S.dysenteriae, S.flexneri (MSM)
The most effective enteric pathogen (low ID 50)
No animal reservoir
No carrier state
Dysentery
-invading cells of mucosa of distal ileum and colon
-producing enterotoxin (Shiga toxin)
Avoid antibiotics (ciprofloxacin if required)
Shigellae
1044
Microbiology - GI infections
O1 group: epidemics, biotypes El Tor, Cholerae and serotypes Ogawa, Inaba, Hikojima
Non O1 group: sporadic or non pathogens
Transmitted by contamination of water and food from human faeces ( shellfish, oysters, shrimp)
Colonisation of small bowel and secretion of enterotoxin with A and B subunit, causing persistent stimulation of adenylate cyclase
Causes massive diarrhoea (rice water stool) without inflammatory cells
Treat the losses
Vibrio cholerae
1045
Microbiology - GI infections
Curved, comma shaped, late lactose fermenters, oxidase positive.
Vibrio cholerae
1046
Microbiology - GI infections
- Ingestion of raw or undercooked seafood (ie oysters),
- major cause of diarrhoea in Japan..or when cruising in the Carribean.. ,
- self limited for 3 days
- cholerae : grows in salty 8.5% NaCl..
Which vibrio?
Vibrio parahaemolyticus
1047
Microbiology - GI infections
- cellulitis in shellfish handlers
- fatal septicaemia with D+V in HIV patients
Treat with doxycycline
Which vibrio?
Vibrio vulnificus
1048
Microbiology - GI infections
Curved, comma or S shaped
Microaerophilic
oxidase pos ,motile
Self limiting but symptoms can last for weeks (20 days)
Only treat if immunocompromised (macrolide)
Campylobacter
1049
Microbiology - GI infections
Transmitted via contaminated food and water with animal faeces ( poultry, meat,unpast. milk)
? Enterotoxin (watery diarrhoea) ? Invasion (+/- blood)
Watery, foul smelling diarrhoea, bloody stool, fever and severe abdo pain
Treat with erythromycin or cipro if in the first 4-5days
GBS syndrome, reactive arthritis, Reiter’s ..
Campylobacter
1050
Microbiology - GI infections
- Non lactose fermenter, prefers 4ºC “cold enrichment”
- Transmitted via food contaminated with domestic animals excreta
- enterocolitis
- mesenteric adenitis
- associated with reactive arthritis , Reiter’s
Yersinia enterocolitica
1051
Microbiology - GI infections
- will appear as Gram variable
- always think of TB
Mycobacteria (M.Tuberculosis, M.Avium Intracellulare)
1052
Microbiology - GI infections
motile trophozoite in diarrhoea
non motile cyst in nondiarrhoeal illness
Killed by boiling, removed by water filters
4 nuclei
No animal reservoir
What protozoa?
Entamoeba histolytica
1053
Microbiology - GI infections
Ingestion of cysts >> trophos in
ileum >> colonize cecum, colon >> “flask shaped” ulcer
-dysentery,flatulence,
tenesmus
-chronic : wt loss,+/- diarrhoea
-liver abscess
```
Diagnosis
-stool micro (wet
mount, iodine and trichrome )
-serology in invasive disease
Treat : metronidazole + paromomycin in luminal disease
```
Entamoeba histolytica
1054
Microbiology - GI infections
How is entamoeba histolytica diagnosed?
```
Diagnosis
-stool micro (wet
mount, iodine and trichrome )
-serology in invasive disease
Treat : metronidazole + paromomycin in luminal disease
```
1055
Microbiology - GI infections
How is entamoeba H Rx?
```
Diagnosis
-stool micro (wet
mount, iodine and trichrome )
-serology in invasive disease
Treat : metronidazole + paromomycin in luminal disease
```
1056
Microbiology - GI infections
trophozoite “pear shaped”
2 nuclei
4 flagellas and a suction disk
Ingestion of cyst from fecally contaminated water,food
```
Excystation at duodenum
tropho attaches
no invasion
malabsorption of protein and
fat
```
Travellers, hikers,
day care, mental hospitals,
MSM
foul smelling non
bloody diarrhoea, cramps
flatulence, no fever
Diagnosis : stool micro, ELISA, “string test”
Treatment :metronidazole
What protozoa?
Giardia lamblia
1057
Microbiology - GI infections
Rx giardia lamblia?
Metronidazole
1058
Microbiology - GI infections
Diagnosis of G Lamblia?
Diagnosis : stool micro, ELISA, “string test”
1059
Microbiology - GI infections
Infects the jejunum
Severe diarrhoea in the immunocomromised
Oocysts seen in stool by
modified Kinyoun acid fast stain
Treatment : reconstitution of immune system
What protozoa?
Cryptosporidium parvum
1060
Microbiology - GI infections
```
outbreaks
Low ID (18-1000 viral particles)
Environmental resilience (0-60 ºC)
No long term immunity
GII.4 currently predominant strain
```
What virus?
Norovirus
1061
Microbiology - GI infections
dsRNA “wheel like”
Replicates in mucosa of small intestine
Secretory diarrhoea, no inflammation
Watery diarrhoea ? by stimulation of enteric nervous system
By age 6 most children worldwide have antibodies to at least one type
Exposure to natural infection twice confers lifelong immunity
Huge economic burden worldwide
What virus?
Rotavirus
1062
Microbiology - GI infections
Types 40, 41 cause non bloody diarrhoea <2yrs of age
Any type in immunocompromised
Diagnosis : stool EM, antigen detection, PCR
What virus?
Adenovirus
1063
Microbiology - GI infections
What type of vaccine is the cholera vaccine?
```
Cholera : serogroups O1(Inaba , Ogawa, biotypes El Tor and classical), O139
Inactivated, whole cell, contains all above + B subunit of toxin (PO)
Live attenuated (PO) not recommended
```
1064
Microbiology - GI infections
What type of vaccine for S.typhi?
Vi capsular PS (IM) and (PO)live
1065
Microbiology - GI infections
What type of vaccines exist for rotavirus?
Rotarix : live attenuated human strain monovalent, 2(PO) doses
Rotateq : pentavalent, 3 (PO) doses, one bovine and four human strains
Rotashield and intussusception (8-20 weeks)
Age of vaccine is 6-12 weeks
1066
Microbiology - GI infections
Which GI infections are notifiable diseases?
Notifiable disease
Each trust to notify to local Health Protection Unit
Campylobacter, Clostridium sp, Listeria monocytogenes, Vibrio, Yersinia
Identify outbreaks in areas
Environmental Health Officers to inspect premises and take samples from environment and food
1067
Microbiology - HIV in African Children
How do most children contract HIV?
HIV in children:
| > 90% due to mother-to-child transmission
1068
Microbiology - HIV in African Children
List the clinical features of HIV infection in children?
```
Suppurative ear infection
Enlarged parotids
Enlarged LNs
Enlarged liver/spleen
Clubbing
Herpes zoster infection
Severe nappy rash
Recurrent/persistent diarrhoea
Easy bruising
Severe pneumonia, TB, pneumocystis Carinii, lymphoid interstitial pneumonitis
Failure to thrive
Oral thrush
Frequent nose bloeeds
Anaemia
Progressive encephalopathy
```
1069
Microbiology - HIV in African Children
How can HIV be transmitted perinatally?
In utero
Intrapartum
Breast feeding
1070
Microbiology - HIV in African Children
What is the MAJOR RF for maternal to child HIV transmission?
HIV Viral load
1071
Microbiology - HIV in African Children
Risk of MTCT increases by 2% for every hour post-rupture of membranes
T/F?
True
Meta-analysis of DROM (n > 4000):
Data for women with advanced HIV infection
Landesman et al, NEJM 1996;334;1620
1072
Microbiology - HIV in African Children
Risk from drinking 1 litre of breast milk is lower risk than from one episode of unprotected sex
True or false?
FALSE
Risk from drinking 1 litre of breast milk = risk from one episode of unprotected sex
1073
Microbiology - HIV in African Children
What is the percentage risk of HIV transmission for every 6months breast feeding?
4% transmission of HIV-1 for every 6 months of breast-feeding
1074
Microbiology - HIV in African Children
Best method to prevent transmission whilst breast feeding?
```
Intervention Tx rate
None 25 - 40%
Avoid B/F 12 - 25%
AZT mono Rx 6 - 8%
ELCS + AZT mono < 2%
Combo Rx (VL < 50) << 1%
```
1075
Microbiology - HIV in African Children
What is the WHO guidance regarding ARV for pregnant and BF women?
All pregnant and BF women should initiate triple ARVs
Fixed dose combination Tenofovir+3TC+efavirenz
BF infants should receive daily NVP for 6 weeks
Maintain ARVs for duration of MTCT risk
Maintain ARVs lifelong with those meeting Rx eligibility (CD4< 500) (strong recommendation)
Maintain ARVs lifelong in all for programmatic reasons (conditional recommendation)
Uninfected infants should exclusively BF for 6 months and continue to BF until atleast 12 months
1076
Microbiology - HIV in African Children
Name the classes of antiretroviral drugscurrently used for children in Africa?
Non-nucleoside reverse transcriptase inhibitors
Nucleoside analogues
Nucleotide analogues
Protease inhibitors
1077
Microbiology - HIV in African Children
Indications for Initiation of ART in Children <5 years of age
Regardless of clinical symptoms, immune status, or viral load
TREAT ASAP
1078
Microbiology - HIV in African Children
Name a 3in1 pill used to treat children with HIV?
Triomune Junior and babyd4T (6,12mg) 3TC (30, 60mg) NVP (50,100mg)
1079
Microbiology - Infection CPC
NA a 68yr old Scottish gentleman
```
Presented with
Shortness of breath and reduced exercise tolerance past few weeks
Productive cough with green sputum
Lethargy
Fever
```
```
PMHx
Congential deafness
Chronic Obstructive Lung disease
Alzheimers Dementia
Coronary Artery Disease
GORD
Alcohol excess
SHx
Heavy smoker and drinker
Lives with wife who also congenitally deaf
Daughter helps to care for both
```
On examination:
```
Afebrile
HR 96bpm, BP 130/70
Sats 92% air. 95% on 10 Litres
RR 28
Looked thin
HS normal
Some creps at bases
Abdo NAD
```
ABG on air
P02 6.7
pC02 4.6
pH/lactate norm
```
FBC
WCC 6.4
Hb 15.1
Plts 196
Lymph 1.4
CRP 191
```
```
LFTs
ALT 47
ALP 175
Bili 11
Ca 2.21
Alb 28
TP 78
Glob 50
Renal function norm
```
ECG - norm
Xray - bilateral upper lobe consolidation and bronchopulmonary windows
Whats the diagnosis?
What Rx would you give?
Diagnosed as Community Acquired Pneumonia
Infective exacerbation of COPD
Commenced on co-amoxiclav and clarithromycin
Patient had minimal response to antibiotics and remained hypoxic and tachypnoeic
CT chest performed due to suspicious lesion ?malignancy
1080
Microbiology - Infection CPC
What should be considered with minimal response to ABx in CAP?
Patient had minimal response to antibiotics and remained hypoxic and tachypnoeic
CT chest performed due to suspicious lesion ?malignancy
1081
Microbiology - Infection CPC
A patient is diagnosed with Community Acquired Pneumonia
Infective exacerbation of COPD
Commenced on co-amoxiclav and clarithromycin
Patient had minimal response to antibiotics and remained hypoxic and tachypnoeic
CT chest performed due to suspicious lesion ?malignancy
CT REPORT:
There is widespread patchy consolidation and groundglass opacity in both lungs which is predominantly upper and mid zone in distribution with relative sparing of the lung bases. Within some of these areas, the subsegmental airways are mildly prominent, particularly apices, raising the possibility of traction bronchiectasis.
Small volume hilar and mediastinal lymph nodes are likely reactive in nature
Appearances are most in keeping with atypical infection
What infection would you suspect?
Bronchoscopy performed
BAL samples showed 40 cysts of Pneumocystis jiroveci
Diagnosed as Pneumocystis Pneumonia
Commenced on co-trimoxazole 960mg BD
Day 2 of treatment developed widespread erythematous rash – co-trimoxazole stopped
Oral prednisolone commenced
1082
Microbiology - Infection CPC
What should be considered with PCP infection?
Subsequent HIV test reactive – positive confirmed on repeat testing
```
Changed to second line treatment for PCP
Clindamycin and Primiquine (G6PD norm)
IV methylprednisolone commenced
Further examination
Oral candidiasis – given fluconazole
Seborrhoeic Dermatitis
CD4 51, CD4% 7.9%. Viral Load 250000
```
1083
Microbiology - Infection CPC
What factors may suggest infections in the immunodeficient?
```
Infectious agents
Common infectious agents
Uncommon infectious agents
Atypical mycobacteria
Fungal
Viral
CMV
Herpes simplex
Other e.g. toxoplasmosis
Presentation
Speed of progression
```
1084
Microbiology - Infection CPC
Actinomyces lung abscesses are typically seen in what cohort of individuals?
Alcoholics
1085
Microbiology - Infection CPC
What is the stain for actinomycetes?
Grocott stain
1086
Microbiology - Infection CPC
Most important action in prosthetic joint infection?
Removal of prosthesis and adequate debridement most important.
Antibiotics play a secondary role.
In this case the organism was sensitive to antibiotics given for months but treatment failed without the development of resistance because of the presence of infected prosthetic material in the first instance and possibly inadequate debridement subsequently.
1087
Microbiology - Infection CPC
CK
75 year old woman
History of smoking, type 2 diabetes, previous TIA
Presented to Charing Cross with chronic leg ulcers which had become erythematous, painful and fevers
Commenced on i.v. vancomycin, i.v. cefuroxime and i.v metronidazole
Leg ulcer swab grew Pseudomonas aeruginosa
Antibiotics changed after 7 days to p.o. ciprofloxacin and p.o. metronidazole in light of culture results
Leg ulcers improved and fevers settled however, 3 days after commencing ciprofloxacin and metronidazole patient began having diarrhoea.
Faeces was sent for culture: Salmonella, Shigella, E. coli O157 and Campylobacter and for C. difficile toxin testing
C. difficile test positive
WHAT ARE THE NEXT ACTIONS?
WHAT IS THE RX FOR C.DIF?
C. difficile test positive
Next actions:
1) Isolate in a single room
2) Assess severity
3) Stop offending antibiotics if possible
4) Wash hands with soap and water before and after each patient contact and use gloves and aprons
5) Commence C. difficile care pathway, fluid balance chart and Bristol stool chart
Non-severe:
metronidazole 400mg PO TDS 10-14 days.
If intolerant of metronidazole, or if not responding to treatment at 72 hours (and no other indicators of severity), consider changing to: vancomycin 125mg PO QDS 10-14 days
Severe: vancomycin 125mg PO QDS 14 days plus consider adding metronidazole 500mg IV TDS.
Higher doses of vancomycin may be appropriate in more severely ill patients, and should be discussed with Micro/ID.
Severe + colonic dilatation: vancomycin 125mg-250mg PO QDS plus metronidazole 500mg IV TDS 14 days
and liaise with ID/Micro & Gastroenterologists/ Surgeons.
Severe + ileus/vomiting: consider intracolonic vancomycin – discuss with ID/Micro & Gastroenterologists/ Surgeons.
AKA THINK METRO + VANC
1088
Microbiology - Infection CPC
What is the Rx for Cdif?
Non-severe:
metronidazole 400mg PO TDS 10-14 days.
If intolerant of metronidazole, or if not responding to treatment at 72 hours (and no other indicators of severity), consider changing to: vancomycin 125mg PO QDS 10-14 days
Severe: vancomycin 125mg PO QDS 14 days plus consider adding metronidazole 500mg IV TDS.
Higher doses of vancomycin may be appropriate in more severely ill patients, and should be discussed with Micro/ID.
Severe + colonic dilatation: vancomycin 125mg-250mg PO QDS plus metronidazole 500mg IV TDS 14 days
and liaise with ID/Micro & Gastroenterologists/ Surgeons.
Severe + ileus/vomiting: consider intracolonic vancomycin – discuss with ID/Micro & Gastroenterologists/ Surgeons.
1089
Microbiology - Infection CPC
How is C.dif graded as severe?
C.difficile severity score:
Severe = 1 or more of the following:
* T>38.5ºC
* HR>90
* WCC>15
* Rising Creatinine
* Clinical signs of severe colitis, or colitis on radiology
* failure to respond to therapy at 72h
Patients with a score of 1 or more warrant early surgical and gastroenterology review
1090
Microbiology - Infection CPC
A patient has non-severe C.difficile associated diarrhoea:
```
Temp 37ºC
• HR 84 bpm regular
• WCC 6.0 x 109/l
• Creatinine 105 µmol/l and stable
• no clinical signs of severe colitis, or colitis on radiology
```
However lab phoned and stated patient had ribotype 027.
What would the Rx be?
Patient commenced on p.o. vancomycin 125mg QDs for 14 days as recommended by microbiology
Ribotype 027:
Increased severity of disease.
Samples sent to HPA Anaerobe Reference Laboratory.
Identified by PCR ribotyping as type 027.
Similar strains belonging to this ribotype responsible for outbreaks in Quebec and in six states of the USA.
```
This strain produces:
16 times more toxin A
23 times more toxin B
than control strains
(Warny et al. 2005 Lancet vol 366, 1079-1084)
```
```
In Quebec fluoroquinolones were found to be the class of antimicrobials most prone to induce C.diff. associated diarrhoea
(Pepin et al 2005 CID 41, 1254-1260).
```
1091
Microbiology - Infection CPC
How is C.dif spread?
C.diff is spread by the faecal oral route through spores.
Risk factors for C.diff. associated diarrhoea:
Administration of antibiotics (multiple antibiotics, long duration).
Age over 65 years.
Duration of hospital stay (it has been reported that after 4 weeks ½ patients tested were culture positive).
Severe underlying disease(s).
1092
Microbiology - Infection CPC
What are the RFs for C.dif?
C.diff is spread by the faecal oral route through spores.
Risk factors for C.diff. associated diarrhoea:
Administration of antibiotics (multiple antibiotics, long duration).
Age over 65 years.
Duration of hospital stay (it has been reported that after 4 weeks ½ patients tested were culture positive).
Severe underlying disease(s).
1093
Microbiology - Infection CPC
Almost always associated with a recent history of antibiotic use (also: cytotoxics (?antacids/ PPIs), non surgical gastrointestinal procedures eg NGs).
Disease may occur during antibiotic therapy or in the weeks after a course of antibiotics.
Onset is frequently abrupt with explosive, watery, foul smelling diarrhoea.
C. difficile
1094
Microbiology - Infection CPC
How can C.dif be prevented?
```
Prudent antibiotic prescribing
Hand Hygiene with soap and water
Enhanced environmental cleaning
Isolation of infected patients
Use of Personal protective equipment
```
1095
Microbiology - UTIs
What is an uncomplicated UTI?
Uncomplicated urinary tract infection refers to infection in a structurally and neurologically normal urinary tract.
1096
Microbiology - UTIs
What is a complicated UTI?
Complicated urinary tract infection refers to infection in a urinary tract with functional or structural abnormalities (including indwelling catheters and calculi).
1097
Microbiology - UTIs
Prevalence of bacteruria in non-pregnant women?
The prevalence of bacteriuria in young nonpregnant women is about 1% to 3%
1098
Microbiology - UTIs
What percentage of women get UTIs in their life?
Up to 40% to 50% of the female population will experience a symptomatic urinary tract infection at some time during their life.
1099
Microbiology - UTIs
More than 95% of urinary tract infections are caused by a single bacterial species
What is this species?
More than 95% of urinary tract infections are caused by a single bacterial species
E. coli is by far the most frequent infecting organism in acute infection
1100
Microbiology - UTIs
What other organisms, aside from E.Coli, cause UTIs?
```
Proteus mirabilis
Klebsiella aerogenes
Enterococcus faecalis
Staphylococcus saprophyticus
Staphylococcus epidermis
```
1101
Microbiology - UTIs
When do UTIs, caused by non-E.coli species, typically occur?
```
NON E.Coli species:
Proteus mirabilis
Klebsiella aerogenes
Enterococcus faecalis
Staphylococcus saprophyticus
Staphylococcus epidermis
```
In recurrent urinary tract infections, especially in the presence of structural abnormalities of the urinary tract, the relative frequency of infection caused by Proteus, Pseudomonas, Klebsiella, and Enterobacter species and by enterococci and staphylococci increases greatly
1102
Microbiology - UTIs
Name the Antibacterial Host Defences in the Urinary Tract
Urine (osmolality, pH, organic acids)
Urine flow and micturition
Urinary tract mucosa (bactericidal activity, cytokines)
1103
Microbiology - UTIs
Why do women get more UTIs?
The urethra is usually colonized with bacteria
The female urethra is short and is in proximity to the warm moist vulvar and perianal areas, making contamination likely
It has been shown that the organisms that cause urinary tract infection in women colonize the vaginal introitus and the periurethral area before urinary infection results
Massage of the urethra in women and sexual intercourse can force bacteria into the female bladder
Once within the bladder, bacteria may multiply and then pass up the ureters, especially if vesicoureteral reflux is present, to the renal pelvis and parenchyma
1104
Microbiology - UTIs
Why do renal tract abnormalities increase UTIs?
Several abnormalities of the urinary tract interfere with its natural resistance to infection
Obstruction inhibits the normal flow of urine, and the resulting stasis is important in increasing susceptibility to infection
1105
Microbiology - UTIs
List extrarenal causes of obstruction?
Mechanical reasons
Extrarenal: valves, stenosis, or bands; calculi; extrinsic ureteral compression from a variety of causes; and benign prostatic hypertrophy
Intrarenal: nephrocalcinosis, uric acid nephropathy, analgesic nephropathy, polycystic kidney disease, hypokalemic nephropathy, and the renal lesions of sickle cell trait or disease
1106
Microbiology - UTIs
List the intrarenal causes of obstruction?
Mechanical reasons
Extrarenal: valves, stenosis, or bands; calculi; extrinsic ureteral compression from a variety of causes; and benign prostatic hypertrophy
Intrarenal: nephrocalcinosis, uric acid nephropathy, analgesic nephropathy, polycystic kidney disease, hypokalemic nephropathy, and the renal lesions of sickle cell trait or disease
1107
Microbiology - UTIs
list causes of neurological malfunction, leading to obstruction?
Neurogenic malfunction
- poliomyelitis,
- tabes dorsalis,
- diabetic neuropathy,
- spinal cord injuries
1108
Microbiology - UTIs
What effect does vesicoutereral reflex have on UTIs?
Vesicoureteral reflux tends to perpetuate infection by maintaining a residual pool of infected urine in the bladder after voiding
1109
Microbiology - UTIs
Can UTIs occur haematogenously?
Yes
The kidney is frequently the site of abscesses in patients with Staphylococcus aureus bacteremia or endocarditis, or both
It appears that in humans, infection of the kidney with gram-negative bacilli rarely occurs by the hematogenous route
1110
Microbiology - UTIs
What are the symptoms of UTIs in children <2?
Symptoms in neonates and children younger than 2 years are nonspecific
Failure to thrive
vomiting
fever
1111
Microbiology - UTIs
What are the Sx of children >2?
more likely to display localized symptoms such as:
frequency
dysuria
abdominal or flank pain
1112
Microbiology - UTIs
What are the symptoms that indicate a lower UTI?
The lower tract symptoms result from bacteria producing irritation of urethral and vesical mucosa, causing frequent and painful urination of small amounts of turbid urine.
Patients sometimes complain of suprapubic heaviness or pain.
Occasionally, the urine is grossly bloody or shows a bloody tinge at the end of micturition.
Fever tends to be absent in infection limited to the lower tract.
1113
Microbiology - UTIs
What are the symptoms that indicate an upper UTI?
fever (sometimes with rigors)
flank pain
and frequently lower tract symptoms (e.g., frequency, urgency, and dysuria)
at times, the lower tract symptoms antedate the appearance of fever and upper tract symptoms by 1 or 2 days
the symptoms described, although classic, may vary greatly
1114
Microbiology - UTIs
How do UTI Sx differ in elderly patients?
The vast majority of older adult patients with urinary infection are asymptomatic
Symptoms, when present, are often not diagnostic, because noninfected older adults often experience frequency, dysuria, hesitancy, and incontinence
Symptoms of upper tract infection are often atypical e.g., abdominal pain, change in mental status
1115
Microbiology - UTIs
Ix for uncomplicated UTIs?
```
Uncomplicated UTI/pyelonephritis:
- Urine dipstick
- MSU for urine microscopy, culture and
sensitivities
- Bloods – FBC, UE, CRP (inflammatory
markers and renal function)
```
1116
Microbiology - UTIs
What further Ix should be performed for complicated UTIs?
Further investigation of complicated UTI:
- Renal USS
- Intravenous urography
1117
Microbiology - UTIs
What's the problem with sampling urine?
What is the solution for this?
Urine in the bladder is normally sterile. Because the urethra and periurethral areas are very difficult to sterilise, even the most carefully collected specimens (including those obtained by catheterisation) are frequently contaminated.
MSU - mid stream urine
Or less frequently:
Catheterisation
Suprapubic aspiration
1118
Microbiology - UTIs
On microscopy what indicates contamination?
Presence of:
| Squamous epithelial cells – indicative of contamination
1119
Microbiology - UTIs
On microscopy what indicates infection?
White cells Pyuria – indicative of infection
1120
Microbiology - UTIs
What are the causes of sterile pyuria?
```
Prior treatment with antibiotics
Calculi
Catheterisation
Bladder neoplasm
TB
Sexually Transmitted Disease
```
1121
Microbiology - UTIs
Rx for UT in:
Uncomplicated female
Pregnant
UTI male
Female: 3 day cefalexin 500mg BD, or nitrofurantoin 50mg QDS 7 days
Preg: 7 day cefalexin 500mg BD, Co-Amox 625mg TDS 7 days
Male: 7 day cefalexin 500mg BD, Cipro 500mg TDS 7 days
1122
Microbiology - UTIs
Rx of pyelonephritis?
Co-Amxoiclav 1.2g IV TDS, can add gentamicin IV or amikacin IV
UROSEPSIS - gentamicin IV/amikacinIV
1123
Microbiology - UTIs
Catheter associated UTI Rx?
Gentamicin 80mg STAT IV/IM
| Amikacin 140mg STAT IV/IM
1124
Microbiology - UTIs
Most Candida urinary tract infections occur in patients with indwelling catheters.
What is the Rx?
Removal of the catheter may result in cure
oral fluconazole is no more effective than no therapy
There is no demonstrated benefit in the treatment of asymptomatic infection, and therefore therapy is not recommended.
Exceptions include renal transplant patients and patients who are to undergo elective urinary tract surgery.
In these instances, attempts should be made to eliminate or at least suppress the candiduria
1125
Microbiology - UTIs
Complications of pyelonephritis?
```
Perinephric abscess
Chronic pyelonephritis
scarring
chronic renal impairment
Septic shock
Acute papillary necrosis
```
1126
Microbiology - Viral Hepatitis
Incubation period for Hep A
2-6 weeks
1127
Microbiology - Viral Hepatitis
How is Hep A spread
```
Acute hepatitis IP 2-6 weeks
Often subclinical
Faecal-oral spread
Notifiable
Occupational risks
GUM clinics
```
1128
Microbiology - Viral Hepatitis
Is Hep A notifiable?
```
Acute hepatitis IP 2-6 weeks
Often subclinical
Faecal-oral spread
Notifiable
Occupational risks
GUM clinics
```
1129
Microbiology - Viral Hepatitis
```
Acute hepatitis IP 2-6 weeks
Often subclinical
Faecal-oral spread
Notifiable
Occupational risks
GUM clinics
```
Which hepatitis?
A
1130
Microbiology - Viral Hepatitis
Anti-HAV IgM in the blood depicts what?
Recent infection or vaccine
1131
Microbiology - Viral Hepatitis
Anti-HAV IgG in the blood depicts what?
Previous infection or vaccine
1132
Microbiology - Viral Hepatitis
Name the antigens on Hep B?
HBsAg
| HBeAg
1133
Microbiology - Viral Hepatitis
```
Sexual
Vertical
Blood products
ACUTE and CHRONIC
Chronic = 6 months or more
```
Which hepatitis?
B
1134
Microbiology - Viral Hepatitis
How is hep B transmitted?
```
Sexual
Vertical
Blood products
ACUTE and CHRONIC
Chronic = 6 months or more
```
1135
Microbiology - Viral Hepatitis
What length of infection indicates CHRONIC hep B infection?
```
Sexual
Vertical
Blood products
ACUTE and CHRONIC
Chronic = 6 months or more
```
1136
Microbiology - Viral Hepatitis
When do HBsAg and HBeAg appear post infection?
12-16 weeks
| HBeAg slightly before
1137
Microbiology - Viral Hepatitis
HBV disease stages?
```
Immune tolerant
Immune reactive
Inactive HBV carrier state
HBeAg negative chronic HBV
HBsAg negative phase
```
1138
Microbiology - Viral Hepatitis
Chronic Hep B Rx?
```
Interferon alpha
Lamivudine
Adefovir
Tenofovir
Entecavir
Emtricitabine
```
1139
Microbiology - Viral Hepatitis
```
Flaviviridae
Mainly blood product spread
60-80% chronicity
Natural history
HCV and the brain?!
```
Which Hep?
C
1140
Microbiology - Viral Hepatitis
How is Hep C spread?
```
Flaviviridae
Mainly blood product spread
60-80% chronicity
Natural history
HCV and the brain?!
```
1141
Microbiology - Viral Hepatitis
What percentage of people clear Hep C, vs becoming a chronic sufferer?
Clears 20-40%
Chronic 60-80%
1142
Microbiology - Viral Hepatitis
Which heps lead to cirrhosis/hepatocellular carcinomas?
Mainly Hep C but also Hep B
1143
Microbiology - Viral Hepatitis
Which drug has greatly improved reponses to hep C?
Why?
Pehinterferon Alfa(2b)
Delayed plasma clearance of pegylated vs non-pegylated interferon
1144
Microbiology - Viral Hepatitis
```
What class of drugs are:
telaprevir
boceprevir
simeprevir
asunaprevir
paritaprevir (ABT-450/r)
grazoprevir (MK5172)
vaniprevir
faldaprevir
deleoprevir
```
Hep C protease inhibitors
1145
Microbiology - Viral Hepatitis
What other infection must occur first before it is possible to get Hep D?
Hep B
1146
Microbiology - Viral Hepatitis
Genotype 1 and 2 – human, epidemic
Genotype 3 and 4 – swine and other
(humans accidental host = zoonosis)
Very little person to person spread
Case reports
Shellfish consumption, blood transfusion
Sausages, pig liver consumption
Hep E
1147
Microbiology - Viral Hepatitis
Incubation period 3-8 weeks
High mortality rate in pregnancy ( genotype 1)
RARE COMPLICATIONS
CNS disease – Bell’s palsy, Guillain Barre, other neuropathy
Chronic infection
TREATMENT – supportive ? ribavirin
VACCINE – EFFECTIVE - trials with recombinant HEVg1
In Nepalese military and Chinese (100 000)
Hep E
1148
Microbiology - Viral Hepatitis
Incubation period for Hep E?
Incubation period 3-8 weeks
High mortality rate in pregnancy ( genotype 1)
RARE COMPLICATIONS
CNS disease – Bell’s palsy, Guillain Barre, other neuropathy
Chronic infection
TREATMENT – supportive ? ribavirin
VACCINE – EFFECTIVE - trials with recombinant HEVg1
In Nepalese military and Chinese (100 000)
1149
Microbiology - Viral Hepatitis
Complications of Hep E?
Incubation period 3-8 weeks
High mortality rate in pregnancy ( genotype 1)
RARE COMPLICATIONS
CNS disease – Bell’s palsy, Guillain Barre, other neuropathy
Chronic infection
TREATMENT – supportive ? ribavirin
VACCINE – EFFECTIVE - trials with recombinant HEVg1
In Nepalese military and Chinese (100 000)
1150
Microbiology - Viral Hepatitis
Rx of Hep E?
Incubation period 3-8 weeks
High mortality rate in pregnancy ( genotype 1)
RARE COMPLICATIONS
CNS disease – Bell’s palsy, Guillain Barre, other neuropathy
Chronic infection
TREATMENT – supportive ? ribavirin
VACCINE – EFFECTIVE - trials with recombinant HEVg1
In Nepalese military and Chinese (100 000)
1151
Microbiology - Metabolic Bone Disease
In what form is calcium stored in bone?
```
INORGANIC - 65%
calcium hydroxyapatite (10Ca 6PO4 OH2)
is storehouse for 99% of Ca in the body
85% of the phosphorous, 65% Na & Mg
ORGANIC - 35%
– bone cells and protein matrix
```
1152
Microbiology - Metabolic Bone Disease
What percentage of bone is organic vs inorganic?
```
INORGANIC - 65%
calcium hydroxyapatite (10Ca 6PO4 OH2)
is storehouse for 99% of Ca in the body
85% of the phosphorous, 65% Na & Mg
ORGANIC - 35%
– bone cells and protein matrix
```
1153
Microbiology - Metabolic Bone Disease
Difference between cortical and cancellous bone?
```
CANCELLOUS
Vertebrae & pelvis
20% of skeleton
Axial
15-25% calcified
mainly metabolic
Large surface
```
```
CORTICAL
Long bones
80% of skeleton
Appendicular
80-90% calcified
mainly mechanical and protective
```
1154
Microbiology - Metabolic Bone Disease
Which bones are cortical vs cancellous
```
CANCELLOUS
Vertebrae & pelvis
20% of skeleton
Axial
15-25% calcified
mainly metabolic
Large surface
```
```
CORTICAL
Long bones
80% of skeleton
Appendicular
80-90% calcified
mainly mechanical and protective
```
1155
Microbiology - Metabolic Bone Disease
Function of cortical vs cancellous
```
CANCELLOUS
Vertebrae & pelvis
20% of skeleton
Axial
15-25% calcified
mainly metabolic
Large surface
```
```
CORTICAL
Long bones
80% of skeleton
Appendicular
80-90% calcified
mainly mechanical and protective
```
1156
Microbiology - Metabolic Bone Disease
Function of osteoblasts
Osteoblasts - build bone by laying down osteoid
1157
Microbiology - Metabolic Bone Disease
Function of osteoclasts
Osteoclasts - multinucleate cells of macrophage family resorb or chew bone
1158
Microbiology - Metabolic Bone Disease
Function of osteocytes
Osteocytes - osteoblast like cells which sit in lacunae in bone
1159
Microbiology - Metabolic Bone Disease
What binds to osteoblasts, and is present on stem cells, T+B Lymphocytes, that causes osteoclast precursors to differentiate into mature osteoclasts and increase bone resorption?
RANKL
1160
Microbiology - Metabolic Bone Disease
What inhibits RANK/RANKL binding, inhibiting osteoclastogenesis?
OPG
1161
Microbiology - Metabolic Bone Disease
Immature bone type
Woven
--not as strong as lamellae
1162
Microbiology - Metabolic Bone Disease
3 main categories of metabolic bone disease
Non-endocrine (e.g. age related osteoporosis)
Related to endocrine abnormality (Vit D; Parathyroid hormone)
Disuse osteopaenia
1163
Microbiology - Metabolic Bone Disease
Where are bone biopsies typically sampled from?
Histology requires bone biopsy from iliac crest,
processed undecalcified for histomorphometry.
‘Static’ parameters include
cortical thickness & porosity
trabecular bone volume
thickness, number & separation of trabeculae
Bone mineralisation studied using osteoid parameters
‘Histodynamic parameters’ obtained from fluorescent tetracycline labelling.
1164
Microbiology - Metabolic Bone Disease
Pathogenesis – low initial bone mass or accelerated bone loss can reduce bone mass below the fracture threshold
Osteoporosis
1165
Microbiology - Metabolic Bone Disease
Primary and secondary causes of osteoporosis?
1º - age, post-menopause
| 2º - drugs, systemic disease
1166
Microbiology - Metabolic Bone Disease
What is the difference between high and low turnover osteoporosis?
‘High turnover’ OP results from ↑ bone resorption
| ‘Low turnover’ OP results from ↓ bone formation
1167
Microbiology - Metabolic Bone Disease
RFs osteoporosis?
```
Advanced age
Female sex
Smoking
XS Alcohol
Early menopause
Long-term immobility
```
```
Low body mass index
Poor diet ↓vit D, ↓Ca2+
Malabsorption
Thyroid disease
Low testosterone
Chronic renal disease
Steroids
```
Nutrition & social practices (etoh, smoking, malabsorption, vit C&D deficiency)
Endocrine abnormalities (menopause, hyperthyroidism, hyperparathyroidism, cushings, DM)
Immobilisation
Iatrogenic (corticosteroids, long-term heparin or phenytoin therapy, castration, XS thyroid therapy)
Age, menopause
1168
Microbiology - Metabolic Bone Disease
```
UK Facts
Incidence 1/3 women 1/12 men >50
£1.7bn / yr = Cost of rx 310k fractures
50% fracture patients cannot live independently post fracture
20% die
```
Osteoporosis
1169
Microbiology - Metabolic Bone Disease
What are the Sx of osteoporosis?
Patients commonly present with back pain and #
wrist (Colles’), hip (NOF and intertrochanteric) & pelvis may be the first sign of disease
> 60% vertebral # are asymptomatic
Compression # usually in T11-L2 distribution
1170
Microbiology - Metabolic Bone Disease
Ix for osteoporosis
Lab investigations:
Serum calcium, phosphorous & alk phos (usually N)
Urinary calcium
Collagen breakdown products
Imaging
Bone Densitometry
T score between 1 & 2.5 SD below normal peak bone mass = osteopaenia
T score >2.5 SD below normal peak bone mass = osteoporosis
1171
Microbiology - Metabolic Bone Disease
Hypocalcaemia stimulates?
PTH release
1172
Microbiology - Metabolic Bone Disease
Liver makes 25 dihydroxyvit D, where is this converted to 1,25OHvitD3?
Kidney
1173
Microbiology - Metabolic Bone Disease
Defective bone mineralisation
2 types effectively
1. Deficiency of vitamin D
2 Deficiency of PO4
Osteomalacia
1174
Microbiology - Metabolic Bone Disease
What are the two types of osteomalacia?
Defective bone mineralisation
2 types effectively
1. Deficiency of vitamin D
2 Deficiency of PO4
1175
Microbiology - Metabolic Bone Disease
Sx of osteomalacia?
Sequelae
bone pain/tenderness
fracture
proximal weakness
bone deformity
1176
Microbiology - Metabolic Bone Disease
What is seen on Xrays of osteomalacia?
Loosers zone
1177
Microbiology - Metabolic Bone Disease
Effects of hyperparathyroidism on skeleton
Excess PTH
Leads to loss of phosphate
Hypercalcaemia
skeletal changes of osteitis fibrosa cystica (increased bone resorption)
1178
Microbiology - Metabolic Bone Disease
Primary and secondary causes of hyperparathyroidism?
1º -
parathyroid adenoma (85-90%)
chief cell hyperplasia
2º -
chronic renal deficiency
vit D deficiency
malabsorption
1179
Microbiology - Metabolic Bone Disease
Sx of hyperparathyroidism?
Symptoms Mnemonic
Stones (Ca oxalate renal stones)
Bones (osteitis fibrosa cystica, bone resorption)
Abdominal groans (acute pancreatitis)
Psychic moans (psychosis & depression)
1180
Microbiology - Metabolic Bone Disease
What is renal osteodystrophy?
Comprises all the skeletal changes of chronic renal disease:-
Increased bone resorption (osteitis fibrosa cystica)
Osteomalacia
Osteosclerosis
Growth retardation
Osteoporosis
1181
Microbiology - Metabolic Bone Disease
Is PO4 low or high in renal osteodystrophy?
High
```
PO4 retention – hyperphosphataemia
Hypocalcaemia as a result of decreased vit D
2o hyperparathyroidism
Metabolic acidosis
Aluminium deposition
```
1182
Microbiology - Metabolic Bone Disease
3 stages in Pagets disease?
Disorder of bone turnover
Divided into 3 stages
1. Osteolytic
2. Osteolytic-osteosclerotic
3. Quiescent osteosclerotic
1183
Microbiology - Metabolic Bone Disease
Aetiology is unknown
Familial cases show autosomal pattern of inheritance with incomplete penetrance (mutation 5q35-qter - sequestosome 1 gene)
Parvomyxovirus type particles have been seen on EM in bone
Pagets
1184
Microbiology - Metabolic Bone Disease
Pagets chromosome
5q35
1185
Microbiology - Metabolic Bone Disease
Sx Pagets?
Clinical:-
pain
microfractures
nerve compression (incl. Spinal N and cord)
skull changes may put medulla at risk
+/- haemodynamic changes, cardiac failure
Development of sarcoma in area of involvement 1%
1186
Microbiology - Metabolic Bone Disease
Indications for bone biopsy?
Suspected osteomalacia
Diagnostic classification of renal osteodystrophy
Osteopaenia in young patients <50y
Osteopaenia associated with abnormal Ca metabolism
Classification of hereditary childhood bone disease
Evaluation of treatment
(osteomalacia, hypophosphatasia)
1187
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Classification of fractures
Complete or Incomplete
Closed (Simple)- clean break with intact soft tissue
Comminuted - splintered bone with intact soft tissue
Compound - fracture site communicates with skin surface
Greenstick - "crack"
1188
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Briefly describe the 4 stages of bone fracture repair
1. Organisation of haematoma at # site (pro-callus)
2. Formation of fibrocartilaginous callus
3. Mineralisation of fibrocartilaginous callus
4. Remodelling of bone along weightbearing lines
Call = newly formed primary bone
1189
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Typical sites of osteomyelitis?
Sites
Adults- vertebrae
jaw (2º to dental abscess)
toe (2º to diabetic skin ulcer) (>3mm)
Children- long bones (usually metaphysis)
1190
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Sx osteomyelitis?
General - malaise, fever , chills , leucocytosis
Local - pain, swelling and redness
1191
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Ix for osteomyeitis?
60% positive blood cultures
X-ray - mixed picture eventually lytic
FDG
1192
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Routes of infection in osteomyelitis?
Almost always bacterial
Rarely fungal
Routes of infection- a) haematogenous (blood borne)
b) direct extension
c) traumatic (inc surgery)
1193
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Main causative organisms in osteomyelitis?
```
Adults Staph Aureus(90%)
E. Coli
Klebsiella
Salmonella (associated with sickle cell disease)
Psuedomonas (IVDA)
```
Neonates Haemophilus influenzae
Group B Streptococcus
Occasionally enterobacter
1194
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What is cortical bone?
Dense outer layer
1195
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What is medullary bone?
Where bone marrow is
1196
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What staging system is this:
```
Anatomic type
Stage 1 – medullary OM
Stage 2 – superficial OM
Stage 3 – localised OM
Stage 4 - diffuse
Physiologic Class
Host A = normal ; Host B = local or systemic compromise
Host C = treatment worse than disease
```
Cierny-Mader staging system
1197
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What is a rare systemic SE from TB osteomyelitis?
Systemic amyloidosis may result in protracted cases
TB OM:
```
Rare cause of OM (3-5% cases of extra-pulmonary TB)
Affects immunocompromised patients
More destructive and resistant to control
Spinal disease (50% cases) may result in psoas abscess and severe skeletal deformity (Pott’s disease)
```
1198
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Another rare cause of OM (Treponema pallidum)
May be congenital or acquired
Congenital skeletal lesions:-
Osteochondritis
Osteoperiostitis
Diaphyseal osteomyelitis
Late skeletal lesions
Non-gummatous periostitis
gummatous inflammation of bone and joints
Neuropathic joints (Tabes Dorsalis)
Neuropathic shaft fractures
Syphilis
1199
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Inflammatory arthropathy as part of a complex multisystem illness resulting from tick bite.
It is the most prevalent vector bone disease in temperate Northern hemisphere
Lyme disease
1200
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Definition:-
Inflammatory arthropathy as part of a complex multisystem illness resulting from tick bite.
It is the most prevalent vector bone disease in temperate Northern hemisphere
Organism:-
Borrelia burgdorferi
Tick Species:-
Ixodes dammini
Lyme Disease
1201
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What organism causes lymes disease?
Organism:-
Borrelia burgdorferi
Tick Species:-
Ixodes dammini
1202
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What are the three stages of Lyme disease?
Affects both sexes equally.
Onset between May and November
Clinically there are 3 stages
Stage 1 - Early localised
characterised by rash (90%) usually within 7-10 days and between 1 & 50cm diameter.
Often thigh, groin, axilla (earlobe in children)
Stage 2 - Early Disseminated
affects many organs, musculoskeletal, heart, nervous system.
Stage 3- Late, persistent
dominated by arthritis.
1203
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What is the treatment of lyme disease?
```
Treatment is based on prevention.
Vaccines are available.
Antibiotics for proven disease.
No effective prophylaxis.
Diagnosis is clinical. No specific histological features.
```
1204
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
cartilage degeneration
fissuring
abnormal matrix calcification
osteophytes
Osteoarthritis
1205
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What sites are typically affected by osteoarthritis
Main sites vertebrae hips and knees
+/-DIPJ PIPJ of the hand
+/- carpometacarpal and metatarsophalangeal joints
1206
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Severe chronic relapsing synovitis
Unpredictable course
Incidence 1% world population
(Europeans 0.3-1%; Asians 0.1-1.5%; Native Americans 5-7%)
3F:1M Age 30-40y
What bone disease?
RhA
1207
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Aetiology
most likely autoimmune
80% patients RF +ve
RF mostly IgM
RF forms immunocomplexes with IgG
These circulating immune complexes may underlie associated extra-articular disease
RhA
1208
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What HLA are associated with RhA
Genetic predisposition (risk alleles TNFA1P3, STAT4)
Increased incidence amongst first degree relatives
Associated with HLA DR4 & DR1 (Chr 6p21)
1209
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Mild anaemia
Raised ESR
RF+ve(80%)
+/- rheumatoid nodules (25%)
Rheumatoid Arthritis
1210
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Sx of
Course variable, usually slow,progressive
```
Characteristic deformities include:-
Radial deviation of wrist
Ulnar deviation of fingers
‘Swan neck’ & ‘Boutonniere’ deformity of fingers
‘Z’ shaped thumb
```
Symmetrical
Small joints, hands and feet, sparing DIPJ
Wrists elbows ankles and knees
1211
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
What can aid differentiation of RhA with osteo?
RhA:
Symmetrical
Small joints, hands and feet, sparing DIPJ
Wrists elbows ankles and knees
1212
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
iN WIn what condition is:
Proliferative synovitis with
1. Thickening of synovial membranes ( villous)
2. Hyperplasia of surface synoviocytes
3. Intense inflammatory cell infiltrate
4. Fibrin deposition and necrosis
Pannus is the exuberant inflamed synovium the articular surface
..seen?
RhA
1213
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Grimley-Sokoloff cells
RhA
1214
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
5 stages
1. Unknown antigen reaches synovial membrane
2. T – cell proliferation associated with increased
B - cells and angiogenesis
3. Chronic inflammation with inflammatory cytokines
4. Pannus formation
5. Cartilage and bone destruction
RhA
1215
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Affects any joint but great toe in 90%
Usually limited to lower extremities
Precipitate of needle shaped crystals into joint
Tophus is the pathognomic lesion
Gout
1216
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Crystals of
Calcium pyrophosphate - mainly knees or
Calcium phosphates (hydroxyapatite) - knees and
shoulders
Usual age > 50y
Pseudogout
1217
Histopathology - Bone & Joint Pathology Non-Neoplastic Disease
Causes of pseudogout
Distinct subsets
a) Sporadic (8% pts <75; 22%>85 ?F>M)
b) Metabolic (haemochromatosis, primary HPT, hypoMg; low PO4)
c) Hereditary (autosomal dominant) ANKH mutn – transmembrane glygoprotein. Chr 8q, 5p, younger age 18% OA knee; 10% hip)
d) Traumatic
