High Yield Path Prompts Flashcards
(1426 cards)
1
Q
Histopathology
Systolic dysfunction
Aetiology
Idiopathic, alcohol, peripartum, genetic, sarcoidosis, haemochromatosis, myocarditis.
Which cardiomyopathy?
A
Dilated cardiomyopathy
2
Q
Histopathology
HCM mutation
A
Beta-MHC gene
3
Q
Histopathology
Beta-MHC gene
A
HCM mutation
4
Q
Histopathology
Diastolic dysfunction
Aetiology - Genetic, storage diseases
Which cardiomyopathy?
A
Hypertrophic
5
Q
Histopathology
Diastolic dysfunction
Aetiology
Sarcoidosis, amyloidosis, radiation-induced fibrosis,
Which cardiomyopathy?
A
Restrictive
6
Q
Histopathology
septal hypertrophy resulting in
an outflow tract obstruction
A
Hypertrophic obstructive cardiomyopathy (HOCM)
7
Q
Histopathology
MYBP-C and Trop-T gene mutations also common
A
HCM
8
Q
Histopathology
Jones’ Major Criteria: ○ Carditis ○ Arthritis ○ Sydenham’s chorea ○ Erythema marginatum ○ Subcutaneous nodules ● Minor criteria: ○ fever ○ raised ESR or CRP ○ migratory arthralgia ○ prolonged PR interval ○ previous rheumatic fever ○ malaise ○ tachycardia
A
Rheum Fever
9
Q
Histopathology
Name of criteria for rheumatic fever?
A
Jones’ Major Criteria: ○ Carditis ○ Arthritis ○ Sydenham’s chorea ○ Erythema marginatum ○ Subcutaneous nodules ● Minor criteria: ○ fever ○ raised ESR or CRP ○ migratory arthralgia ○ prolonged PR interval ○ previous rheumatic fever ○ malaise ○ tachycardia
10
Q
Histopathology
Lancefield group A strep is the main pathogen. Antigenic mimicry: cell-mediated immunity and antibodies to streptococcal antigen cross-react with myocardial antigens. Histology: Beady fibrous vegetations (verrucae), Aschoff bodies (small giant-cell granulomas) and Anitschkov myocytes (regenerating myocytes).
A
Rheumatic fever
11
Q
Histopathology
Beady fibrous vegetations (verrucae), Aschoff bodies (small giant-cell granulomas) and Anitschkov myocytes (regenerating myocytes).
A
Rheum Fever
12
Q
Histopathology
Rx rheumatic fever?
A
BenPen
13
Q
Histopathology
Small, bland vegetations attached to lines of closure. Formed of thrombi.
Ass. DIC / Hypercoagulable states
A
Non-bacterial thrombotic endocarditis
14
Q
Histopathology
Large, irregular masses on valve cusps, extending into the chordae.
A
Infective endocarditis
15
Q
Histopathology
Pathogenesis unknown. Associated with SLE and anti- phospholipid syndrome.
Small (up to 2mm), warty vegetations that are sterile and platelet-rich.
A
Libman-Sacks endocarditis
16
Q
Histopathology
Causative organisms acute endocarditis
A
Staph. aureus, Strep. pyogenes
17
Q
Histopathology
Causative organisms subacute endocarditis
A
Strep. viridans, Staph. epidermis, HACEK* (culture -ve), Coxiella, Mycoplasma,candida
N.B: HACEK are group of unusual bacterial causes of infective endocarditis.
Haemophilus, Aggregatibacter, Cardiobacterum, Eikenella, Kingella
18
Q
Histopathology
● immune phenomena: ○ Roth spots ○ Osler’s nodes ○ haematuria due to glomerulonephritis ● thromboembolic phenomena: 136 ○ Janeway lesions ○ septic abscesses in lungs/brain/spleen/kidney ○ microemboli ○ splinter haemorrhages ○ splenomegaly
A
Endocarditis
19
Q
Histopathology
Endocarditis criteria
A
Duke criteria: ● Major:
○ positive blood culture growing typical IE organisms or 2 positive cultures >12hrs apart
○ evidence of vegetation/abscess on echo or new regurgitant murmur ● Minor:
○ risk factor (e.g. prosthetic valve, IVDU, congenital valve abnormalities)
○ fever >38
○ thromboembolic phenomena
○ immune phenomena
○ positive blood cultures not meeting major criteria
Diagnosis:
● 2 major
● 1 major + 3 minor
● 5 minor
20
Q
Histopathology
Subacute Rx endocarditis
A
Subacute: Benzylpenicillin + gentamicin; or vancomycin for 4 weeks
21
Q
Histopathology
Acute Rx endocarditis
A
Acute: Flucloxacillin for MSSA, rifampicin + vancomycin + gentamicin for MRSA.
22
Q
Histopathology
● Fibrinous (MI, uraemia) of the pericardium. Types (causes): ● Purulent (Staphylococcus) ● Granulomatous (TB) ● Hemorrhagic (tumour, TB, uraemia) ● Fibrous (a.k.a. Constrictive) (arises from any of above)
A
Types of pericarditis
23
Q
Histopathology
ILD’s restrictive or obstructive?
A
Account for 15% of respiratory practice
Show features of RESTRICTIVE lung disease on spirometry:
● Decreased CO diffusion capacity
● Decreased lung volume
● Decreased compliance
Usually present with:
● SOB
● End-inspiratory crackles
● Cyanosis, pulmonary HTN and cor pulmonale
Difficult to differentiate initial cause in end-stage as all have honey-comb lung
24
Q
Histopathology
Histological pattern of fibrosis = Usual Interstitial Pneumonia, required for diagnosis
(also seen in connective tissue disease, asbestosis and EAA)
o Progressive patchy interstitial fibrosis with loss of normal lung architecture and
honeycomb change, beginning at periphery of the lobule, usually sub-pleural o Hyperplasia of type II pneumocytes causing cyst formation – honeycomb
fibrosis.
● Can have inflammatory cause e.g. RA, SLE, systemic sclerosis
A
a) Cryptogenic Fibrosing Alveolitis / Idiopathic Pulmonary Fibrosis
25
Histopathology
Typically an occupational lung disease; a non-neoplastic lung reaction to inhalation of mineral dusts or inorganic particles. The majority of pneumoconioses affect the upper lobe. e.g. coal worker’s pneumoconiosis, silicosis, asbestosis.
NB: asbestosis can cause benign pleural lesions (plaques, fibrosis) but can also cause malignant lesions (adenocarcinoma, mesothelioma). Asbestosis tends to affect the lower lobe.
b) Pneumoconiosis
26
Histopathology
collection of histiocytes, macrophages +/- multi-nucleate giant cells.
Granuloma
27
Histopathology
Define granuloma
collection of histiocytes, macrophages +/- multi-nucleate giant cells.
28
Histopathology
TB, fungal (histoplasma, Cryptococcus, coccidioides, aspergillus, mucor) and others (pneumocystis, parasites). Non-infectious granulomatous conditions include sarcoid, foreign body (aspiration or IVDU), drugs or occupational lung disease.
All have what in common?
Granulomatous lung diseases
29
Histopathology
Acute presentation: inhalation of antigenic dust in SENSITISED individual -→ systemic symptoms (fever, chills, chest pain, SOB, cough) within hours of exposure, usually settle by following day. Progresses to chronic EAA.
Chronic presentation: progressive persistent productive cough and SOB, finger clubbing and severe weight loss
e.g. Farmers lung (mouldy hay/grain/silage – Saccharopolyspora rectivirgula), Pigeon fancier’s lung (proteins in excreta/feathers), Humidifier’s lung (heated water reservoirs – thermactinomyces spp.), Malt-workers lung (germinating barley – Aspergillus clavatus/fumigatus), Cheese washer’s lung (mouldy cheese – Aspergillus clavatus/penicillium casei).
Recognise early as progression to fibrosis can be prevented by early removal of antigen.
Extrinsic allergic alveolitis / Hypersensitivity pneumonitis/ Cryptogenic organising pneumonia / Bronchiolitis obliterans organising pneumonia (BOOP)
30
Histopathology
Histology – Keratinisation, intercellular prickles (desmosomes).
There are a variety of subtypes e.g. papillary, basaloid. It is associated with
cavitation and hypercalcaemia
What lung carcinoma?
Squamous cell carcinoma (30-50%)
31
Histopathology
● Most common in women and non-smokers.
What lung carcinoma?
Adenocarcinoma (20-30%)
● Malignant epithelial tumour with glandular differentiation or mucin production.
● Tumour occurs peripherally and metastasizes early.
32
Histopathology
Histology – glandular differentiation (gland formation and mucin production).
Cytology – cells containing mucin vacuoles. Molecular – EGFR mutations. Progression;
What lung carcinoma?
Adenocarcinoma (20-30%)
33
Histopathology
Usually occurs centrally, proximal bronchi.
● Arising from neuroendocrine cells.
Associated with ectopic ACTH secretion, Lambert-Eaton, cerebellar degeneration.
What lung carcinoma?
Small cell carcinoma (20% - 25%)
34
Histopathology
What mutations in
Small cell carcinoma (20% - 25%)?
p53 and RB1
35
Histopathology
Poorly differentiated malignant epithelial tumour – large cells, large nuclei, prominent nucleoli. Histology – no evidence of glandular or squamous differentiation. Poor prognosis.
What lung carcinoma?
Large cell carcinoma (10% - 15%)
36
Histopathology
EGFR molecular treatment
What lung carcinoma?
EGFR – adeno (usually) = target for Anti-EGFR (usually tyrosine kinase inhibitor
(TKI)) therapy
37
Histopathology
What type of adenocarcinoma does not benefit from TKI?
● EML4-ALK – adeno (usually) = no benefit from TKI
38
Histopathology
Poor cisplatin response. What molecular mutation?
ERCC1
| NSCLC
39
Histopathology
Arise from either parietal or visceral pleura. It spreads widely within the pleural space and usually associated with extensive pleural effusion, chest pain and dyspnoea. There is a long latent period of 25-45 years for development of asbestos-related mesothelioma.
Mesothelioma
40
Histopathology
MAP in PHTN?
Mean pulmonary arterial pressure of >25mmHg at rest.
41
Histopathology
Mean pulmonary arterial pressure of >25mmHg at rest.
PHTN
42
Histopathology
5 classes of PHTN?
● Class 1:
○ Pulmonary arterial hypertension (idiopathic, hereditary, drug/toxins,
associated with congenital heart disease) - primary PAH most common
in women aged 20-40yrs
● Class 2:
○ Pulmonary hypertension associated with left heart disease (systolic/diastolic dysfunction, valve disease)
● Class 3:
○ Pulmonary hypertension due to lung disease
● Class 4:
○ Chronic Thromboembolic Pulmonary Hypertension
● Class 5:
○ Pulmonary Hypertension with unclear multifactorial mechanisms
(metabolic disorders, systemic disorders, haematological disorders)
43
Histopathology
```
Pulmonary arterial HTN
Left heart disease
Lung disease
Thromboembolic
Idiopathic
```
The 5 classes of PHTN
44
Histopathology
Intra alveolar fluid accumulation leads to poor gas exchange. Main aetiology: left heart failure. Histology: intra-alveolar fluid, iron laden macrophages (“heart failure cells”).
Pulmonary oedema
45
Histopathology
Histo: lung expanded, firm, plum-coloured, airless.
Diffuse alveolar damage: ARDS in adults (e.g. infection, aspiration, trauma etc); HMD (hyaline membrane disease) in neonates (e.g. insufficient surfactant production in prems).
46
Histopathology
Squamous epithelium (proximal 2/3) and columnar epithelium (distal 1/3), joined by the squamo-columnar junction/ Z-line
Histopathology of oesophagus - aka what cell types where?
47
Histopathology
Histopathology of oesophagus - aka what cell types where?
Squamous epithelium (proximal 2/3) and columnar epithelium (distal 1/3), joined by the squamo-columnar junction/ Z-line
48
Histopathology
Los Angeles Classification
GORD
49
Histopathology
Risk factors incl: achalasia of cardia, Plummer-Vinson syndrome, nutritional deficiencies, nitrosamines, HPV (in high prevalence areas)
6x more common in Afro-Carribeans, M>F
Squamous cell
| oesophageal carcinoma
50
Histopathology
Types of gastritis
Acute (neutrophils) insult e.g. aspirin, NSAIDs, corrosives (bleach), acute H.
pylori, severe stress (burns)
Chronic (lymphocytes and plasma cells) insult e.g. H-pylori tends to be Antral, AI e.g. pernicious anaemia, ETOH, smoking
Special types – Chemical (foveolar hyperplasia, chronic inflammation), Infection (CMV, HSV, strongyloides), Inflammatory Bowel Disease Complications: Chronic gastritis may lead to gastric ulcer formation
51
Histopathology
H pylori triple therapy?
H. pylori using triple therapy – PPI, Clarithromycin + Amox or Metro
52
Histopathology
PPI, Clarithromycin + Amox or Metro
H pylori triple therapy
53
Histopathology
DQ2, DQ8 HLA status
What GI disease?
Coeliac disease
54
Histopathology
Which coeliac antibody has the best sensitivity and specificity?
Anti-endomysial ab (best sen and spec)
55
Histopathology
villous atrophy, crypt hyperplasia, lymphocyte infiltrate
Coeliac
56
Histopathology
Commonly in ‘Watershed areas'
Ischaemic colitis – arterial or venous occlusion, small vessel disease, low flow states, obstruction
Commonly in ‘Watershed areas' eg: splenic flexure (SMA transition to IMA), rectosigmoid (IMA transition to internal iliac).
57
Histopathology
− Western populations
− Peak onset 20’s, F>M
− White 2-5x >non-white
− Smoking worsens symptoms
Crohns
58
Histopathology
− Slightly more common than Crohn’s
− White > non-whites
− Peak age is 20-25 yrs
UC
59
Histopathology
MZ twin concordance 50%
UC or Crohns?
Crohns
60
Histopathology
MZ twin concordance 15%
UC or Crohns
UC
61
Histopathology
```
"skip lesions"
"cobblestone appearance"
"apthous ulcer"
"rosethorn ulcer (deep)"
"non-caseating granulomas"
"transmural"
"fistulae/fissure"
```
Crohns
62
Histopathology
Small bowel not affected unless v. severe pancolitis causes ‘backwash ileitis’
UC
63
Histopathology
"Islands of regenerating mucosa bulge into lumen pseudopolyps (can fuse to form mucosal bridges)"
UC
64
Histopathology
Bloody diarrhoea
UC or Crohns?
More UC
65
Histopathology
C.dif Rx
Rx: Metronidazole (covers anerobic) or Vancomycin (effective but 2nd line)
66
Histopathology
C.dif also caused by:
Other bacteria: Campylobacter, Salmonella, Shigella spp.
67
Histopathology
Diverse group of tumours of enterochromaffin cell origin, Produce 5-HT (serotonin)
Carcinoid syndrome
68
Histopathology
● Bronchoconstriction ● Flushing
● Diarrhoea
Carcinoid
69
Histopathology
Ix: 24hr urine 5-HIAA (main metabolite of serotonin)
Carcinoid Syndrome
70
Histopathology
Carcinoid Syndrome Rx
Rx: Octreotide (somatostatin analogue)
71
Histopathology
What electrolyte abnormality is seen with villous adenoma of the colon/rectum?
```
Villous adenoma (rare) hypoproteinaemic hypokalaemia because they
leak large amounts of protein and K.
```
72
Histopathology
First mutation in adenoma?
APC
73
Histopathology
Second mutation in adenoma-adenocarcinoma?
APC gene (two hits)->KRAS->p53
74
Histopathology
What type of polyp is found sporadically in some genetic/acquired syndromes?
Hamartomatous polyp
75
Histopathology
Peutz-Jeghers syndrome (AD - LKB1) = multiple polyps
Juvenile polyposis (AD)
What type of polyps?
Hamartomatous polyp
76
Histopathology
Multiple polyps, mucocutaneous hyperpigmentation, freckles around mouth, palms and soles. Have increased risk of intussusception and of malignancyregular surveillance of GI tract, pelvis and gonads.
Peutz-Jeghers syndrome (AD - LKB1) = multiple polyps
77
Histopathology
Seen at 50-60yrs, thought to be caused by shedding of epithelium cell buildup
What type of polyp?
Hyperplastic polyp
78
Histopathology
2nd commonest cause of cancer deaths in UK. Age 60-79 yrs
If found <50yrs consider familial syndrome. Commoner in western population
98% are adenocarcinoma, 45% in rectum
Colorectal cancer
79
Histopathology
Why are NSAIDs protective against colonic cancer?
NSAIDS protective (COX2 over-expressed in 90%)
80
Histopathology
Carcinoembryonic antigen (CEA) – monitor disease
Colorectal cancer
81
Histopathology
Colorectal cancer disease monitoring
CEA
Carcinoembryonic antigen
82
Histopathology
Staging for colorectal cancer?
Duke’s Staging- helps determine Rx: (TNM staging also used)
A: confined to mucosa (5yr survival >95%)
B1: extending into muscularis propria (5yr survival 67%)
B2: transmural invasion, no lymph nodes involved (5yr survival 54%)
C1: extending to muscularis propria, with LN metastases (5yr survival 43%) C2: transmural invasion, with lymph node metastases (5yr survival 23%)
D: distant metastases (5yr survival <10%)
83
Histopathology
What chemo is used as palliative Rx for colonic carcinoma?
Chemotherapy in palliation: 5-FU (fluorouracil)
84
Histopathology
70% AD mutation in APC gene (C5q1), 30% AR mutation in DNA mismatch repair genes
Familial adenomatous polyposis (FAP)
85
Histopathology
Familial adenomatous polyposis (FAP) mutation?
70% AD mutation in APC gene (C5q1), 30% AR mutation in DNA mismatch repair genes
86
Histopathology
How many polyps needed to diagnose Familial adenomatous polyposis (FAP)?
>100 adenomatous polyps required for diagnosis, usually 100-1000s seen. ALL will adenocarcinoma if left untreated by 30yrs therefore most have prophylactic colectomy.
− Increased risk of neoplasia elsewhere, eg: ampulla of Vater and stomach
− At birth, hypertrophy of retinal pigment epithelium
87
Histopathology
Similar to FAP with extra intestinal features eg: osteoma’s, dental caries
Gardners – like FAP with extra intestinal features eg: osteoma’s, dental caries
88
Histopathology
AD mutations in DNA mismatch repair genes
− Carcinomas usually in right colon, few polyps but fast progression to
malignancy therefore present usually <50yrs
− Associated with endometrial, ovarian, small bowel, transitional cell and
stomach carcinoma.
Hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC)
89
Histopathology
Mutation in Hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC)
AD mutations in DNA mismatch repair genes
90
Histopathology
Produces 2L a day of enzymic HCO3- rich fluid, stimulated by secretin and CCK.
Pancreas
91
Histopathology
What is the action of pancreatic D1?
D1: a vasoactive peptide, stimulates the secretion of H20 into pancreatic system
92
Histopathology
A vasoactive peptide, stimulates the secretion of H20 into pancreatic system
pancreatic D1
93
Histopathology
What is the action of pancreatic PP?
PP: pancreatic polypeptide, self regulates secretion activities
94
Histopathology
What do delta cells of the pancreas secrete?
Delta cells: somatostatin regulates the above cells
95
Histopathology
Responsible for stimulating digestion of fat and protein. Made by I-cells in the duodenum. Causes release of digestive enzymes.
CCK
96
Histopathology
Action of CCK?
Responsible for stimulating digestion of fat and protein. Made by I-cells in the duodenum. Causes release of digestive enzymes.
97
Histopathology
```
● Fasting hyperglycaemia >6 mmol/l.
● BP >140/90
● Central obesity (>94cm in M, >80cm F)
● Dyslipidemia: Decreased HDL cholesterol <1mmol/l & Increased TGs >2mmol/l
● Microalbuminaemia
```
Metabolic Syndrome
98
Histopathology
DM diagnostic glucose levels?
Diagnosis: fasting plasma glucose >7 mmol/L or random plasma glucose >11.1 mmol/L
99
Histopathology
Autoimmune destruction of beta cells by CD4+ and CD8+ T-lymphocytes. May present with DKA. Insulin dependent.
T1DM
100
Histopathology
Causes of acute pancreatitis?
I GET SMASHED
‘I GET SMASHED’: Idiopathic, Gallstones, Ethanol, Trauma, Steroids, Mumps, Autoimmune, Scorpion venom, Hyperlipidaemia, ERCP, Drugs e.g. thiazides
101
Histopathology
Coagulative necrosis of the pancreas?
Acute Pancreatitis
102
Histopathology
What antibody in autoimmune chronic pancreatitis?
IgG4 sclerosing
103
Histopathology
IgG4 sclerosing
autoimmune chronic pancreatitis
104
Histopathology
"fibrosis and loss of exocrine tissue, duct dilatation with thick secretions, calcification"
"Pseudocysts"
Chronic Pancreatitis
105
Histopathology
Histopathology: neoplastic epithelial cells with eosinophilic granular cytoplasm. Positive immunoreactivity for lipase, trypsin and chymotrypsin.
Prognosis: median survival is 18 months from diagnosis. 5yr survival <10%
Acinar Cell Carcinoma
106
Histopathology
85% of all pancreatic malignancies
Ductal adenocarcinoma of the pancreas
107
Histopathology
Where do ductal adenocarcinoma of the pancreas usually present?
Normally head of the pancreas
108
Histopathology
Weight loss (cachexia) and anorexia
Upper abdominal and back pain (chronic, persistent and severe) Jaundice (painless), pruritis, steatorrhoea
DM
Trousseau’s syndrome (25%)- recurrent superficial thrombophlebitis Ascites
Abdominal mass
Virchow’s node
Courvoisier’s sign
Ductal adenocarcinoma of the pancreas
109
Histopathology
Where do Neuroendocrine tumours (islet cell tumours) of the pancreas usually present?
Normally body or tail of the pancreas.
110
Histopathology
Name 2 types of functional neuroendocrine tumours of the pancreas?
▪ Insulinoma – hypoglycaemic attacks
▪ Gastrinoma – Zollinger-Ellison syndrome (high acid output): recurrent ulceration
▪ Others e.g. VIPoma – diarrhoea
▪ Glucagonoma – necrolytic migrating erythema
111
Histopathology
Features MEN1
MEN 1= ‘PPP’ - Parathyroid hyperplasia/adenoma, Pancreatic endocrine tumour (often phaeo), Pituitary adenoma.
112
Histopathology
Features MEN2a
MEN 2A- Parathyroid, Thyroid, Phaeo
113
Histopathology
Features MEN 2b
MEN 2B- Meduallary Thyroid, Phaeo, Neuroma. Marfanoid phenotype
114
Histopathology
1. Metabolism – involved in glycolysis, glycogen storage, glucose synthesis, amino
acid synthesis, fatty acid synthesis and lipoprotein metabolism. Drug metabolism.
2. Protein synthesis – makes all circulating proteins (except gamma globulins)
including albumin, fibrinogen, and coagulation factors.
3. Storage–glycogen, vitaminsA, D and B12 in large amounts, small amounts of vitamin K, folate, iron and copper
4. Hormone metabolism – Activates vitamin D. Conjugation and excretion of steroid hormones (oestrogen/glucocorticoids). Peptide hormone metabolism (insulin, GH, PTH)
5. Bilesynthesis–600-1000mldaily
6. Immune function – antigens from gut reach liver via portal circulation. Phagocytosed by Kupffer cells.
Functions of the liver:
115
Histopathology
```
Associated with
OCP
● Present with
abdo pain/ intraperitoneal bleeding
● Resection if symptomatic, >5cm or if no
shrinkage when stopping OCP
```
Hepatic
| adenoma
116
Histopathology
Causes: Hepatitis B + C,
alcoholic cirrhosis, haemochromatosis, NAFLD, Aflatoxin, androgenic steroids.
● Ix: alpha-fetoprotein, USS
Hepatocellular
| Carcinoma
117
Histopathology
Most common benign lesion of liver
● No rx
Haemangioma
118
Histopathology
● =adenocarcinomas arising from bile ducts
● 10% of liver tumours
● Can be intra or extrahepatic
● Poor prognosis
● Causes: primary sclerosing
cholangitis, parasitic liver disease, chronic liver disease, congenital liver abnormalities, Lynch syndrome type II
Cholangiocarcinoma
119
Histopathology
| Criteria for cirrhosis?
4
1. Hepatocyte necrosis
2. Fibrosis
3. Nodules of regenerating hepatocytes
4. Disruption of liver architecture ↑resistance to blood flow through liver portal hypertension
120
Histopathology
Haemochromatosis mutation
HFE gene Chr 6
121
Histopathology
HFE gene Chr 6
Haemochromatosis mutation
122
Histopathology
ATP7B gene Chr 13
Wilson’s disease mutation
123
Histopathology
Wilson’s disease mutation
ATP7B gene Chr 13
124
Histopathology
Alcoholic cirrhosis, biliary tract disease - micro or macronodular?
MICRONODULAR (nodules < 3mm). Uniform liver involvement. Caused by: alcoholic hepatitis, biliary tract disease
125
Histopathology
Viral hepatitis, Wilson’s disease, alpha1 antitrypsin deficiency, micro or macronodular?
MACRONODULAR (nodules > 3mm). Variable nodule size.
| Caused by: viral hepatitis, Wilson’s disease, alpha1 antitrypsin deficiency
126
Histopathology
Cells activated in cirrhosis?
Chronic inflammation causes activation of stellate cells that are usually quiescent in the space of Disse.
● They become myofibroblasts that initiate fibrosis by deposition of collagen in the space of Disse.
● Myofibroblasts contract constricting sinusoids and increasing vascular resistance.
● Undamaged hepatocytes regenerate in nodules between fibrous septa.
127
Histopathology
What score is used to indicate prognosis in liver cirrhosis?
Modified Child’s Pugh score - Used to indicate prognosis in liver cirrhosis
Total Score <7 = Child’s Pugh A (45% 5yr survival) Total Score 7-9 = Child’s Pugh B (20% 5yr survival) Total Score 10+ = Child’s Pugh C (<20% 5yr survival)
128
Histopathology
List pre/intra/post hepatic causes of portal vein thrombosis?
o Prehepatic: Portal vein thrombosis (e.g. in Factor V Leiden) o Hepatic:
▪ Pre-sinusoidal: Schistosomiasis, primary biliary cirrhosis, sarcoid
▪ Sinusoidal: Cirrhosis
▪ Post-sinusoidal: veno-occlusive disease
o Posthepatic: Budd-Chiari syndrome = occlusion of hepatic vein,
30% idiopathic, otherwise thrombophilia, OCP, leukaemias, compression by renal tumours, HCC, radiotherapy etc. Rx: thrombolytic, treat underlying cause, TIPS (transjugular intrahepatic portosystemic shunt)
129
Histopathology
Large, pale, yellow and greasy liver
Hepatic Steatosis (Fatty Liver)
130
Histopathology
Large, fibrotic liver
Hepatocyte ballooning and necrosis due to accumulation of fat, water and proteins
Mallory bodies
Fibrosis
Alcoholic hepatitis
131
Histopathology
Yellow-tan, fatty, enlarged. Transforms into shrunken, non- fatty, brown organ.
Alcoholic Cirrhosis
132
Histopathology
Associated with HLA-DR3
● Treatment: Immune suppression until transplant, BUT disease returns in up to 40%
Steroid
AUTOIMMUNE HEPATITIS
133
Histopathology
What antibodies in type 1 AI hepatitis?
Type 1: ANA (antinuclear Ig), anti-SMA (anti-smooth muscle Ig), anti-actin Ig, anti-
soluble liver antigen Ig
ASMA ANA
134
Histopathology
What antibodies in type 2 AI hepatitis?
Type 2: Anti-LKM Ig (anti liver-kidney-microsomal Ig)
135
Histopathology
"↑serum ALP, ↑cholesterol, ↑IgM, hyperbilirubinaemia (late)"
"Anti-mitochondrial antibodies in > 90%"
"bile duct loss with granulomas"
PBC
136
Histopathology
↑ serum ALP, several associated auto-Ig, particularly p-ANCA
"bile duct dilatation"
"beading of bile ducts"
PSC
137
Histopathology
AR
Mutated HFE gene at 6p21.3↑Fe gut absorption which deposits in liver, heart, pancreas, adrenals, pituitary, joints, skinfibrosis
HAEMOCHROMATOSIS
138
Histopathology
Autosomal recessive
Mutated HFE gene at 6p21.3↑Fe gut absorption which deposits in liver, heart, pancreas, adrenals, pituitary, joints, skinfibrosis
Autosomal recessive
Mutated gene ATP7B (Chr 13): Encodes copper transporting ATPase expressed on canalicular membrane
therefore↓biliary Cu excretion and deposition in liver, CNS, iris.
WILSON’S DISEASE
139
Histopathology
What gene mutation - Wilsons?
Mutated gene ATP7B (Chr 13): Encodes copper transporting ATPase expressed on canalicular membrane
140
Histopathology
Stains with Prussian blue stain
HAEMOCHROMATOSIS
● ↑ Fe, ↑ Ferritin
● Transferrin saturation > 45% ● ↓TIBC
141
Histopathology
Stain in HAEMOCHROMATOSIS
Stains with Prussian blue stain
● ↑ Fe, ↑ Ferritin
● Transferrin saturation > 45% ● ↓TIBC
142
Histopathology
Stains with Rhodanine stain
Mallory bodies and fibrosis on microscopy
Wilsons
● ↓ serum caeruloplasmin
● ↓ serum copper
● ↑ urinary copper
143
Histopathology
Stain in Wilsons?
Cu stains with Rhodanine stain
Mallory bodies and fibrosis on microscopy
● ↓ serum caeruloplasmin
● ↓ serum copper
● ↑ urinary copper
144
Histopathology
Stain with Periodic acid Schiff
ALPHA 1 ANTITRYPSIN DEFICIENCY
↓A1AT
Absent α-globulin band on electrophoresis
145
Histopathology
ALPHA 1 ANTITRYPSIN DEFICIENCY stain?
Intracytoplasmic inclusions of A1AT which stain with Periodic acid Schiff
↓A1AT
Absent α-globulin band on electrophoresis
146
Histopathology
"Absent α-globulin band on electrophoresis"
A1AT def
147
Histopathology
Lifelong penicillamine.
Good prognosis with early treatment but any neuro damage is permanent and may require liver transplant
Wilsons
148
Histopathology
Rx in Wilsons?
Lifelong penicillamine.
| Good prognosis with early treatment but any neuro damage is permanent and may require liver transplant
149
Histopathology
Dihydrotestosterone-mediated hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large nodules.
BPH
150
Histopathology
Staging in prostate cancer?
Grading: Gleason system, based on degree of differentiation and glandular patterns. Diagnosis: History, examination, PSA (over 4ng/ml is indicative )
151
Histopathology
"Radiosensitive testicular tumour"
Seminoma: most common type of germinal tumour. Peak age: 30s. Radiosensitive.
152
Histopathology
"chemosensitive"
"post-pubertal male"
"AFP, HCG, LDH"
testicular tumour
Teratoma
153
Histopathology
Seminoma, spermatocytic seminoma, embryonal carcinoma, yolk sac tumour, choriocarcinoma, teratoma
Germ cell tumours
95%
154
Histopathology
Leydig cell tumour (derived from stroma), Sertoli cell tumour (derived from sex cord)
SEX CORD – STROMAL
5%
155
Histopathology
Syndrome characterised by:
Proteinuria (>3g/24h) + hypoalbuminaemia + oedema (+ hyperlipidaemia)
Key words in EMQs:
● “Swelling” (characteristically facial in kids and peripheral in adults)
● “Frothy urine
Nephrotic syndrome
SyndromeProteinuria (>3g/24h) + hypoalbuminaemia + oedema (+ hyperlipidaemia)
Key words in EMQs:
● “Swelling” (characteristically facial in kids and peripheral in adults)
● “Frothy urine
156
Histopathology
Nephrotic Syndrome features?
SyndromeProteinuria (>3g/24h) + hypoalbuminaemia + oedema (+ hyperlipidaemia)
Key words in EMQs:
● “Swelling” (characteristically facial in kids and peripheral in adults)
● “Frothy urine
157
Histopathology
Most common Nephrotic Syndrome in children (75% cases) with second peak in elderly
Minimal change disease
158
Histopathology
Minimal change light microscopy changes?
No changes
159
Histopathology
"Loss of podocyte foot processes"
"No immune deposits"
Minimal change disease
160
Histopathology
"Diffuse glomerular basement membrane thickening"
Membranous glomerular disease
161
Histopathology
"Loss of podocyte foot processes, Subepithelial deposits = ‘spikey’"
Membranous glomerular disease
162
Histopathology
Changes in Membranous glomerular disease
"Diffuse glomerular basement membrane thickening"
"Loss of podocyte foot processes, Subepithelial deposits = ‘spikey’"
"Ig and complement in granular deposits along BM"
163
Histopathology
Nephrotic syndrome most common in Afro- Caribbean people
Focal Segmental Glomerulosclerosis (FSGS)
164
Histopathology
"Focal and segmental glomerular consolidation and scarring,
Hyalinosis"
"Loss of podocyte foot processes"
Focal Segmental Glomerulosclerosis (FSGS)
165
Histopathology
"Ig and complement in scarred areas"
Focal Segmental Glomerulosclerosis (FSGS)
166
Histopathology
Steroid responsive nephrotic syndrome?
Minimal change disease
167
Histopathology
"Mesangial matrix nodules – aka Kimmelstiel Wilson nodules"
"Asian"
Diabetic glomerulonephropathy
168
Histopathology
"Apple green birefringence with Congo red stain"
Amyloidosis
169
Histopathology
A manifestation of glomerular inflammation (i.e. glomerulonephritis (GN)) Syndrome characterised by:
● Haematuria (coca-cola urine)
● Dysmorphic RBCs and red cell casts in urine May also have
● Oliguria – to some degree
● ↑Urea and creatinine
● Hypertension
● Proteinuria (but not nephrotic range)
Nephritic Syndrome
170
Histopathology
Nephritic Syndrome features?
```
● Haematuria (coca-cola urine)
● Dysmorphic RBCs and red cell casts in urine May also have
● Oliguria – to some degree
● ↑Urea and creatinine
● Hypertension
● Proteinuria (but not nephrotic range)
```
171
Immunology
Failure of stem cells to differentiate along myeloid or lymphoid lineage
Failure of production of: Neutrophils, Lymphocytes, Monocyte/macrophages, Platelets
Fatal in very early life unless corrected with bone marrow transplantation
Reticular dysgenesis
172
Immunology
Autosomal recessive severe SCID (most severe form) Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
Reticular dysgenesis
173
Immunology
Reticular dysgenesis
Failure of stem cells to differentiate along myeloid or lymphoid lineage
Failure of production of: Neutrophils, Lymphocytes, Monocyte/macrophages, Platelets
Autosomal recessive severe SCID (most severe form) Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
174
Immunology
Specific failure of neutrophil maturation
Autosomal recessive severe congenital neutropenia
Kostmann syndrome
Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
175
Immunology
Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
Kostmann syndrome
Specific failure of neutrophil maturation
Autosomal recessive severe congenital neutropenia
176
Immunology
Kostmann syndrome
Specific failure of neutrophil maturation
Autosomal recessive severe congenital neutropenia
Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
177
Immunology
Specific failure of neutrophil maturation
Autosomal dominant episodic neutropenia every 4-6 weeks
Cyclic neutropenia
Mutation in neutrophil elastase (ELA-2)
178
Immunology
Mutation in neutrophil elastase (ELA-2)
Cyclic neutropenia
Specific failure of neutrophil maturation
Autosomal dominant episodic neutropenia every 4-6 weeks
179
Immunology
Cyclic neutropenia
Specific failure of neutrophil maturation
Autosomal dominant episodic neutropenia every 4-6 weeks
Mutation in neutrophil elastase (ELA-2)
180
Immunology
CD11a/CD18 and CD11b/CD18 are usually expressed on
neutrophils, bind to ligands on endothelial cells and so regulate neutrophil adhesion/transmigration
Here neutrophils lack these adhesion molecules and fail to exit from the bloodstream
Leukocyte
adhesion deficiency
[Deficiency of CD18 (b2 integrin subunit) in LAD1]
181
Immunology
Very high neutrophil counts in blood
Absence of pus formation
Delayed umbilical cord separation
Leukocyte
adhesion deficiency
[Deficiency of CD18 (b2 integrin subunit) in LAD1]
182
Immunology
[Deficiency of CD18 (b2 integrin subunit) in LAD1]
Leukocyte
| adhesion deficiency
183
Immunology
Leukocyte
adhesion deficiency
[Deficiency of CD18 (b2 integrin subunit) in LAD1]
CD11a/CD18 and CD11b/CD18 are usually expressed on
neutrophils, bind to ligands on endothelial cells and so regulate neutrophil adhesion/transmigration
Here neutrophils lack these adhesion molecules and fail to exit from the bloodstream
Very high neutrophil counts in blood
Absence of pus formation
Delayed umbilical cord separation
184
Immunology
Absent respiratory burst
Deficiency of one of components of NADPH oxidase
Inability to generate oxygen free radicals Impaired killing of intracellular micro-organisms
Excessive inflammation
Persistent neutrophil/ macrophage accumulation
Failure to degrade antigens
Granuloma formation
Lymphadenopathy and hepatosplenomegaly
Susceptibility to bacteria esp. catalase positive bacteria i.e. PLACESS
(Pseduomonas, Listeria, Aspergillus, Candida, E.Coli, Staph Aureus, Serratia)
Chronic
| granulomatous disease
185
Immunology
Negative Nitro-Blue Tetrazolium test (NBT). NBT is a dye that changes colour from yellow to blue following interaction with hydrogen peroxide.
Dihydrorhodamine (DHR) flow cytometry test. DHR is oxidized to rhodamine, which is strongly fluorescent, following interaction with hydrogen peroxide.
Chronic
| granulomatous disease
186
Immunology
What stains in Chronic
granulomatous disease
Negative Nitro-Blue Tetrazolium test (NBT). NBT is a dye that changes colour from yellow to blue following interaction with hydrogen peroxide.
Dihydrorhodamine (DHR) flow cytometry test. DHR is oxidized to rhodamine, which is strongly fluorescent, following interaction with hydrogen peroxide.
187
Immunology
What sort of bacteria are Chronic
granulomatous disease sufferers at risk from?
Susceptibility to bacteria esp. catalase positive bacteria i.e. PLACESS
(Pseduomonas, Listeria, Aspergillus, Candida, E.Coli, Staph Aureus, Serratia)
Granuloma formation
Lymphadenopathy and hepatosplenomegaly
Absent respiratory burst
Deficiency of one of components of NADPH oxidase
Inability to generate oxygen free radicals Impaired killing of intracellular micro-organisms
Excessive inflammation
Persistent neutrophil/ macrophage accumulation
Failure to degrade antigens
188
Immunology
Deficiency of IL-12 and IFNγ and their receptors results in susceptibility to what?
Susceptibility to infection with mycobacteria (TB and atypical), BCG, Salmonella.
Infection with mycobacteria activates IL12- IFN γ network:
Infected macrophages stimulated to produce IL12
IL12 induces T cells to secrete IFN γ
IFN γ feeds back to macrophages & neutrophils
Stimulates production of TNF
Activates NADPH oxidase
Stimulates oxidative pathways
Inability to form granulomas
189
Immunology
In what primary immune deficiency can no granulomas be formed?
Deficiency of IL-12 and IFNγ and their receptors
Susceptibility to infection with mycobacteria (TB and atypical), BCG, Salmonella.
Infection with mycobacteria activates IL12- IFN γ network:
Infected macrophages stimulated to produce IL12
IL12 induces T cells to secrete IFN γ
IFN γ feeds back to macrophages & neutrophils
Stimulates production of TNF
Activates NADPH oxidase
Stimulates oxidative pathways
Inability to form granulomas
190
Immunology
Complement deficiency in alternative pathway results in susceptibility to what?
Inability to mobilise complement rapidly in response to
bacterial infections
Recurrent infections with encapsulated bacteria
All very rare
191
Immunology
Immune complexes fail to activate complement pathway increased susceptibility to infection
Increased load of self-antigens – particularly nuclear components – which may promote auto-immunity (SLE)
Deposition of immune complexes which stimulates local inflammation in skin, joints and kidneys (SLE)
Deficiency in early classical pathway (C1/2/4)
Antibody dependent.
Necessary against infection and clearance of waste (apoptotic cells and immune complexes).
192
Immunology
Most common complement deficiency in SLE?
C1q, C1r, C1s, C2, C4 deficiency are all described in SLE
All are rare
```
C2 deficiency most common
Clinical phenotype
Almost all patients with C2 deficiency have SLE
Severe skin disease
Increased no. infections
```
193
Immunology
Caused by active lupus, due to the persistent production of immune complexes and consequent depletion of complement
Secondary complement deficiency
194
Immunology
30% of all individuals are heterozygote for mutant protein 6-10% have no circulating MBL
Associated with increased infection in patients who have another cause of immune impairment
Premature infants Chemotherapy
HIV infection
Antibody deficiency
MBL deficiency
Involves C2 and C4 but not C1
195
Immunology
Where do all complement pathways converge?
Therefore, what is the most severe complement deficiency?
All pathways
converge on C3
Severe susceptibility to bacterial infections (esp. encapsulated – meningococcus, streptococcus, haemophilis)
Increased risk of development of connective tissue disease
196
Immunology
Severe susceptibility to bacterial infections (esp. encapsulated – meningococcus, streptococcus, haemophilis)
Increased risk of development of connective tissue disease
C3 deficiency
197
Immunology
What are nephritic factors?
What happens with increased production of nephritic factors?
Nephritic factors: auto-antibodies directed against parts of
the complement pathway.
Nephritic factors cause C3 activation and consumption, by stabilising the enzyme which breaks them down - c3 convertases.
This causes a secondary C3 deficiency.
198
Immunology
How is secondary C3 deficiency caused?
Nephritic factors: auto-antibodies directed against parts of
the complement pathway.
Nephritic factors cause C3 activation and consumption, by stabilising the enzyme which breaks them down - c3 convertases.
This causes a secondary C3 deficiency.
199
Immunology
Inability to make membrane attack complex
Inability to use complement to lyse encapsulated bacteria
Results in specific hole in immune system
Neisseria meningitis
Streptococcus pneumonia
Haemophilus influenza
Any defect
Terminal common pathway
200
Immunology
Unwell by 3 months of age (protected beforehand by IgG
from mother across placenta then colostrum) with:
Infections of all types
Failure to thrive
Persistent diarrhoea
Unusual skin disease:
Colonisation of infant’s empty bone marrow by
maternal lymphocytes
Graft versus host disease
Family history of early infant death
20 possible pathways identified
Deficiency of cytokine receptors
Deficiency of signalling molecules
Metabolic defects
Effect on different lymphocyte subsets (T, B, NK) depend on exact mutation
SCID
201
Immunology
45% of all severe combined immunodeficiency
Mutation of gamma chain of IL2 receptor on chromosome Xq13.1
Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells
Phenotype
Very low or absent T cell numbers
Normal or increased B cell numbers
Poorly developed lymphoid tissue and thymus
X-linked SCID
202
Immunology
Phenotype
Very low or absent T cell numbers
Normal or increased B cell numbers
Poorly developed lymphoid tissue and thymus
X-linked SCID
203
Immunology
45% of all severe combined immunodeficiency
Mutation of gamma chain of IL2 receptor on chromosome Xq13.1
Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells
X-linked SCID
204
Immunology
X-linked SCID
Where is the mutation?
What is the cellular phenotype?
45% of all severe combined immunodeficiency
Mutation of gamma chain of IL2 receptor on chromosome Xq13.1
Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells
Phenotype
Very low or absent T cell numbers
Normal or increased B cell numbers
Poorly developed lymphoid tissue and thymus
205
Immunology
22q11.2 deletion syndrome
TBX1 may be responsible
DiGeorge
206
Immunology
What is CATCH22 for DiGeorge Sx?
Developmental defect of pharyngeal pouch.
Remember CATCH-22:
Cardiac abnormalities (especially tetralogy of Fallot)
Abnormal facies (high forehead, low set ears)
Thymic aplasia (T cell lymphopenia)
Cleft palate
Hypocalcaemia/hypoparathyroidism
22 – chromosome
Normal numbers B cells and reduced numbers T cells Homeostatic proliferation with age Immune function improves with age
207
Immunology
Normal numbers B cells and reduced numbers T cells Homeostatic proliferation with age Immune function improves with age
```
DiGeorge
syndrome (22q11.2 deletion syndrome)
```
Developmental defect of pharyngeal pouch.
Remember CATCH-22:
Cardiac abnormalities (especially tetralogy of Fallot)
Abnormal facies (high forehead, low set ears)
Thymic aplasia (T cell lymphopenia)
Cleft palate
Hypocalcaemia/hypoparathyroidism
22 – chromosome
208
Immunology
Defect in one of the regulatory proteins involved in Class II gene expression
Regulatory factor X or Class II transactivator
Absent expression of MHC Class II molecules Profound deficiency of CD4+ cells
Usually have normal number of CD8+ cells
Normal number of B cells
Failure to make IgG or IgA antibody (no class
switching)
Clinically:
Unwell by 3 months of age and failure to thrive
Infections of all types
May be associated with sclerosing cholangitis
Family history of early infant death
Bare lymphocyte syndrome type II
209
Immunology
Usually have normal number of CD8+ cells
Normal number of B cells
Failure to make IgG or IgA antibody (no class
switching)
Unwell by 3 months of age and failure to thrive
Infections of all types
May be associated with sclerosing cholangitis
Family history of early infant death
Bare lymphocyte syndrome type II
210
Immunology
Defective B cell tyrosine kinase gene (BTK)
Pre B cells cannot develop to mature B cells causing absence of mature B cells and no circulating Ig after ~ 3 months
Recurrent infections during childhood, bacterial, enterovirus
Bruton’s X- linked hypogamma globulinaemia
Pro B cells → Pre B cells → Mature B cells
211
Immunology
Phenotype of Bruton’s X- linked hypogamma globulinaemia
Defective B cell tyrosine kinase gene (BTK)
Pre B cells cannot develop to mature B cells causing absence of mature B cells and no circulating Ig after ~ 3 months
Recurrent infections during childhood, bacterial, enterovirus
212
Immunology
Prevalence = 1:600
2/3rd individuals asymptomatic and 1/3rd have recurrent respiratory tract infections. Also GI infections.
Genetic component but cause unknown
Selective IgA deficiency
213
Immunology
Selective IgA deficiency
Prevalence = 1:600
2/3rd individuals asymptomatic and 1/3rd have recurrent respiratory tract infections. Also GI infections.
Genetic component but cause unknown
214
Immunology
```
Inability of B cells to class switch causing production of only
IgM due to a T cell defect
```
Most cases caused by mutation in CD40 ligand gene (CD40L, CD154)
Member of TNF Receptor family encoded on Xq26
Involved in T-B cell communication
Expressed by activated T cells – B cells and other
APCs express CD40
Boys present with failure to thrive in first few years of life with:
Recurrent infections - bacterial
Pneumocystis jiroveci infection, autoimmune
disease and malignancy
Results in:
Normal number circulating B cells
Normal number of T cells and normal in vitro T cell responses
Elevated serum IgM
Undetectable IgA, IgE, IgG (failure of class
switching)
No germinal centre development within lymph
nodes and spleen
Hyper IgM syndrome
215
Immunology
Boys present with failure to thrive in first few years of life with:
Recurrent infections - bacterial
Pneumocystis jiroveci infection, autoimmune
disease and malignancy
Results in:
Normal number circulating B cells
Normal number of T cells and normal in vitro T cell responses
Elevated serum IgM
Undetectable IgA, IgE, IgG (failure of class
switching)
No germinal centre development within lymph
nodes and splee
Hyper IgM syndrome
216
Immunology
Where is the mutation in Hyper IgM syndrome?
Most cases caused by mutation in CD40 ligand gene (CD40L, CD154)
Member of TNF Receptor family encoded on Xq26
Involved in T-B cell communication
Expressed by activated T cells – B cells and other
APCs express CD40
```
Inability of B cells to class switch causing production of only
IgM due to a T cell defect
```
Normal number of T cells and normal in vitro T cell responses
Elevated serum IgM
Undetectable IgA, IgE, IgG (failure of class
switching)
No germinal centre development within lymph
nodes and spleen
217
Immunology
Normal number circulating B cells
Normal number of T cells and normal in vitro T cell responses
Elevated serum IgM
Undetectable IgA, IgE, IgG (failure of class
switching)
No germinal centre development within lymph
nodes and spleen
Hyper IgM
218
Immunology
Heterogenous group of disorders with disease mechanism
unknown
Low IgG, IgA and IgE
Clinical features
Recurrent bacterial infections with severe end-organ
damage
1. Bronchiectasis, persistent sinusitis, recurrent
GIT infection
Autoimmune disease
Granulomatous disease
Common
| variable immune deficiency
219
Immunology
Heterogenous group of disorders with disease mechanism
unknown
Low IgG, IgA and IgE
Common
| variable immune deficiency
220
Immunology
Specific Rx for chronic granulomatous disease?
IFNgamma
221
Immunology
NBT colour change [testing for phagocyte deficiency]
NBT is a dye that changes colour from yellow to blue, following interaction with hydrogen peroxide
222
Immunology
| DHR oxidant change [testing for phagocyte deficiency]
DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide
223
Immunology
Immediate reaction provoked by re-exposure to an allergen. IgE mediated: mast cells release mediators resulting in vasodilation, increased permeability, smooth muscle spasm.
Typical Sx: Angioedema, urticaria, rhinoconjunctivitis, wheeze, D&V, ANAPHYLAXIS
4% of children with asthma also had concurrent clinical food allergy
Remember atopic triad (eczema, asthma and hay fever), ? hygiene hypothesis
Type I Hypersensitivity Disorders
224
Immunology
Defects in β defensin predispose to Staph aureus superinfection
Atopic dermatitis
225
Immunology
Chestnut, avocado, banana, potato, tomato, kiwi, papaya, eggplant, mango, wheat, melon
Latex Food Syndrome
226
Immunology
Causes of non-IgE-mediated mast cell degranulation
Non-IgE-mediated mast cell degranulation: NSAIDs, IV contrast, opioids, exercise.
227
Immunology
Which peanut allergen confers a high risk of anaphylaxis?
Ara h 2 – High risk anaphylaxis to peanut and nuts
Ara h 8 – Localised oral reactions to peanut and stone fruit only
228
Immunology
Gold standard for food allergy
Double-blind oral food challenge is gold standard for food allergy BUT risk of severe reaction when testing.
Increasing volumes of offending food/drug are ingested under close supervision.
229
Immunology
IgG or IgM antibody reacts with cell or matrix associated self antigen. Results in tissue damage, receptor blockade/ activation.
Type II Hypersensitivity Disorders
230
Immunology
Antigens on neonatal erythrocytes
Maternal IgG mediated reticulocytosis and anaemia
Positive Direct Coombs Test
Rx: Maternal Plasma Exchange, Exchange Transfusion
Heamolytic Disease of the Newborn (HDN)
231
Immunology
Numerous autoantigens eg: Rh blood group Ag
Destruction of red blood cells by auto antibody + complement + FcR+ phagocytes, anaemia
Positive Direct Coombs Test, Anti Red Cell Ab
Rx: Steroids
Autoimmune Haemolytic Anaemia (+ ITP = Evan’s Syndrome)
232
Immunology
Antigen: Glycoprotein IIb/IIIa on platelets
Bruising/ Bleeding (Purpura)
Anti Platelet Antibody
Rx: Steroids, IVIG, Anti-D Antibody, splenectomy
Autoimmune Thrombocytopaenic Purpura
233
Immunology
Antigen: Non-collagenous domain of basement membrane collagen type IV
Glomerulonephritis, pulmonary haemorrhage
Anti GBM Ab
Rx: Linear Smooth IF staining of IgG deposits on BM
Corticosteroids and Immunosuppression
Goodpasture’s
| Syndrome
234
Immunology
Antigen: Epidermal Cadherin
Non-tense blistering of skin and Bullae
Direct Immuno- fluorescence showing IgG deposition
Rx: Corticosteroids and Immunosuppression
Pemphigus Vulgaris
235
Immunology
Antigen: TSH receptor
Hyperthyroidism
Anti TSH-R Ab
Rx: Carbimazole and Propylthiouracil
Graves disease
236
Immunology
Antigen: Acetylcholine receptor
Fatiguable muscle weakness, Double Vision
Anti Ach-R Ab Abnormal EMG Tensilon Test
Rx: Neostigmine, Pyridostigmine, (If serious use IVIG and Plasmaphoresis)
Myasthenia Gravis
237
Immunology
Antigen: M proteins on Group A strep
Myocarditis, Arthritis, Sydenham’s Chorea
Clinical, based on Jones Criteria
Rx: Aspirin, Steroids and Penicillin
Acute Rheumatic Fever
238
Immunology
Antigen: Intrinsic Factor
and Gastric Parietal Cells
↓Hb ↓B12
Anti Gastric
Parietal Cell Ab, Anti-IF Ab,
Schilling Test
Rx: Dietary B12 or IM
B12
Pernicious
| Anaemia
239
Immunology
Medium and Small Vessel Vasculitis
Allergy →Asthma→ Systemic Disease (Male predominance)
p-ANCA (against myeloperoxidase ), Granulomas, Eosinophil Granulocytes
Rx: Prednisolone, Azathioprine, Cyclophosphami de
Churg-Strauss Syndrome (eGP A)
240
Immunology
Medium and Small Vessel Vasculitis
Sinus Problems, Lung Cavitations + haemorrhage, Cresentic Glomerulonephritis
c-ANCA (against Proteinase 3) granulomas
Rx: Corticosteroids, cyclophosphamid e, co-trimoxazole
Wegener’s
| Granulomatosis (GPA)
241
Immunology
Antigen: Pauci-immune necrotizing, small vessel vasculitis
Purpura, livedo, many different organs affected
p-ANCA (against myeloperoxidase )
Rx: Prednisolone, Cyclophosphami de or Azathioprine, plasmaphoresis
Microscopic Polyangiitis (MPA)
242
Immunology
Antigen: Medications (NSAIDS) Cold, Food, Pressure, Sun, Exercise, Insect Stings, Bites and Idiopathic
Persistent Itchy Wheals Lasting > 6 Weeks. Associated with Angioedema in 50% of cases. IgG against FcR1 or IgG against IgE (Exclude Urticarial Vasculitis in those who respond poorly to Anti-histamine)
Challenge Test, ESR (Raised in Urticarial Vasculitis), Skin Prick Testing
Rx: Avoid precipitants, Check for thyroid disease, Preventative antihistamine, IM adrenaline for pharyngeal angioedema, 1% Menthol in Aqueous Cream for pruritis (Also Doxepin and Cyclosporin)
Chronic Urticaria
243
Immunology
List type 3 hypersensitivity reactions
```
Mixed Essential Cryoglobulinaemia
SLE
Rheum A
Polyarteritis Nodosa (PAN)
Serum Sickness
```
244
Immunology
Antigen: IgM against IgG +/- hepatitis C antigens
Joint pain, splenomegaly, skin, nerve and kidney involvement.
Associated with Hep C.
A mixture of clinical and biopsies
Rx: NSAIDs, Corticosteroids and plasmaphoresis
Mixed Essential Cryoglobulinaemia
245
Immunology
Antigen: Reaction to Proteins in Antiserum (Penicillin)
Rashes, Itching, arthralgia, lymphadenopathy, fever and malaise.
Symptoms take 7-12 days to develop
↓C3
Blood shows immune complexes or signs of blood vessel inflammation.
Rx: Discontinuation of precipitant, steroids, antihistamines (+/- analgesia)
Serum Sickness
246
Immunology
Antigen: Hep B, Hep C virus Antigens
Fever, fatigue, weakness, arthralgia, skin, nerve and kidney involvement, pericarditis and MI.
Associated with Hep B
Diagnosed by clinical criteria and Biopsy (↑ESR, ↑WCC, ↑CRP) ‘Rosary sign’
Rx: Prednisolone and Cyclophosphamide
Polyarteritis Nodosa (PAN)
247
Immunology
‘Rosary sign’
Polyarteritis Nodosa (PAN)
248
Immunology
Antigen: Mainly intracellular components: DNA, histones, RNP
M:F=1:9
4 of these 11: serositis, seizures, apthous ulcers, arthritis, photosensitivity, discoid rash, malar rash, haematology, kidney findings, Antinuclear antibody (ANA +ve), immunological findings (anti-dsDNA, anti-sm)
↓C4 (↓C3 only in SEVERE disease) Ab’s to dsDNA, Histones (Drug Induced), Ro, La, Sm, U1RNP ↑ESR, normal CRP
(N.B. Hydralyzine, Procainamide and Isoniazid can cause Drug induced SLE)
Rx: Mainly; Analgesia Steroids and cyclophosphamide
Systemic Lupus Erythematosis (SLE)
249
Immunology
Delayed hypersensitivity. T-cell mediated.
Type IV Hypersensitivity Disorders
250
Immunology
IgG or IgM immune complex (Ab vs soluble Ag) mediated tissue damage.
Type III Hypersensitivity Disorders
251
Immunology
IgG or IgM antibody reacts with cell or matrix associated self antigen. Results in tissue damage, receptor blockade/ activation.
Type II Hypersensitivity Disorders
252
Immunology
Antigen: Pancreatic Beta Cell proteins. (Glutamate Decarboxylase GAD)
Insulitis, Beta Cell Destruction
Blood Glucose, Ketonuria, Glutamate Decarboxylase Antibodies, Islet Cell Antibodies
Rx: Insulin via Injections or continuous infusion
Type 1 Diabetes Mellitus
253
Immunology
Antibodies seen in T1DM
Glutamate Decarboxylase Antibodies, Islet Cell Antibodies
254
Immunology
Antigen: Oligodendrocyte Proteins (Myelin Basic Protein, Proteolipid Protein)
Demyelinating Disease, Perivascular Inflammation, Paralysis, Ocular Lesions
CSF shows Oligoclonal Bands of IgG on Electrophoresis.
Rx: Corticosteroids, Interferon-β
Multiple Sclerosis
255
Immunology
Antigen: Antigen in Synovial Membrane
Chronic Arthritis, Rheumatoid Nodules, Lung Fibrosis
X-Ray, Rheumatoid Factor (85% Sensitive), Anti-CCP (95% Specific), ↑ESR, ↑CPR
Rx: Analgesia, steroids, DMARDs
Rheumatoid Arthritis (Also type III: IgM Ab vs Fc region of IgG)
256
Immunology
Antigen: Environmental Chemicals, Poison Ivy, Nickel
Dermatitis with usually short- lived itching, blisters and wheals
Clinical or use Patch Test
Rx: If no resolution use corticosteroids or antihistamines
Contact Dermatitis
257
Immunology
Antigen: Tuberculin
Skin Induration indicates TB exposure
Mantoux Test
258
Immunology
TH1 mediated. Chronic inflammation in skip lesions in GIT. NOD2 gene mutation in 30%.
Biopsy of lesion
(can affect any part of GIT from mouth to anus)
Rx: Antibiotics, anti- inflammatory drugs e.g. Mesalazine, TNF alpha antagonists e.g. infliximab, steroids
Crohn’s
| Disease
259
Immunology
NOD2 gene mutation in 30%.
Crohn’s
| Disease
260
Immunology
```
HLA B27
Relative risk (fold) - 87
```
Ankylosing spondylitis
261
Immunology
HLA DR15/DR2
Relative risk (fold) - 10
Goodpasture’s syndrome
262
Immunology
HLA- DR3
GRAVES
| SLE
263
Immunology
```
HLA DR3/DR4
Relative risk (fold) - 25
```
Type I diabetes
264
Immunology
HLA-DR4
Relative risk (fold) - 4
Rheumatoid arthritis
265
Immunology
PTPN22 polymorphism: tyrosine phosphatase expressed in lymphocytes, associated with
development of what conditions?
PTPN22: tyrosine phosphatase expressed in lymphocytes, associated
development of RA, SLE and T1DM.
266
Immunology
CTLA4: receptor for CD80/CD86 expressed by T cells, transmits inhibitory signal to
control T cell activation. Associated with development of what conditions?
CTLA4: receptor for CD80/CD86 expressed by T cells, transmits inhibitory signal to
control T cell activation. Associated with SLE, T1DM, Autoimmune thyroid disease.
267
Immunology
A tyrosine phosphatase expressed in lymphocytes, associated
development of RA, SLE and T1DM.
PTPN22
268
Immunology
A receptor for CD80/CD86 expressed by T cells, transmits inhibitory signal to
control T cell activation. Associated with SLE, T1DM, Autoimmune thyroid disease.
CTLA4
269
Immunology
Anti-Centromere Antibodies for diagnosis
Limited Cutaneous Scleroderma (CREST syndrome)
Calcinosis, Raynaud’s, Oesophageal dysmotility, Sclerodactyly, Telangiectasia
+ primary pulmonary hypertension
(skin involvement up to forearms only + perioral)
Anti-Centromere Antibodies for diagnosis
High risk of Lung Fibrosis and Renal Crisis
270
Immunology
CREST + GIT + interstitial pulmonary disease + renal problems
Diffuse Cutaneous Scleroderma
Anti- Topoisomerase/Scl70, RNA Pol I, II, III, Fibrillarin Antibodies
Females are affected more than men in the ratio 4:1
271
Immunology
Anti- Topoisomerase/Scl70, RNA Pol I, II, III, Fibrillarin Antibodies
Diffuse Cutaneous Scleroderma
CREST + GIT + interstitial pulmonary disease + renal problems
272
Immunology
M:F=1:9 Onset in late 40s
Dry mouth (xerostomia), eyes (keratoconjunctivitis sicca), nose and skin
May affect kidneys, blood vessels, lungs, liver, pancreas and PNS
Anti-Ro and anti-La antibodies present
Use Schirmer test to measure production of tears-assessing for dry eye
May get parotid or salivary gland enlargement
Sjogren’s Syndrome
273
Immunology
Schirmer test
Sjogren’s Syndrome
274
Immunology
Anti-Ro and anti-La antibodies present
Sjogren’s Syndrome
275
Immunology
Eczematous dermatitis, nail dystrophy and autoimmune skin conditions such as alopecia universalis and bullous pemphigoid
Most affected children die within the first 2 years of life.
X-linked recessive disorder with exclusive expression in males.
Bone marrow transplant is only cure. Can use immunomodulators to help.
IPEX syndrome
Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome + autoimmune diseases
276
Immunology
Deficiencies in coeliacs?
Iron, B12, folate, fat, vitamins A,D,E & K and calcium deficiencies
277
Immunology
IgA EMA (anti-endomysial antibody) disappears with exclusion diet (~95% specific, 85% sensitive)
IgA TGT (anti-transglutaminase antibody) (~95% specific, 90-94% sensitive)
IgG anti-gliadin antibody – most persistent (30-50% specific, 57-80% sensitive)
Coeliac Disease
278
Immunology
Coeliac Disease ABs
Which is most specific+sensitive?
IgA EMA (anti-endomysial antibody) disappears with exclusion diet (~95% specific, 85% sensitive)
IgA TGT (anti-transglutaminase antibody) (~95% specific, 90-94% sensitive)
IgG anti-gliadin antibody – most persistent (30-50% specific, 57-80% sensitive)
Ireland (memo EMA) – 3-10/1000. North Africa (memo TGT) – 20/1000
279
Immunology
DQ2 or DQ8 – Remember: Two eight or not to eat?
Coeliac
280
Immunology
Coeliac HLA association?
DQ2 or DQ8 – Remember: Two eight or not to eat?
281
Immunology
Antiphospholipid Syndrome
(Hugh’s Syndrome)
What antibody(s)?
Antibodies against cardiolipin and β2 glycoprotein, lupus anticoagulant,
282
Immunology
Autoimmune hepatitis
What antibody(s)?
Anti-smooth muscle antibody, Anti Liver Kidney microsomal-1 (anti-LKM-1). Anti Soluble Liver Antigen (anti-SLA)
283
Immunology
Name the 4 ENAs?
4 extractable nuclear antibodies (ENA’s) are: Ro, La, Sm and U1RNP
284
Immunology
Autoimmune haemolytic Anaemia
What antibody(s)?
Anti-Rh Blood Group Antigen
285
Immunology
Autoimmune Thrombocytopenic Purpura
What antibody(s)?
Anti-Glycoprotein IIb-IIIa or Ib-IX Antibody
286
Immunology
Churg-Strauss Syndrome (eGPA)
What antibody(s)?
Perinuclear/protoplasmic-staining antineutrophil cytoplasmic antibodies (p-ANCA)
287
Immunology
Coeliac disease
What antibody(s)?
Anti-tissue transglutaminase antibody (IgA), Anti- endomysial antibody (IgA)
288
Immunology
Congenital heart block in infants of mothers with SLE
What antibody(s)?
Anti-Ro antibody
289
Immunology
Dermatitis herpetiformis
What antibody(s)?
Anti-endomysial antibody (IgA)
290
Immunology
Dermatomyositis
What antibody(s)?
Anti-Jo-1 (t-RNA Synthetase)
291
Immunology
Diffuse Cutaneous Scleroderma
What antibody(s)?
Antibodies to Topoisomerase/Scl70, RNA Pol I,II,III, Fibrillarin (nucleolar pattern)
292
Immunology
Goodpasture’s Syndrome
What antibody(s)?
Anti-GBM Antibody
293
Immunology
Graves Disease
What antibody(s)?
Anti-TSH Receptor Antibody (stimulatory antibody)
294
Immunology
Hashimoto's Thyroiditis
What antibody(s)?
Antibodies to Thyroglobulin and Thyroperoxidase
295
Immunology
Limited cutaneous scleroderma (CREST)
What antibody(s)?
Anti-centromere antibody
296
Immunology
Microscopic Polyangitis (MPA)
What antibody(s)?
Perinuclear/protoplasmic-staining antineutrophil cytoplasmic antibodies (p-ANCA)
297
Immunology
Mixed connective tissue disease
What antibody(s)?
Anti-U1RNP antibody (speckled pattern)
298
Immunology
Myasthenia Gravis
What antibody(s)?
Anti-Ach Receptor Antibody
299
Immunology
Pernicious anaemia
What antibody(s)?
Antibody to gastric parietal cells (90%) and intrinsic factor (50%)
300
Immunology
Polymyositis
What antibody(s)?
Anti-Jo-1 (t-RNA Synthetase)
301
Immunology
Primary biliary cirrhosis
What antibody(s)?
Anti-mitochondrial antibody
302
Immunology
Rheumatoid Arthritis
What antibody(s)?
Anti-CCP Antibodies, Rheumatoid Factor (less specific)
303
Immunology
Sjogren’s syndrome
What antibody(s)?
Anti-Ro, Anti-La antibody (speckled pattern), 60-70% have positive RF
304
Immunology
Systemic Lupus Erythematosis
What antibody(s)?
Antibodies to dsDNA+ Histones(Homogenous) and Ro La, Sm, U1RNP (speckled)
305
Immunology
Type 1 Diabetes Mellitus
What antibody(s)?
Antibodies to Glutamate Decarboxylase and pancreatic β Cells
306
Immunology
Wegener's Granulomatosis (GP A)
What antibody(s)?
Cytoplasmic antineutrophil cytoplasmic antibodies (c- ANCA)
307
Immunology
Specific Immunoglobulin (passive vaccination) – post- exposure prophylaxis are available for what conditions?
Ig specific to Rabies, Varicella Zoster, Hep B, Tetanus
308
Immunology
Antibody specific for CTLA4 – blocks immune checkpoint and allows T cell activation; indications: advanced melanoma
Ipilimumab
309
Immunology
Antibody specific for PD-1 - blocks immune checkpoint and allows T cell activation; indications: advanced melanoma
Pembrolizumab/Nivolumab
310
Immunology
Cyclophosphamide
Mycophenolate Mofetil
Azathioprine
Methotrexate
Are all types of what class?
Anti-proliferative agents
| cytotoxic agents: inhibit DNA synthesis; cells with rapid turnover most sensitive
311
Immunology
Alkylates guanine base of DNA, Damages DNA and prevents cell replication, Affects B cells > T cells, but at high doses affects all cells with high turnover
Connective tissue disease, vasculitis, anti- cancer agent
SEs: Bone marrow suppression, infection, malignancy, teratogenic, hair loss, sterility, haemorrhagic cystitis
Cyclophosphamide
312
Immunology
Cyclophosphamide MOA
Alkylates guanine base of DNA, Damages DNA and prevents cell replication, Affects B cells > T cells, but at high doses affects all cells with high turnover
Connective tissue disease, vasculitis, anti- cancer agent
SEs: Bone marrow suppression, infection, malignancy, teratogenic, hair loss, sterility, haemorrhagic cystitis
313
Immunology
Inhibits IM PDH prevents guanine synthesis Blocks de novo nucleotide synthesis – prevents replication of DNA,
Prevents T>B cell proliferation
Transplantation, auto- immune diseases, vasculitis
SEs: Bone marrow supression, infection (herpes virus reactivation, progressive multifocal leukoencephalopathy), malignancy, teratogenic
Mycophenolate Mofetil
314
Immunology
Mycophenolate Mofetil MOA
Inhibits IM PDH prevents guanine synthesis Blocks de novo nucleotide synthesis – prevents replication of DNA,
Prevents T>B cell proliferation
Transplantation, auto- immune diseases, vasculitis
SEs: Bone marrow supression, infection (herpes virus reactivation, progressive multifocal leukoencephalopathy), malignancy, teratogenic
315
Immunology
Antimetabolite agent
Metabolised by liver to 6 mercaptopurine, blocks de novo purine (eg adenine, guanine) synthesis – prevents replication of DNA, preferentially inhibits T cell activation & proliferation
Transplantation, Auto-
immune disease, Auto- inflammatory diseases
SEs: Bone marrow supression, infection,
malignancy, teratogenic, hepatotoxicity, neutropenia
Some people have TPMT polymorphism, and are therefore unable to metabolise azathioprine
Azathioprine
316
Immunology
Azathioprine MOA
Antimetabolite agent
Metabolised by liver to 6 mercaptopurine, blocks de novo purine (eg adenine, guanine) synthesis – prevents replication of DNA, preferentially inhibits T cell activation & proliferation
Transplantation, Auto-
immune disease, Auto- inflammatory diseases
SEs: Bone marrow supression, infection,
malignancy, teratogenic, hepatotoxicity, neutropenia
Some people have TPMT polymorphism, and are therefore unable to metabolise azathioprine
317
Immunology
Inhibits dihydrofolate reductase (DHFR) therefore decreases DNA synthesis
RA, Psoriasis, Crohn’s, used in chemotherapy and as an abortifacient
SEs: Bone marrow supression, infection, malignancy, teratogenic, pneumonitis, pulmonary fibrosis, hepatotoxicity, folate deficiency (macrocytic megaloblastic anaemia)
Methotrexate
318
Immunology
Methotrexate MOA
Inhibits dihydrofolate reductase (DHFR) therefore decreases DNA synthesis
RA, Psoriasis, Crohn’s, used in chemotherapy and as an abortifacient
SEs: Bone marrow supression, infection, malignancy, teratogenic, pneumonitis, pulmonary fibrosis, hepatotoxicity, folate deficiency (macrocytic megaloblastic anaemia)
319
Immunology
Inhibits phospholipase A2 hence blocks arachidonic acid, reduces prostaglandin synthesis inhibits phagocyte trafficking, phagocytosis and release of proteolytic enzymes, lymphopenia, promotes apoptosis, blocks cytokine gene expression, decreased Ab production
Auto-immune disease, auto-inflammatory disease, prevention and treatment of transplant rejection
Transient neutrophilia, diabetes, central obesity, adrenal supression, cataracts, glaucoma, pancreatitis, osteoporosis, moon face, acne, hirtuism, hypertension, dyslipidaemia, peptic ulceration, avascular necrosis
Prednisolone
320
Immunology
MOA: prednisolone
MOA: Inhibits phospholipase A2 hence blocks arachidonic acid, reduces prostaglandin synthesis inhibits phagocyte trafficking, phagocytosis and release of proteolytic enzymes, lymphopenia, promotes apoptosis, blocks cytokine gene expression, decreased Ab production
Auto-immune disease, auto-inflammatory disease, prevention and treatment of transplant rejection
Transient neutrophilia, diabetes, central obesity, adrenal supression, cataracts, glaucoma, pancreatitis, osteoporosis, moon face, acne, hirtuism, hypertension, dyslipidaemia, peptic ulceration, avascular necrosis
321
Immunology
Aim - removal of pathogenic antibody; Plasma treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)
Severe antibody- mediated disease (Goodpastures syndrome, myasthenia gravis, vascular rejection) Antibody mediated rejection
SE: Rebound antibody production limits efficacy, anaphylaxis
Plasmapheresis
322
Immunology
List immunotherapies that act as inhibitors of cell signalling
```
Tacrolimus
Cyclosporin
Sirolimus
Tofacitinib
Apremilast
```
323
Immunology
MOA: inhibits calcineurin which normally activates transcription of IL-2, hence reduces T cell proliferaion
Rejection prophylaxis in transplantation
Nephrotoxic, hypertension, neurotoxic, diabetogenic, [[gingival (gum) hypertrophy]]
Tacrolimus
Cyclosporin
NB gingival (gum) hypertrophy is SE of ciclosporin
324
Immunology
MOA of:
Tacrolimus
Cyclosporin
MOA: inhibits calcineurin which normally activates transcription of IL-2, hence reduces T cell proliferaion
Rejection prophylaxis in transplantation
Nephrotoxic, hypertension, neurotoxic, diabetogenic, [[gingival (gum) hypertrophy]]
NB gingival (gum) hypertrophy is SE of ciclosporin
325
Immunology
MOA of sacrolimus
Blocks clonal proliferation of Tcells
Rejection prophylaxis in transplantation
Hypertension, less nephrotoxic
326
Immunology
Blocks clonal proliferation of Tcells
Rejection prophylaxis in transplantation
Hypertension, less nephrotoxic
Sacrolimus
327
Immunology
JAK inhibitor
Rheumatoid arthritis
Tofacitinib
328
Immunology
MOA of Tofacitinib
JAK inhibitor
| Rheumatoid arthritis
329
Immunology
PDE4 inhibitor
Psoriasis, psoriatic arthritis
Apremilast
330
Immunology
Apremilast MOA
PDE4 inhibitor
| Psoriasis, psoriatic arthritis
331
Immunology
Anti-CD25 (alpha chain of IL-2 receptor), inhibits T cell proliferation
Allograft rejection
SEs: Infusion reactions, Infection, Malignancy, GI disturbance
Basiliximab
CD-25 is an absolute SNAKE
332
Immunology
Basiliximab MOA
_____ is an absolute SNAKE
Anti-CD25 (alpha chain of IL-2 receptor), inhibits T cell proliferation
Allograft rejection
SEs: Infusion reactions, Infection, Malignancy, GI disturbance
CD-25 is an absolute SNAKE
333
Immunology
Anti-CTLA4-Ig, reduces T cell activation
Rheumatoid arthritis
SEs: Infusion reactions, infection (TB, HBV, HCV), malignancy, cough
Abatacept
I'm abata lose the will to live over CTLA4
334
Immunology
Abatacept MOA
I'm abata lose the will to live over _____
Anti-CTLA4-Ig, reduces T cell activation
Rheumatoid arthritis
SEs: Infusion reactions, infection (TB, HBV, HCV), malignancy, cough
I'm abata lose the will to live over CTLA4
335
Immunology
Anti-CD20, depletes mature B cells (not plasma cells)
Lymphoma, rheumatoid arthritis, SLE
SEs: Infusion reactions, infection (PML), exacerbation CV disease
Rituximab
336
Immunology
Rituximab MOA
Anti-CD20, depletes mature B cells (not plasma cells)
Lymphoma, rheumatoid arthritis, SLE
SEs: Infusion reactions, infection (PML), exacerbation CV disease
337
Immunology
Anti-alpha4 integrin (binds to VCAM1 and MadCAM1 to mediate rolling/arrest of leukocytes), inhibits T cell migration
Relapsing-remitting MS, Crohn's disease
SEs: Infusion reactions, infection (PML), malignancy, hepatotoxic
_____ has a vCAMera
Natalizumab
Anti-AlphA4 integrin - nAtAlizumAb
AAA
AAA
Natalie has a vCAMera
338
Immunology
Natalizumab MOA
Natalie has a ______
_ _ _
_ _ _
Anti-alpha4 integrin (binds to VCAM1 and MadCAM1 to mediate rolling/arrest of leukocytes), inhibits T cell migration
Relapsing-remitting MS, Crohn's disease
SEs: Infusion reactions, infection (PML), malignancy, hepatotoxic
339
Immunology
Anti-IL-6 receptor, Reduces macrophage, T cell, B cell, neutrophil activation
Castleman’s disease, Rheumatoid arthritis
SEs: Infusion reactions, Infection, Hepatotoxic, hyperlipidaemia, malignancy
You _____ to me IL6?
Tocilizumab
You talkin' (TOCIN) to me IL6?
340
Immunology
Tocilizumab MOA
You talkin' (TOCIN) to me ___?
Anti-IL-6 receptor, Reduces macrophage, T cell, B cell, neutrophil activation
Castleman’s disease, Rheumatoid arthritis
SEs: Infusion reactions, Infection, Hepatotoxic, hyperlipidaemia, malignancy
341
Immunology
Blocks CD3 on T cells, mouse monoclonal antibody (OKT3)
Active allograft transplant rejection
SEs: Fever, leucopenia
Mormons love 3 wives
Muromonab-CD3
OKT3
Mormons love 3 wives
342
Immunology
Muromonab-CD3 MOA
OKT3
Mormons love 3 wives
Blocks CD3 on T cells, mouse monoclonal antibody (OKT3)
Active allograft transplant rejection
SEs: Fever, leucopenia
343
Immunology
Lymphocyte depletion, Modulation of T cell activation and migration
allograft rejection (renal, heart)
SEs: Infusion reactions, Leukopenia, Infection, malignancy
Anti-thymocyte globulin
AKA THYMus + lymphoCYTE
344
Immunology
Anti-thymocyte globulin MOA
AKA THYMus + lymphoCYTE
Lymphocyte depletion, Modulation of T cell activation and migration
allograft rejection (renal, heart)
SEs: Infusion reactions, Leukopenia, Infection, malignancy
345
Immunology
IL-2 receptor antibody, targets CD25
Organ transplant rejection prophylaxis
__ _____ targets 25yos
Daclizumab
Da cleeze (John Cleese) targets 25yos
346
Immunology
Daclizumab MOA
Da cleeze (John Cleese) targets __yos
IL-2 receptor antibody, targets CD25
Organ transplant rejection prophylaxis
347
Immunology
Anti-CDIIa, inhibits migration of T cells
Efalizumab
Eh, Faliz! Do you have 2 A those CDs?
348
Immunology
Efalizumab MOA
Eh, Faliz! Do you have _ __ those ___?
Anti-CDIIa, inhibits migration of T cells
Eh, Faliz! Do you have 2 A those CDs?
349
Immunology
Monoclonal antibody that binds to CD52 found on lymphocytes resulting in depletion
Chronic lymphoid leukaemia, MS
SE: CMV infection
__ and __ went Tu Ze bar for B52s
Alemtuzumab (Campath)
Al and Em went Tu Ze bar for B52s
350
Immunology
MOA of: Alemtuzumab (Campath)
Monoclonal antibody that binds to CD52 found on lymphocytes resulting in depletion
Chronic lymphoid leukaemia, MS
SE: CMV infection
351
Immunology
anti-TNFa
Rheumatoid arthritis, Ankylosing spondylitis, Psoriasis, psoriatic arthritis, Inflammatory bowel disease
Infusion/injection site reactions, Infection (TB, HBV, HCV), Lupus-like conditions, Demyelination, Malignancy (lymphoma)
Infliximab
Adalimumab (fully human monoclonal antibody)
Certolizumab
Golimumab
352
Immunology
MOA of:
Infliximab
Adalimumab (fully human monoclonal antibody)
Certolizumab
Golimumab
anti-TNFa
Rheumatoid arthritis, Ankylosing spondylitis, Psoriasis, psoriatic arthritis, Inflammatory bowel disease
Infusion/injection site reactions, Infection (TB, HBV, HCV), Lupus-like conditions, Demyelination, Malignancy (lymphoma)
353
Immunology
TNFalpha/TNFbeta receptor p75-IgG fusion protein
Rheumatoid arthritis, Ankylosing spondylitis, Psoriasis and psoriatic arthritis
Injection site reactions, Infection (TB, HBV, HCV), Lupus-like conditions, Demyelination, Malignancy
Etanercept
354
Immunology
MOA of: Etanercept
TNFalpha/TNFbeta receptor p75-IgG fusion protein
Rheumatoid arthritis, Ankylosing spondylitis, Psoriasis and psoriatic arthritis
Injection site reactions, Infection (TB, HBV, HCV), Lupus-like conditions, Demyelination, Malignancy
355
Immunology
anti-IL-12 and IL-23 (binds to p40 subunit)
psoriasis/psorarthritis
injection site reactions, infection (TB),
malignancy, cough
I'm gonna _____ in IL 12 + 23 to get this answer
Ustekinumab
I'm gonna stek a knife in IL 12 + 23 to get this answer
356
Immunology
MOA of: Ustekinumab
I'm gonna stek a knife in IL __ + __ to get this answer
anti-IL-12 and IL-23 (binds to p40 subunit)
psoriasis/psorarthritis
injection site reactions, infection (TB),
malignancy, cough
I'm gonna stek a knife in IL 12 + 23 to get this answer
357
Immunology
anti-IL-17A
psoriasis, psoriatic arthritis, ankylosing spondylitis
infection (TB)
Secukinumab
SEventeen + SEcukinumab
358
Immunology
MOA of: Secukinumab
anti-IL-17A
SEventeen + SEcukinumab
psoriasis, psoriatic arthritis, ankylosing spondylitis
infection (TB)
359
Immunology
anti-RANK ligand antibody, Inhibits RANK mediated osteoclast differentiation and function
Osteoporosis, multiple myeloma, bone metastases
118
infection, avascular necrosis of jaw
_______ have strong bones
Denosumab
Denosaurs have strong bones
360
Immunology
MOA of: Denosumab
Denosaurs have strong _____
anti-RANK ligand antibody, Inhibits RANK mediated osteoclast differentiation and function
Osteoporosis, multiple myeloma, bone metastases
118
infection, avascular necrosis of jaw
361
Immunology
Recognition
T-Cells (TCs) recognise antigen with MHCs on APCs B-Cells (BCs) can recognise just antigen
T/F?
True
T-Cells (TCs) recognise antigen with MHCs on APCs B-Cells (BCs) can recognise just antigen
362
Immunology
```
HLA class I?
Present on what cells?
```
A/B/C
ALL
363
Immunology
```
HLA class II
Present on what cells?
```
DR/DP/DQ
| APCs and upregulated on other cells when stressed
364
Immunology
Most important HLAs in transplant?
DR-BA-rbera
HLA (most important DR>B>A)
Also consider minor HLA and ABO grouping
365
Immunology
What chromosome are HLAs coded on?
6
366
Immunology
Mins - Hrs
Preformed Ab which activates complement
Thrombosis and Necrosis
Prevention: Crossmatch (ABO groups) HLA-matching
Hyperacute rejection
367
Immunology
Hyperacute rejection time, mechanism and Rx?
Mins - Hrs
Preformed Ab which activates complement
Thrombosis and Necrosis
Prevention: Crossmatch (ABO groups) HLA-matching
368
Immunology
Weeks - Mths
CD4 activating a Type IV reaction
Cellular Infiltrate
T-Cell Immunosuppression
Acute – Cellular rejection
369
Immunology
Acute – Cellular rejection time, mechanism and Rx?
Weeks - Mths
CD4 activating a Type IV reaction
Cellular Infiltrate
T-Cell Immunosuppression
370
Immunology
Weeks - Mths
B-Cell activation - antibody attacks vessels
Vasculitis, C4d
Ab Removal and B-Cell Immunosuppression
Acute – Antibody Mediated rejection
371
Immunology
Acute – Antibody Mediated rejection time, mechanism and Rx?
Weeks - Mths
B-Cell activation - antibody attacks vessels
Vasculitis, C4d
Ab Removal and B-Cell Immunosuppression
372
Immunology
Mths - Years
Immune and non-immune mechanism
Risk factors:
1. multiple acute rejections 2. HTN
3. hyperlipidaemia
Fibrosis Glomerulopathy Vasculopathy (ischaemia) Bronchiolitis obliterans (lung)
Minimise Organ Damage with immunosuppression
Chronic rejection
373
Immunology
Chronic rejection time, mechanism and Rx?
Mths - Years
Immune and non-immune mechanism
Risk factors:
1. multiple acute rejections 2. HTN
3. hyperlipidaemia
Fibrosis Glomerulopathy Vasculopathy (ischaemia) Bronchiolitis obliterans (lung)
Minimise Organ Damage with immunosuppression
374
Immunology
Days - Weeks
Donor cells attacking host
Skin (rash), gut (D+V, bloody stool) and liver (jaundice) involvement
Prevention/ Immunosuppression- corticosteroids
GVHD
375
Immunology
GVHD time, mechanism and Rx?
Days - Weeks
Donor cells attacking host
Skin (rash), gut (D+V, bloody stool) and liver (jaundice) involvement
Prevention/ Immunosuppression- corticosteroids
376
Immunology
After xenograft, similar to hyperacute but 4-6 days after transplant
Acute vascular rejection
377
Immunology
How do you check recipient’s pre-formed Ab against ABO and HLA ?
CDC = Complement Dependent Cytotoxicity
FACS = Flow Cytometry
Luminex = like solid phase FACS – can pick up Abs to individual HLAs
378
Immunology
3 stages of immunosuppression with transplants?
1. Pre-transplant induction agent: suppress T cell responses eg: anti-CD52 Alemtuzumab or anti-CD25 Basiliximab or OKT3/ATG
2. Immunosuppressants post-transplant to reduce rejection eg: CNI + MMF/Aza +/- steroids
3. Treat episodes of acute rejection:
Cellular – Steroids, OKT3/ATG
Ab-mediated – IVIG, plasma exchange, anti-C5, anti-CD20
379
Immunology
Eliminate hosts immune system (total body irradiation; cyclophophamide; other
drugs)
Replace with own (autologous) or HLA-matched donor (allogeneic) bone marrow
Allogeneic HSCT leads to reaction of donor lymphocytes against host tissues
Related to degree of HLA-incompatibility
Also graft-versus-tumour effect
GVHD prophylaxis: Methotrexate/Cyclosporine
Symptoms: skin (rash), gut (nausea, vomiting, abdominal pain, diarrhoea, bloody stool), liver (jaundice)
Treat with corticosteroids
Haematopoietic stem-cell transplantation (HSCT) –
380
Immunology
Sx of graft-versus-host disease post stem cell transplantation?
Symptoms: skin (rash), gut (nausea, vomiting, abdominal pain, diarrhoea, bloody stool), liver (jaundice)
Treat with corticosteroids
381
Immunology
What cardiac related complication occurs in transplant patients?
Hypertension, hyperlipidaemia
| X20 increase risk in death from MI compared to age-matched general population
382
Immunology
Receptor for HIV
CD4
383
Immunology
What does HIV bind to first?
The virus binds via gp120 (initial binding) and gp41 (conformational change) – on CD4+ T cells
384
Immunology
What coreceptors does HIV use for entry?
CCR5 and CXCR4 chemokine co-receptors (on macrophages)
385
Immunology
Name the neutralising antibodies seen in HIV infection?
Neutralising antibodies: anti-gp120 and anti-gp41
386
Immunology
Name the non-neutralising antibody seen in HIV infection?
Non-neutralising antibodies: anti-p24 gag IgG
387
Immunology
CD8+ T Cells can prevent HIV entry by producing what chemokines?
MIP-1a, MIP-1b, and
| RANTES which block co-receptors.
388
Immunology
Function of MIP-1a, MIP-1b, and
RANTES in HIV infection
CD8+ T Cells can prevent HIV entry by producing chemokines MIP-1a, MIP-1b, and
RANTES which block co-receptors.
389
Immunology
HIV remains infectious even when Ab coated
T/F
T
390
Immunology
MoA of HIV screening test?
Detects anti-HIV Ab via ELISA
391
Immunology
MoA of confirmation HIV test?
Detects Ab via Western Blot
A positive test requires the patient to have SEROCONVERTED (i.e. started to produce Ab) This happens after ~10 weeks incubation period
392
Immunology
How many CD4 T cells in aids?
IDS <200cells/μL blood.
393
Immunology
2 methods of HIV viral resistance testing?
Phenotypic: Viral replication is measured in cell cultures under selective pressure of
increasing concentrations of antiretroviral drugs – compared to wild-type
Genotypic: Mutations determined by direct sequencing of the amplified HIV genome
394
Immunology
What does HAART consist of?
2NRTIs + PI (or NNRTI)
395
Immunology
2NRTIs + PI (or NNRTI)
HAART
396
Immunology
Emtricitabine + Tenofovir + Efavirenz
Atripla
397
Immunology
Limitations of HAART
Doesn’t eradicate latent HIV-1; fails to restore HIV-specific T-cell responses; toxicities; high pill burden; adherence; threat of drug resistance; QoL; cost.
398
Immunology
Interrupts transcription of HIV RNA->DNA?
NRTIs
| NNTRIs
399
Immunology
VUD in an HIV medication = what class of Rx?
In general = NRTI
Zidovudine
Stavudine
Lamivudine
400
Immunology
VIR in MIDDLE of HIV medication = what class of Rx?
NNRTI (think that RT of viral DNA is in the MIDDLE of steps for HIV replication
401
Immunology
VIR at END of HIV medication name = what class of Rx?
Protease Inhibitors
Prevent release of viral particles
402
Immunology
DTaP/IPV/HiB
(1 injection – Pediacel)
PCV
R
What age?
2 months
403
Immunology
DTaP/IPV/HiB
Men C
R
What age?
3 months
404
Immunology
DTaP/IPV/HiB
PCV
What age?
4 months
405
Immunology
Hib/Men C
PCV
MMR
What age?
12-13 months
406
Immunology
DTaP/IPV
MMR
What age?
3 years 4 months
407
Immunology
HPV
Vaccine
What age?
Girls 12-13 years
408
Immunology
Td/IPV
Men C
Vaccine
What age?
13-18 years
409
Immunology
CD45 RO present on what cells?
Memory T cells
410
Immunology
CD45 RA present on what cells?
naïve T cells
411
Immunology
Found in lymph nodes & tonsils- roll along and extravasate in High Endothelial Venules (HEVs)
Central Memory Cells
412
Immunology
CCR7+ and CD62L high (allow entry/migrate via HEVs to peripheral lymph nodes)
Central Memory Cells
413
Immunology
Produce IL-2 (to support other cells)
More central memory in CD4 population
Central Memory Cells
414
Immunology
Found in liver and lungs & gut
Which memory cells?
Effector Memory Cells
415
Immunology
CCR7-ve and CD62L low (therefore not found in lymph nodes)
Which memory cells?
Effector Memory Cells
416
Immunology
Effector so produce – perforin and IFN-γ
More effector memory in CD8 population
Effector Memory Cells
417
Immunology
Why doesn’t vaccination work effectively in the elderly?
Immune senescence: Increased frequency of terminally differentiated effector memory T cells in the elderly; Increased expression of senescence markers; Much reduced production of recent thymic emigrants which drive the naïve T-cell repertoire.
Nutrition: insufficient energy because of poor nutrition; Reduced availability of trace elements and minerals (reduced gut absorption)
418
Immunology
```
Sabin polio - no longer used)
MMR
Chicken pox (varicella)
Yellow fever
BCG
Typhoid
```
what types of vaccine?
LIVE
Live attenuated: BCG, MMR, typhoid
419
Immunology
Salk (polio), Anthrax, Cholera, Bubonic plague, Hep A, Rabies, Pertussis, Influenza
what types of vaccine?
Inactivated: Salk (polio), Anthrax, Cholera, Bubonic plague, Hep A, Rabies, Pertussis, Influenza
420
Immunology
Hep B (HbS antigen), HPV (Capsid), Influenza (haemagglutinin, Neuraminidase),
what types of vaccine?
Component/subjunit: Hep B (HbS antigen), HPV (Capsid), Influenza (haemagglutinin, Neuraminidase),
421
Immunology
Tetanus (Exotoxin), Hib, Meningococcus, Pneumococcus
what types of vaccine?
Conjugate: Tetanus (Exotoxin), Hib, Meningococcus, Pneumococcus
422
Immunology
Diphtheria, Tetanus
what types of vaccine?
Toxoids: Diphtheria, Tetanus
423
Immunology
Which SPECIFIC vaccines CANT HIV sufferers have?
HIV positive patients may have MMR but not BCG or Yellow fever
424
Immunology
Antigens are adsorbed to this so acts as means of slowly releasing antigen.
Activates Gr1+ cells to produce IL-4 helps prime naïve B cells (mainly antibody mediated response). Generally safe and mild
What adjuvant?
ALUM: Primary adjuvant utilized in humans. Antigens are adsorbed to alum so acts as means of slowly releasing antigen. Activates Gr1+ cells to produce IL-4helps prime naïve B cells (mainly antibody mediated response). Generally safe and mild
425
Immunology
What adjuvant?
Immunostimulatory adjuvant activity is linked to unmethylated DNA motif rich in DNA where a cytosine nucleotide is situated next to a guanine nucleotide.
Activates TLRs(9) on APCs stimulating expression of costimulatory molecules.
CpG: Immunostimulatory adjuvant activity is linked to unmethylated DNA motif rich in CpG (DNA where a cytosine nucleotide is situated next to a guanine nucleotide) Activates TLRs on APCs stimulating expression of costimulatory molecules.
426
Immunology
Water-in-oil emulsion containing mycobacterial cell wall components. Mainly for animals, painful in humans (not used clinically)
What adjuvant?
Complete Freund’s adjuvant: water-in-oil emulsion containing mycobacterial cell wall components. Mainly for animals, painful in humans (not used clinically)
427
Immunology
Experimental – multimeric antigen with adjuvant built in. Cell-mediated immune response and humoral response. With saponin results in strong serum antibody response.
What adjuvant?
ISCOMS (Immune Stimulating Complex): Experimental – multimeric antigen with adjuvant built in. Cell-mediated immune response and humoral response. With saponin results in strong serum antibody response.
428
Immunology
In individuals with Hep B Sag in order to get them to seroconvert
What adjuvant?
Interleukin 2: in individuals with Hep B Sag in order to get them to seroconvert
429
Immunology
What indicates a positive Mantoux?
Inject 0.1 ml of 5 tuberculin (=purified protein derivative) units intradermally, examine arm 48-72 hrs after
A positive result is indicated by induration (swelling that can be felt) of at least 10 mm in diameter (erythema around not measured). This implies previous exposure to tuberculin protein - thus it could represent previous BCG exposure.
430
Microbiology
```
Post-primary (Young adults)
?Re-activation/Re-infection
Upper lobes affected
May progress rapidly to cavitation Classic lesion: caseating granuloma Miliary spread rare
Healing by fibrosis + calcification
```
TB
431
Microbiology
Presentation
Cough ± Haemoptysis Fever (with night sweats) Weight loss (?anorexia) Malaise
Ethnicity
TB
432
Microbiology
Multiplies at pleural surface (Ghon focus). Taken by mΦ to LN (Primary complex). Generalised lympho- haematogenous spread. Granuloma is characteristic lesion (Langhan’s giant cells)
Can be asymptomatic, esp in children Rarely:
Tuberculoma
Progressive primary’; focus or node ulcerates into
bronchus -> pneumonia, cavity formation, bronchiectasis, consolidation, collapse
Miliary TB – progressive, disseminated ematogenous spread. ‘Rich’ foci
Primary infection in:
TB presentation in children, elderly, HIV
433
Microbiology
Primary infection of:
TB in children, elderly, HIV
present differently?
Multiplies at pleural surface (Ghon focus). Taken by mΦ to LN (Primary complex). Generalised lympho- haematogenous spread. Granuloma is characteristic lesion (Langhan’s giant cells)
Can be asymptomatic, esp in children Rarely:
Tuberculoma
Progressive primary’; focus or node ulcerates into
bronchus -> pneumonia, cavity formation, bronchiectasis, consolidation, collapse
Miliary TB – progressive, disseminated ematogenous spread. ‘Rich’ foci
434
Microbiology
Rx TB latent?
1st line
-Rifampicin (RIF) – Drug interactions (raised transaminases, induces cytochrome P450), orange secretions hepatotoxicity
-Isoniazid (INA) – peripheral neuropathy (give B6/pyrodoxine),
hepatotoxicity
-Pyrazinamide – Hyperuricaemia, hepatotoxicity
-Ethambutol – optic neuritis, visual disturbances
-INA + RIF + PYR + ETH for 2/12 then INA + RIF for 4/12 -TB meningitis – Increase 2nd stage of INA + RIF to 8-10/12 - LATENT TB – 6/12 Isoniazid
DOTS, adherence is key. Vit D supplements.
435
Microbiology
Rx TB normal
1st line
-Rifampicin (RIF) – Drug interactions (raised transaminases, induces cytochrome P450), orange secretions hepatotoxicity
-Isoniazid (INA) – peripheral neuropathy (give B6/pyrodoxine),
hepatotoxicity
-Pyrazinamide – Hyperuricaemia, hepatotoxicity
-Ethambutol – optic neuritis, visual disturbances
-INA + RIF + PYR + ETH for 2/12 then INA + RIF for 4/12 -TB meningitis – Increase 2nd stage of INA + RIF to 8-10/12 - LATENT TB – 6/12 Isoniazid
DOTS, adherence is key. Vit D supplements.
436
Microbiology
| TB meningitis Rx
1st line
-Rifampicin (RIF) – Drug interactions (raised transaminases, induces cytochrome P450), orange secretions hepatotoxicity
-Isoniazid (INA) – peripheral neuropathy (give B6/pyrodoxine),
hepatotoxicity
-Pyrazinamide – Hyperuricaemia, hepatotoxicity
-Ethambutol – optic neuritis, visual disturbances
-INA + RIF + PYR + ETH for 2/12 then INA + RIF for 4/12 -TB meningitis – Increase 2nd stage of INA + RIF to 8-10/12 - LATENT TB – 6/12 Isoniazid
DOTS, adherence is key. Vit D supplements.
437
Microbiology
TB stain
ZN/auramine staining
438
Microbiology
Gram e rods, acid fast, aerobic, intracellular
MTB
439
Microbiology
MTB, what morphology bacteria and g stain?
Gram +ve rods, acid fast, aerobic, intracellular
440
Microbiology
Subacute presentation Weight loss, fever, night-sweats Headache, neck- stiffness
Personality change, ↓ GCS
Focal neurological deficit
Diagnosis : CT – tuberculomata, LP – Lymphocytic
Rx – >12/12 anti-TB + steroids
TB meningitis
441
Microbiology
- Fever, sweats, wt loss, Back pain -Haematogenous spread initial discitis Vertebral destruction + collapse ± Anterior extension (causing iliopsoas abscess)
- Ix – MRI/CT ± Biopsy/Aspirate -Treatment – 12/12 anti-TB
Spinal TB
442
Microbiology
What sort of vaccine is BCG?
Attenuated strain of M. Bovis (BCG=Bacille Calmette-Guerin)
Efficacy 0-80% – Bad for pulmonary TB. Good for leprosy, TB meningitis, disseminated TB.
-Babies born in or with parents/grandparents from areas with incidence >40/100,000
-Previously unvaccinated new immigrants from high prevalence countries for TB
443
Microbiology
Can HIV+ve get BCG vaccine?
Contraindicated in HIV pts
-HIV –ve latent TBactive TB 5-10% lifetime risk
-HIV +ve latent TB active TB 5-10% yearly risk
- Be aware of immune reconstitution inflammatory syndrome (IRIS) in HIV
patients – development of symptoms after HIV tx started
444
Microbiology
Key manifestations
-Skin: Depigmentation, macules, plaques, nodules, trophic ulcers
-Nerves: Thickened nerves, sensory neuropathy -Eyes: Keratitis, Iridocyclitis
-Bone: Periositis aseptic necrosis Immunological/Clinical spectrum of leprosy -Tuberculoid (TT). Paucibacillary. Th1-mediated Depigmented lesions
-BT – nerve damage
-Borderline (BB) – multiple plaques
-BL
-Lepromatous (LL). Multibacillary. Th2-mediated.
Neuropathic ulcers (cf DM)
```
M. Leprae + M. Lepromatosis
Life-long illness. Incubation 2-10yrs
Poor transmission via nasal secretions
Most disability 2o to nerve damage
Rx – rifampicin, dapsone, clofazimine – if multibacillary
```
445
Microbiology
Rx for:
M. Leprae + M. Lepromatosis
Life-long illness. Incubation 2-10yrs
```
M. Leprae + M. Lepromatosis
Life-long illness. Incubation 2-10yrs
Poor transmission via nasal secretions
Most disability 2o to nerve damage
Rx – rifampicin, dapsone, clofazimine – if multibacillary
```
446
Microbiology
- Children – Pharyngitis/cervical adenitis
- Pulmonary – Underlying lung disease (resembles TB)
- Disseminated – Cytotoxics, lymphoma etc
- AIDS – Disseminated multibacillary infection, Mycobacteraemia (consider in HIV pts with londstanding diarrhoea)
M. Avium-intracellulare complex
447
Microbiology
- Single or clusters of papules/plaques
- Swimming pool/aquarium owners
What mycobacterium?
M. Marinarum (fish tank granuloma)
448
Microbiology
- Early – painless nodule
- Usually slowly progressive leading to ulceration, scarring + contractures -Seldom fatal, hideous deformity
What mycobacterium?
M. Ulcerans (Buruli Ulcer) – insect transmission; tropics/Aus
449
Microbiology
Inflammation of medium sized airways. Mainly in smokers. Cough with sputum most days for 3 months, for 2 or more consecutive years.
Cough, fever, increased sputum production, increased SOB
Organisms: Viruses, S. pneumoniae, H. influenzae, M. catarrhalis
CXR: normal
Rx – Bronchodilation; Physiotherapy +/- Abx
Bronchitis
450
Microbiology
Rusty-coloured sputum. Usually lobar on CXR. Vaccinate groups at risk
+ve diplococci
S. Pneumonias
451
Microbiology
What morphology+gram is S.pneumoniae?
+ve diplococci
452
Microbiology
What morphology+gram is H. influenza?
-ve cocco-bacilli
453
Microbiology
What morphology+gram is M. catarrhalis?
-ve coccus
454
Microbiology
What morphology+gram is S. aureus
+ve cocci “grape-bunch clusters”
455
Microbiology
What morphology+gram is K. pneumonia?
-ve rod, enterobacter
456
Microbiology
Alcoholism, elderley. Haemoptysis
-ve rod, enterobacter
K. pneumonia
457
Microbiology
Assoc. w/ recent viral infection (EMQs: post-INFLUENZA infection) ± cavitation on CXR
+ve cocci “grape-bunch clusters”
S. aureus
458
Microbiology
Assoc. w/ smoking
-ve coccus
M. catarrhalis
459
Microbiology
Assoc. w/ smoking, COPD
-ve cocco-bacilli
H. influenza
460
Microbiology
What is an atypical pneumonia?
NO signs on chest examination or signs not in keeping with CXR
Organisms with no cell wall don’t respond to penicillin Abx. Use Macrolides +
Tetracyclines
Maybe extrapulmonary
features (eg hepatitis, ↓Na)
461
Microbiology
Travel, air conditioning, water towers, HEPATITIS, Low Na
Which atypical pneumonia?
Legionella pneumophilia
462
Microbiology
Common – systemic symptoms, joint pain, cold agglutinin test, erythema multiforme. Risk SJS, AIHA
Which atypical pneumonia?
Mycoplasma pneumonia
463
Microbiology
Hard to diagnose – TWAR agent
Which atypical pneumonia?
Chlamydia pneumonia
464
Microbiology
Birds
Which atypical pneumonia?
Chlamydia psittaci
465
Microbiology
Whooping cough in unvaccinated – (often travelling community in EMQs)
Bordatella pertussis
466
Microbiology
Poor response to Abx
TB
467
Microbiology
List 3 RTIs seen commonly with HIV immunosuppression?
P. Jiroveci (PCP), TB, Cryptococcus neoformans
468
Microbiology
List an RTI seen commonly with Neutropaenia?
Fungi – Aspergillus spp.
469
Microbiology
List RTIs seen commonly with
Bone Marrow Tx?
Aspergillus + CMV
470
Microbiology
List RTIs seen commonly with Splenectomy?
Encapsulated organisms – H. influenza, S. pneumonia, N. Meningitidis
471
Microbiology
List an RTI seen commonly with
CF?
Pseudomonas aeruginosa, Burkholderia cepacia (v. high mortality)
472
Microbiology
Urine Antigen Tests in severe CAP for....
S. pneumoniae, Legionella
473
Microbiology
For which 2 atypical pneumonias do you perform paired serum samples (At presentation + 10-14/7), looking for a rise in Ab level
over time?
Most useful for difficult-to-culture (Chlamydia, Legionella
474
Microbiology
Silver stain in cytology lab. Boat-shaped organisms
PCP
475
Microbiology
Morphology + stain for PCP?
Silver stain in cytology lab. Boat-shaped organisms
476
Microbiology
>48hrs into hospital stay without previous infection
HAP
477
Microbiology
HAP definition?
>48hrs into hospital stay without previous infection
478
Microbiology
Mild-moderate
Abx for typical Community Acquired Pneumonia
Penicillin 1st line (Amoxicillin) or Macrolide (Penn. Allergic) (5-7days)
479
Microbiology
Moderate-Severe
Abx for typical Community Acquired Pneumonia
Penicillin + Macrolide (Co-amoxiclav + Clarithromycin) (2-3 weeks)
480
Microbiology
Abx for atypical Community Acquired Pneumonia (Chlamydia, Mycoplasma)
Use protein synth. Abx – Macrolide/T etracycline
| At charing cross we use clarithromycin. Interacts with warfarin!
481
Microbiology
1st line HAP Rx
Ciprofloxacin ± Vancomycin
482
Microbiology
2nd Line/ITU HAP Rx
Piptazobactam + Vancomycin (ITU pts increased risk of resistant bacteria/MRSA)
483
Microbiology
What is the ABx Rx for HAP if you need to ASPIRATE
Aspiration: Cefuroxime + Metronidazole (need gram +ve, -ve and anaerobic cover for aspiration)
484
Microbiology
Legionella CAP Rx?
Macrolide + Rifampicin
485
Microbiology
S. aureus CAP Rx? (NON MRSA)
Flucloxacillin
486
Microbiology
Pseudomonas spp. HAP Rx?
Piperacillin+tazobactam (tazocin) or Ciprofloxacin ± Gentamicin
487
Microbiology
MRSA HAP Rx?
Vancomycin
488
Microbiology
Painful genital ulcers
What 2 differentials?
What is more likely?
Painful = herpes > chancroid
489
Microbiology
Painless genital ulcers
What 2 differentials?
Which are more likely?
Painless = syphilis > lymphogranuloma venereum (LGV) + granuloma inguinale
490
Microbiology
Neisseria gonorrhoeae, what morphology and stain?
Obligate intracellular Gram –ve diplococcus.
491
Microbiology
Obligate intracellular Gram –ve diplococcus.
Neisseria gonorrhoeae
492
Microbiology
Complement deficiency + Gonorrhoea infection: what are the repercussions?
They get disseminated gonococcal infection -> Septicaemia, rash and/or arthritis
493
Microbiology
Neonatal infection with Neisseria gonorrhoeae (aka mother untreated when giving birth): what are the repercussions?
Opthalmia neonatorum (neonatal conjunctivitis) develops if left untreated when transfer to child from birth canal.
494
Microbiology
Diagnosis of N.gonorrhoea
Diagnosis: urethral (sensitivity 95%) / rectal (sensitivity 20%) smears – producing a culture from these is Gold Standard.
495
Microbiology
Rx of gonorrhoea?
What about resistant gonorrhoea?
Treatment: Ceftriaxone IM – 250mg single dose OR Cefixime PO – 400mg single dose o If resistant Spectinomycin IM – 2g single dose
496
Microbiology
Obligate intracellular pathogen. Cannot be cultured on agar. Gram negative.
Chlamidya Trachomatis
497
Microbiology
What morphology is Chlamidya Trachomatis?
Obligate intracellular pathogen. Cannot be cultured on agar. Gram negative.
498
Microbiology
Assoc. with younger age. In the UK 10% of <25s are affected.
Often asymptomatic (in 50% of men and 80% of women)
Unique growth cycle, existing in two forms:
o Elementary bodies, stable, extracellular
o Reticulate particles, intracellular, metabolically active
Chlamidya Trachomatis
499
Microbiology
Which serovars of chlamidya infect the eyes?
Serovars A, B, C – Trachoma – infection of the eyes which can -> blindness
500
Microbiology
Which serovars of chlamidya infect the genital tract but can cause ophthalmia neonatorum?
Serovars D-K – Genital chlamydia infection, ophthalmia neonatorum
501
Microbiology
Diagnosis Chalmidya Tracho?
NAAT (nucleic acid amplification tests). Gold standard. High specificity + sensitivity
502
Microbiology
Rx of chlamidya trach?
Azithromycin – 1g (4 capsules) stat Doxycycline – 100mg BD 7/7
503
Microbiology
S/E – N&V, photosensitivity; C/I pregnancy (disturbance bone growth, tooth discoloration)
Doxycyxline
504
Microbiology
What is Lympho-granuloma venereum (LGV)?
What serovars cause it?
Lymphatic infection with Chlamydia trachomatis: serovars L1, L2 and L3
505
Microbiology
Lymphatic infection with Chlamydia trachomatis: serovars L1, L2 and L3
Lympho-granuloma venereum (LGV)
506
Microbiology
o Early LGV – 1o stage 3-12/7 – Genital ulcer: painless, non-indurated. Balanitis, proctitis, cervicitis
o Early LGV – 2o stage 2-25/52 – Inguinal buboes: painful, 2/3 unilateral. May rupture. Fever, malaise, Rarely (hepatitis, meningo-encephalitis, pneumonitis), Proctocolitis, Hyperplasia of lymphoid tissue
o Late LGV – Inguinal LNpathy, abscess formation, genital elephantiasis, genital ulcers, frozen pelvis, rectal strictures, perirectal abscesses + fistulae, lymphorroids
o Current LGV outbreak: Rectal symptoms – Pain, tenesmus, bleeding, mucous discharge. O/E – Proctitis
Lympho-granuloma venereum (LGV)
507
Microbiology
Ix for LGV?
NAAT (currently unlicensed)
If positive will be sent to ref lab at central HPA
Confirmation of C trachomatis by real time PCR on 2 platforms
Genotypic identification of L1, L2 or L3 serovar
508
Microbiology
Rx LGV?
Tetracyclines: Doxycycline 100mg BD for 21/7
| Erythromycin 500mg QDS for 21/7 / Azithromycin 1g weekly 3/52
509
Microbiology
Obligate gram-negative spirochaete
Treponema pallidum – Obligate gram-negative spirochaete. Majority of cases are in those who are HIV +ve. Often co-infected with HCV or another STI. Rising in UK.
Treponemes seen in 1o lesions by dark-ground microscopy. Can be detected with multiplex real-time PCR
Detection of antibody is diagnostic method of choice.
510
Microbiology
What morphology/stain is Treponema pallidum
Obligate gram-negative spirochaete
511
Microbiology
List non-treponemal tests for Treponema pallidum?
Non-Treponemal tests
Detect non-specific antigens
VDRL slide test: detects lipoidal antibody on both host and treponemal cells
Reagents contain cardiolipin, lecithin and cholesterol – can get biological false
+ves (if APLS)
RPR is a modified VDRL test Positive is indicative of treponemal infection
Useful in primary syphilis
Titre falls in response to treatment therefore can be used to monitor response
512
Microbiology
List treponemal tests for Treponema pallidum
Detect Abs against specific antigens from T. pallidum
Examples: Enzyme Immunoassay (EIA), Fluorescent treponemal antibody
(FTA), T. pallidum haemagglutination test (TPHA), T. pallidum particle
agglutination test (TP-PA)
More specific than non-treponemal test
Remains positive for years despite effective tx.
513
Microbiology
Macule->papule->indurated painless genital ulcer appearing 1-12 weeks following transmission. Often solitary. May persist 4-6 weeks (chancre) Clean base with serous exudate. Regional adenopathy.
1o syphilis
514
Microbiology
Systemic bacteraemia. Low grade fever, malaise, Symmetrical, Non-pruritic, Maculo-papular rash on back, trunk, arms, legs, palms, soles, face 1-6/12 following infection. Mucosal lesions, Uveitis, choroidoretinitis, alopecia, ‘snail track’ oral ulcers, condyloma acuminate (genital warts). Neurological involvement (Aseptic meningitis, Cranial nerve palsies, Optic neuritis, Acute nerve deafness)
2o syphilis
515
Microbiology
Gumma (granuloma) – Rare. 2-40 yrs later. Skin, bone, mucosa. Spirochaetes scanty – DTH reaction
• Cardiovascular – 10-30 yrs later. Uncomplicated + complicated aortitis. +++ spirochaetes, +++ inflammation
• Neurosyphilis (most common in HIV +ve) – 2-30 yrs later. Meningovascular, General paresis of the insane, Tabes dorsalis, Gumma. Spirochaetes in CSF. Small vessel vasculitis. Argyll-Robertson pupil (prostitute’s pupil – accommodates but does not react)
3o syphilis
516
Microbiology
What is an Argyll-Robertson pupil?
prostitute’s pupil – accommodates but does not react
3o syphilis
517
Microbiology
Rx syphilis?
Single dose IM Benzathine Penicillin (Doxycycline if allergic)
Monitor RPR, need to see a four-fold reduction to consider tx successful
• NB: Jarisch-Heimer reaction (fever, headache, myalgia, sometimes exacerbation of
syphilitic symptoms) – common, develops within hours of abx administration and
clears within 24hrs.
518
Microbiology
Haemophilus ducreyi
Chancroid
519
Microbiology
What bacteria causes Chancroid?
Haemophilus ducreyi
520
Microbiology
Haemophilus ducreyi/causes chancroid - what morphology/stain?
Haemophilus ducreyi. Gram -ve coccobacillus (like Hib)
Tropical ulcer disease mainly in Africa. Rare in UK
Often multiple ulcers, frequently painful
Diagnosis – Culture (Chocolate agar), PCR
521
Microbiology
Tropical ulcer disease mainly in Africa. Rare in UK
Often multiple ulcers, frequently painful
Diagnosis – Culture (Chocolate agar), PCR
Haemophilus ducreyi/causes chancroid
522
Microbiology
Diagnosis chancroid/Haemophilus ducreyi
Diagnosis – Culture (Chocolate agar), PCR
523
Microbiology
Cause of Donovanosis = Granuloma inguinale?
Klebsiella granulomatis. Gram negative bacillus
524
Microbiology
Klebsiella granulomatis (Donovanosis = Granuloma inguinale) morphology and stain?.
Gram negative bacillus
525
Microbiology
Africa, India, PNG, Australian aboriginal communities
Large, expanding ulcers starting as papule or nodule that breaks down. Beefy red
appearance
Diagnosis – Giemsa stain of biopsy or tissue crush. Donovan bodies
Treated with azithromycin
Donovanosis = Granuloma inguinale
526
Microbiology
Klebsiella granulomatis. Gram negative bacillus
Africa, India, PNG, Australian aboriginal communities
Large, expanding ulcers starting as papule or nodule that breaks down. Beefy red
appearance
Diagnosis – Giemsa stain of biopsy or tissue crush. Donovan bodies
Treated with azithromycin
Donovanosis = Granuloma inguinale
527
Microbiology
Diagnosis of Donovanosis = Granuloma inguinale
Diagnosis – Giemsa stain of biopsy or tissue crush. Donovan bodies
528
Microbiology
Giemsa stain?
Donovanosis = Granuloma inguinale -> Klebsiella granulomatis
529
Microbiology
Rx of Donovanosis = Granuloma inguinale
Treated with azithromycin
530
Microbiology
```
Flagellated protozoan
Diagnosis – Wet prep microscopy, PCR
Asymptomatic or urethritis in men. Discharge in women. Assoc. ↑ risk of HIV
acquisition
Treatment – Metronidazole
```
T . vaginalis
531
Microbiology
Rx of – T . vaginalis
```
Flagellated protozoan
Diagnosis – Wet prep microscopy, PCR
Asymptomatic or urethritis in men. Discharge in women. Assoc. ↑ risk of HIV
acquisition
Treatment – Metronidazole
```
532
Microbiology
Ix for – T . vaginalis
```
Flagellated protozoan
Diagnosis – Wet prep microscopy, PCR
Asymptomatic or urethritis in men. Discharge in women. Assoc. ↑ risk of HIV
acquisition
Treatment – Metronidazole
```
533
Microbiology
Abnormal vaginal flora, polymicrobial, ↓lactobacilli. Discharge, odour
Sexually associated, not transmitted. May be associated with hygiene practices
Diagnosed on microscopy of gram stain, raised pH, whiff test, clue cells
Still not fully understood. Often recurrent. Assoc. with preterm delivery
Bacterial vaginosis
534
Microbiology
whiff test, clue cells
Bacterial vaginosis
535
Microbiology
Usually Candida albicans, yeast
If symptomatic, white thick discharge, itching, soreness, redness
Common presentation in women as vulvovaginitis, men balanitis
Not sexually transmitted, can be part of normal flora
Treated with topical or oral antifungals, e.g. clotrimazole or fluconazole
Recurrence may be associated with immunodeficiency or hygiene practices
Candidiasis
536
Microbiology
Pox virus, dsDNA
Hands + faces in children, spread skin to skin contact.
In adults, causes genital lesions + spread via sexual contact.
Molluscum contagiosum
537
Microbiology
Pox virus, dsDNA
STD
Molluscum contagiosum
Facial molluscum in adult = HIV until proved otherwise. Get giant lesions in the immunocompromised
Treatment if required, is destructive – cryotherapy.
538
Microbiology
dsDNA Human Papillomavirus
Genital warts
539
Microbiology
Genital warts cause
dsDNA Human Papillomavirus. Visible genital warts: HPV 6 or HPV11 (not assoc. with ↑ risk cervical dysplasia)
540
Microbiology
Often Asx; warts can recur after Tx. Incubation time 3 weeks 8months
Diagnosis by Examination – papular, planar, pedunculated, carpet, keratinised,
pigmented
Home treatment – Podophyllotoxin solution or cream. Not for pregnant women
Clinic treatment – Cryotherapy. 2nd line – Imiquimod
Oncogenic HPV types (16, 18) assoc. with Cervical, Anal, Penile, Vulval, Head, Neck
cancers. Vaccine in 2012 changed to quadrivalent to include 6 and 11.
Genital warts
541
Microbiology
Rx of Genital warts
Home treatment – Podophyllotoxin solution or cream. Not for pregnant women
Clinic treatment – Cryotherapy. 2nd line – Imiquimod
542
Microbiology
| List superficial fungal infections?
ie wood lamp diagnosis
o Tinea: Dermatophyte e.g. Tricophyton rubrum: Ringworm, Athlete’s foot
o Pityriasis: Malassezia globosa/furfur : seborrhoeic dermatitis, T. versicolor
(depigmentation in those with darker skin. Often a spot diagnosis in finals)
543
Microbiology
Which 2 fungi need wood lamps for diagnosis?
o Tinea: Dermatophyte e.g. Tricophyton rubrum: Ringworm, Athlete’s foot
o Pityriasis: Malassezia globosa/furfur : seborrhoeic dermatitis, T. versicolor
(depigmentation in those with darker skin. Often a spot diagnosis in finals)
544
Microbiology
Tinea: Dermatophyte e.g. Tricophyton rubrum
Ringworm, Athlete’s foot
545
Microbiology
Ringworm, Athlete’s foot
What are these caused by?
Tinea: Dermatophyte e.g. Tricophyton rubrum
546
Microbiology
Pityriasis: Malassezia globosa/furfur
seborrhoeic dermatitis, T. versicolor
| depigmentation in those with darker skin. Often a spot diagnosis in finals
547
Microbiology
seborrhoeic dermatitis, T. versicolor
(depigmentation in those with darker skin. Often a spot diagnosis in finals)
...caused by?
Pityriasis: Malassezia globosa/furfur
548
Microbiology
Ix for candida?
Dx: Culture, Mannan, Antibodies
549
Microbiology
Rx of Rx: C. albicans + for invasive disease
Rx: fluconazole for C. albicans, amphotericin-B for invasive disease
550
Microbiology
Presents as pneumonia, esp. in immunocompromised. High mortality.
What fungi?
Aspergillus
551
Microbiology
Aspergillus Rx?
Rx: voriconazole
552
Microbiology
Aspergillus Ix?
Dx: ELISA, PCR, β-Glucan test, grows on Czapek dox agar
553
Microbiology
Presents as meningitis with insidious onset in HIV Associated with birds and in particular pigeons!
immunocompromised
What fungi?
o Cryptococcus
554
Microbiology
Ix of cryptococcus?
Cryptococcal Antigen in serum/CSF + india ink staining
555
Microbiology
Stain for Cryptococcus
India ink staining
556
Microbiology
Echinocandin MoA (eg caspofungin)
B-D glucan synthase inhibitor
557
Microbiology
Azoles MoA?
Binds to lanosterol (synthesises ergosterol)
558
Microbiology
MoA polyenes - aka amphotericin B
Binds ergosterol
Form pore
Leakage of Na+ + K+
559
Microbiology
MoA flucytosine?
Converted to 5FU
Pyrimidine analogue
SE BM suppression
560
Microbiology
Cryptococcal meningitis / invasive fungal infection Rx?
Amphotericin B
561
Microbiology
UGR/Jaundice
/Hepatosplenomegally
/Chorioretinitis/Encephalitis incl. Microcephaly, Thrombocytopenia, Death. Late progressive sensorineural deafness, Impaired IQ. Cytomegalice inclusion disease – 13%.
Congenital CMV
562
Microbiology
Fever, Hepatitis, GI – colitis, Retinitis, Pneumonitis, Bone Marrow suppression, Addisons Disease, Radiculopathy.
Pneumonitis = in BMT patients
Retinitis = AIDS
CMV in immunocompromised
563
Microbiology
Owl’s eye inclusion
CMV
564
Microbiology
Rx CMV
Rx – Ganciclovir (Valganciclovir – prodrug), Cidofovir, Foscarnet
565
Microbiology
Diagnosis: Blood PCR, Histopathology, Tissue Immunofluorescence, Cell culture in human fibroblasts – Owl’s eye inclusions, Serology
Immunocompetent: Serology – CMV IgM & IgG (IgG low avidity in 10 infection). Immunocompromised: Serology – Limited diagnostic value
Heterophile Ab’s – Paul Bunnel/monospot – clumping of sheep RBC
CMV
566
Microbiology
Causes roseola infantum (=exanthum subitum, Sixth disease). 3/7 fever, then transient rash. Abx often prescribed for fever then rash is often blamed on pencillin and child branded penicillin allergic. Most common cause of febrile convulsions. Latent in monocytes/lymphocytes. Can cause pneumonitis, hepatitis, encephalitis in BMT
Diagnosis – Blood PCR
Rx – Ganciclovir, foscarnet or cidofovir
HHV6
567
Microbiology
HHV6 Rx (severe)
Rx – Ganciclovir, foscarnet or cidofovir
568
Microbiology
dsDNA. No animal reservoir. Persistent latent phase in DRG. Lytic infection of fibroblasts + epithelial cells. Transmitted via muco-cutaneous contact
HSV1/4/2
569
Microbiology
Incubation 2-12/7. Severe painful ulceration, tendency to coalesce, erythematous base Fever + submandibular lymphadenopathy. Differential – Herpangina (Coxsackie A)
HSV
570
Microbiology
Incubation 4-7/7. Fever, dysuria, malaise, Inguinal lymphadenopathy, Pain++, vesicular rash
Herpes meningitis 1-2/52 later in 4-8% of 1o genital herpes. SACRAL RADICULOMYELTIS – urinary retention (self limiting)
Genial herpes
| HSV
571
Microbiology
Herpetic keratitis — unilateral/bilateral conjunctivitis + pre-auricular LNs
Acute retinal necrosis if immunocompotent, if immunosuppressed: Progressive Outer Retinal Necrosis (PORN) (also caused by VZV, EBV, CMV
Ocular herpes
| HSV
572
Microbiology
1o infections In 1st + 2nd trimester not assoc. with risks to foetus. 1o infection in 3rd Trimester assoc.
with greatest risk of transmitting infection:
Foetal loss
• Skin, eye, mouth (SEM) lesions (7-12/7). Long-term ocular + neural sequelae
• Disseminated disease ± vesicles (4-11/7 post-partum). Risk of fulminant hepatitis or multi-organ failure 80% • Neurological disease ± SEM (17-18/7 post-partum) 50%
Transmission: Most often at delivery, More rarely infection in-utero, Postnatally: mum with cold sores.
Neonatal HSV
573
Microbiology
90% HSV-1 (remember 1 brain). Flu-like prodrome 2/52, focal neurology, fever, confusion, behavioural change, ↓consciousness, seizures, N&V, coma, death. Half cases in pts > 60y/o
MOLLARET'S meningitis — benign recurrent aseptic meningitis usually HSV-2
Fronto-temporal and parietal lobes (lesions on CT/MRI)
CSF– Lymphocytic pleiocytosis, Cytology may be normal, ↔ glucose, ↑protein. Negative PCR doesn’t exclude Rx: IV Acyclovir stat. Don’t wait for test results. 10mg/kg tds then oral ACV for a total of 2-3/52
Herpes encephalitis
574
Microbiology
Herpes encephalitis, which HSV?
HSV1 90%
575
Microbiology
Rx herpes encephalitis?
Rx: IV Acyclovir stat. Don’t wait for test results. 10mg/kg tds then oral ACV for a total of 2-3/52
576
Microbiology
Herpes gladiatorum = scrum pox (painful blisters + inguinal LNpathy, rugby players), Herpetic whitlow (painful red finger); Erythema multiforme; HS Dermatitis, Eczema herpeticum, Zosteriform HS (painless) Diagnosis – Clinical, Culture, ELISA, Swab PCR (or blood PCR if disseminated)
Treatment
Acyclic nucleoside analogues: Aciclovir, Valaciclovir, Famciclovir Ganciclovir (pro-drug Valganciclovir)
Foscarnet (pyrophosphate analogue)
Cidofovir
Skin HSV
577
Microbiology
Tzanck cells
VCZ
| Chickenpox
578
Microbiology
Viral dsDNA
Droplet spread
Viral replication in LNS then liver then spleen
VCZ
579
Microbiology
Rx and indications of VCZ infection
Acyclovir 800mg PO TDS 7/7 or ValAciclovir 1g TDS
◦ Indications: All adults with chickenpox (at risk of complications), Neonates, Immunocompromised, Eye
involvement, All pts presenting with pain
580
Microbiology
What is the vaccine for VCZ?
Live vaccine against varicella – Attenuated Oka strain (Contraindicated in pregnancy)
581
Microbiology
Fever, malaise, headache followed by characteristic crops of rash (dew on a rose petal). Lesions scab after 1/52 (no longer contagious). Complications — scarring/pneumonitis/haemorrhage/Eye involvement/Reye's syndrome/ Neurological – Acute cerebellar ataxia, Guillain Barre, Ramsay Hunt syndrome – facial palsy + vesicles in ear – Geniculate ganglion of CNVII (hearing loss + vertigo), Encephalitis (vasculopathy), Post-herpetic neuralgia
Diagnosis
• Exam – vesicles (?HSV)
• Cytology – scrapings for multinucleated giant cells (Tzanck cells) • Immunofluorescence cytology – cells from vesicles
• PCR – especially if rash is old, CNS and ocular disease
Pregnancy:
Congenital varicella syndrome: Risk in early pregnancy: 0.4% if <12/40, 2% if 12-20/40 – Scarring, hypoplastic
limbs, cortical atrophy, psychomotor retardation, choreoretinitis, cataracts
Risk of disseminated varicella infection if occurs ±7 days from delivery
Rx: Acyclovir 800mg PO TDS 7/7 or ValAciclovir 1g TDS
◦ Indications: All adults with chickenpox (at risk of complications), Neonates, Immunocompromised, Eye
involvement, All pts presenting with pain
Post-exposure prophylaxis: VZIG (Immunocompromised, Pregnant women)
Live vaccine against varicella – Attenuated Oka strain (Contraindicated in pregnancy
VCZ
582
Microbiology
VZV reactivation (DRG)stress/↓immunity (immunocompromised, >50yrs), Painful rash in specific dermatome Rx – Symptomatic children OR (If <24hrs of rash) Healthy Adult smokers, Chronic lung disease, >20/40 gravid
• Aciclovir 800mg PO 5x daily OR Famciclovir 250 mg PO TDS OR Valaciclovir 1000mg PO TDS • Topical eye drops plus oral for ophthalmic
• PEP 7-9/7 for Immunocompromised
VCZ Shingles
583
Microbiology
Triad of fever, pharyngitis, lymphadenopathy
(incubation 4-6/52) + maculopapular rash.
Diagnosis - blood film, monospot agglutination, EBV antibodies Nb: Paul-Bunnell test
Infectious mononucleosis
584
Microbiology
African kids with a big jaw
EBV burkitts lymphoma
585
Microbiology
Nasopharyngeal Ca is associated with which virus?
EBV
586
Microbiology
What is post transplant lymphoproliferative disease?
What Rx?
Condition that predisposes to lymphoma.
Caused by EBV.
Treatment – reduce immunosuppression + give Rituxumab (anti-CD20 monoclonal Ab)
*EBV not dangerous in pregnancy.
587
Microbiology
Which virus causes capos sarcoma?
HHV8
588
Microbiology
Which virus causes castlemans disease?
HHV8
589
Microbiology
Rx of castlemans and kaposi?
What virus?
Ganciclovir and Foscarnet
HHV8
590
Microbiology
Classical PUO definition
As defined above incl. >3/7 in hospital or >3 O/P visits with ambulatory Ix
591
Microbiology
>3/7 in hospital or >3 O/P visits with ambulatory Ix
Classical PUO definition
592
Microbiology
Healthcare-associated PUO definition
Healthcare-associated PUO – develops in a patient following >24hrs in hospital
593
Microbiology
PUO that develops in a patient following >24hrs in hospital
Healthcare-associated PUO – develops in a patient following >24hrs in hospital
594
Microbiology
Neutropaenic PUO definition
Neutropaenic PUO – Fever
| concomitant with neutropaenia (<500/uL) and subsequent lack of cellular response. MEDICAL EMERGENCY .
595
Microbiology
Fever
concomitant with neutropaenia (<500/uL) and subsequent lack of cellular response. MEDICAL EMERGENCY PUO?
Neutropaenic PUO – Fever
| concomitant with neutropaenia (<500/uL) and subsequent lack of cellular response. MEDICAL EMERGENCY .
596
Microbiology
HIV+ve PUO
HIV associated PUO
597
Microbiology
Enteric fever infecting Peyers patches. Transmitted by food + water
Clinically – Fever, Headache, Abdo pain, Diarrhoea or constipation, Rose spots (30%), Relative bradycardia (non-specific & <50%), Hepatosplenomegaly (50%)
Chronic carriage – Gallstones, Immunosuppression
Diagnosis – Hx, Blood cultures, Stool
Management – IV fluids, Oral or iv antibiotics. Notifiable disease.
Salmonella typhi and paratyphi. Anaerobic Gram -ve bacillus
598
Microbiology
Salmonella typhi and paratyphi. What morphology / gram
Salmonella typhi and paratyphi. Anaerobic Gram -ve bacillus
599
Microbiology
Enteric fever infecting Peyers patches. Transmitted by food + water
Anaerobic Gram -ve bacillus
Salmonella typhi and paratyphi. Anaerobic Gram -ve bacillus
600
Microbiology
Most common type of malaria?
P. Falciparum most common esp Africa, Asia
601
Microbiology
V. severe. >2% parasitaemia
48hr (tertian)
Young trophozoites (rings) in the absence of mature trophozoites and schizonts. Crescent-shaped gametocytes.
Uncomplicated: Riamet (Artemether/lum efantrine) Complicated: IV artesunate
P. Falciparum most common esp Africa, Asia
602
Microbiology
Rx of falciparum malaria?
Uncomplicated: Riamet (Artemether/lum efantrine) Complicated: IV artesunate
Mild Disease
Quinine + Doxycycline/Clindamycin
OR Malarone (Atovoquone/Proguanil) OR Riamet (artemether and lumefantrine)
Severe Disease
Artemisinin combination therapy (ACT) OR Quinine + Doxycycline/Clindamycin
603
Microbiology
Chronic liver stage (hypnozites)
48hr
Schüffner's dots, >20 merozites/schizont
Chloroquine then primaquine
P. Vivax
604
Microbiology
Chronic liver stage (hypnozites)
48hr
Schüffner's dots
Chloroquine then primaquine
P. Ovale
605
Microbiology
P. Ovale + P. Vivax Rx?
Chloroquine then primaquine
606
Microbiology
Benign
72hr (Quartan)
Similar morphology to
Plasmodium Knowlesi
P. Malariae
607
Microbiology
On a blood film you see:
Young trophozoites (rings) in the absence of mature trophozoites and schizonts. Crescent-shaped gametocytes.
What type of malaria?
Falciparum
608
Microbiology
Thick vs thin film for malaria - what are the key differences?
Thick film – to find parasitaemia
Thin film – to distinguish malarial species
Various antigen tests Bloods: WCC rarely raised. 70% ↓platelets 50% deranged LFTs, 30% anaemia
609
Microbiology
```
Common symptoms
Fever + Rigors (rigors also feature in septicaemia such as pyelonephritis) Flu-like illness Headache
Back pain Myalgia Nausea + Vomiting
Uncommon symptoms
Diarrhoea Abdominal cramps Cough
Dark urine Confusion
```
Common Signs
Fever, Splenomegaly, No signs
Uncommon signs
Focal neurology/ Reduced GCS/ coma/Shock/ Hepatomegaly
Malaria(falciparum)
610
Microbiology
Canned/vacuum packed foods: Honey(kids), beans (students). Ingestion of preformed toxin (inactivated by cooking)
Blocks Ach release from peripheral nerves paralysis
Descending paralysis - differentiates from GBS
Which GI bacteria?
Clostridia Botulinum
611
Microbiology
Clostridia - anaerobic or aerobic?
anaerobic
612
Microbiology
Canned/vacuum packed foods: Honey(kids), beans (students). Ingestion of preformed toxin (inactivated by cooking)
Blocks Ach release from peripheral nerves paralysis
Descending paralysis - differentiates from GBS
What rx?
Antitoxin
Clostridia Botulinum
613
Microbiology
Clostridia Botulinum Rx
Antitoxin
614
Microbiology
- Reheated meats, superantigen enterotoxin (bind
directly to TCR + MHC outside peptide binding site massive cytokine production by CD4 ie systemic toxicity + suppression of adaptive response)
- Acts on small bowel, 8-16hrs incubation.
- Watery diarrhea +cramps, lasts 24hrs. Also causes gas-gangrene
Which GI bacteria?
Perfringens
615
Microbiology
2 exotoxins (A,B) Get pseudomembranous colitis ( i.e an inflamed bowel) Caused by Abx usually cephalosporins/ fluorquinolones
Which GI bacteria?
Clostridium Difficile
616
Microbiology
2 exotoxins (A,B) Get pseudomembranous colitis ( i.e an inflamed bowel) Caused by Abx usually cephalosporins/ fluorquinolones
What Rx?
Metronidaz ole 2nd line = Vancomyci n - PO
617
Microbiology
Bacillus cereus + S.aureus - aerobic or anaerobic?
Aerobic
618
Microbiology
Reheated rice (spores germinate) and sudden vomiting Superantigen — short incubation(4hrs) Increased cAMP— long incubation (18hrs). Watery non-bloody diarrhoea
Which GI bacteria?
Bacillus cereus
619
Microbiology
What Rx for bacillus cereus
Self limiting
620
Microbiology
Main virulence factor: Protein A. Catalase, coagulase +ve.
Appears in tetrads, clusters on gram stain.
Beta haemolytic on blood agar
Produces enterotoxin (exotoxin that acts as superantigen, releasing IL1 and IL2prominent vomiting + watery, non bloody diarrhoea)
Which GI bacteria?
S. aureus
621
Microbiology
Main virulence factor: Protein A. Catalase, coagulase +ve.
Appears in tetrads, clusters on gram stain.
Beta haemolytic on blood agar
Produces enterotoxin (exotoxin that acts as superantigen, releasing IL1 and IL2prominent vomiting + watery, non bloody diarrhoea)
What Rx?
S. aureus
| Self limiting
622
Microbiology
Gram -ve
Enterobacteriacae (Facultative anaerobes, oxidase negative)
E.Coli
623
Microbiology
What morphology/gram is E.Coli?
Gram -ve
| Enterobacteriacae (Facultative anaerobes, oxidase negative)
624
Microbiology
Toxigenic, Travellers diarrhoea
Heat labile LT stimulates adenyl cyclase and cAMP
Heat stable ST stimulates guanylate cyclase. Act on the jejeunum, ileum not on colon.
Gram -ve
Enterobacteriacae (Facultati ve anaerobes, oxidase negative)
What GI bacteria?
ETEC
625
Microbiology
Invasive dysentery
Gram -ve
Enterobacteriacae (Facultative anaerobes, oxidase negative)
What GI bacteria?
EIEC
626
Microbiology
Haemorrhagic, Caused by verotoxin
Gram -ve
Enterobacteriacae (Facultative anaerobes, oxidase negative)
What GI bacteria?
EHEC
627
Microbiology
Anaemia, thrombocytopenia, renal failure (0157:H7 toxin)
Gram -ve
Enterobacteriacae (Facultative anaerobes, oxidase negative)
What GI bacteria?
HUS
628
Microbiology
Infantile diarrhoea (Paeds)
What GI bacteria?
EPEC
629
Microbiology
Rx for all e.coli GI infections?
Self limiting
| Can use ciprofloxacin
630
Microbiology
What antigens in salmonella typhi/paratyphi?
O, H, Vi Ag’s
631
Microbiology
Only transmitted by humans Ceftriaxone
Multiplies in Peyers patches, 3% carriers (in or gallbladder) Slow onset fever + CONSTIPATION, ciprofloxac relative bradycardia Splenomegaly and rose spots, in
anaemia and leukopaenia
Typhi +
| Paratyphi (enteric fever)
632
Microbiology
Only transmitted by humans Ceftriaxone
Multiplies in Peyers patches, 3% carriers (in or gallbladder) Slow onset fever + CONSTIPATION, ciprofloxac relative bradycardia Splenomegaly and rose spots, in
anaemia and leukopaenia
Poultry, eggs and meat, invasion of small and large bowel Bacteraemia is infrequent. Self limiting non-bloody diarrhoea
What Rx?
Ceftriaxone or ciprofloxacin
Typhi +
Paratyphi (enteric fever)
633
Microbiology
Name non-lactose fermenting GI infection bacteria?
Salmonella
Shigella
Yersinia
634
Microbiology
```
What do:
Salmonella
Shigella
Yersinia
Have in common?
```
non-lactose fermenting GI infection bacteria
635
Microbiology
Mainly affects the distal ileum + colon -> mucosal inflammation, fever, pain, bloody diarrhoea. Shiga enterotoxin
Shigella
Avoid abc (cipro if required)
636
Microbiology
Enterocolitis, mesenteric adenitis w/ necrotising granulomas, assoc reactive arthritis & eythema nodosum.
Transmitted via food contaminated with domestic
Yersinia
637
Microbiology
Vibriosis (comma shaped)
Late lactose fermenters Oxidase +ve
Which bacteria?
Cholera
Parahaemolyticus
Vulnificus
638
Microbiology
Rice water stool. Human faeces (eg in shellfish)
↑cAMP opens Cl- channel at apical membrane of enterocytesefflux of Cl- to lumen (loss of H2O and electrolytes).
Massive diarrhoea without inflammation
Cholera
639
Microbiology
Ingestion of raw undercooked seafood (common in Japan)
Parahaemolyticus
640
Microbiology
Cellulitis in shellfish handlers
Fatal septcaemia with D+V in HIV pts
Vulnificus
641
Microbiology
Ingestion of raw undercooked seafood (common in Japan)
What Rx?
Parahaemolyticus
Doxycycline
642
Microbiology
Cellulitis in shellfish handlers
Fatal septcaemia with D+V in HIV pts
What Rx?
Vulnificus
Doxycycline
643
Microbiology
Rx of cholera?
Supportive
644
Microbiology
Drinking unpasteurised milk, food eg: poultry Prodrome of headache and fever, abdo cramps, bloody (foul-smelling) diarrhoea Curved, S-shaped, Microaerophilic, Oxidase +ve, motile, sensitive to nalidixic acid (first quinolone).
Assoc with Guillain-Barre, reactive arthritis (Reiter’s)
Campylobacter jejuni
645
Microbiology
curved, comma or S shaped
Campylobacter
646
Microbiology
Cholera
Parahaemolyticus
Vulnificus
What morphology / stain?
Vibriosis (comma shaped)
Late lactose fermenters Oxidase +ve
647
Microbiology
Rx C.jejuni
Erythromycin or Cipro if first 4- 5/7
648
Microbiology
GI watery diarrhoea, cramps, headache, fever, little vomiting.
Perinatal infection, immunocompromised patients
Outbreaks of febrile gastroenteritis
Listeria monocytogenes
649
Microbiology
V or L shaped, ß haemolytic, aesculin +ve, tumbling
mobility
Listeria monocytogenes
650
Microbiology
Listeria Rx?
Ampicillin, Ceftriaxone, Cotrimoxazole
651
Microbiology
What morphology/stain is listeria?
V or L shaped, ß haemolytic, aesculin +ve, tumbling
| mobility
652
Microbiology
Motile trophozoite in diarrhoea vegetables)
Non-motile cyst in non-diarrhoeal illness 4 nuclei and no animal reservoir. Colonize colon
Makes a flask-shaped ulcer on histology Symptoms: dysentery, wind, tenesmus. Chronic weight loss + RUQ pain due to liver abscess
Stool microscopy
Entamoeba Histolytica EMQ: MSM
| Also: food, water, soil
653
Microbiology
Rx Entamoeba Histolytica
Metronidazole + Paromomycin if luminal disease
654
Microbiology
Motile trophozoite in diarrhoea vegetables)
Non-motile cyst in non-diarrhoeal illness
Entamoeba Histolytica
655
Microbiology
WBC stool negative causes of diarrhoea?
AKA SECRETORY
Cholerae
ETEC/EPEC/EHEC/EaEC
656
Microbiology
Pear shaped trophozoite 2 nuclei Trophozoites/cysts found in stool
Get it by ingesting cysts from faecally contaminated H2O
Malabsorption of protein + fat - foul smelling non-bloody diarrhoea
Giardia lamblia
EMQ: Travellers/hikers/MSM/ mental hospitals
Metronidazole
657
Microbiology
Dx = ELISA string test
Infects the jejunum. Severe diarrhoea in
immunocompromised.Oocysts seen in stool
Rx with paromomycin
Cryptosporidium Parvum
658
Microbiology
Trasmission: Spore ingestion.
o Predisposing factor: existing gut flora disturbed by antibiotics, particularly 3Cs: clindamycin (often used in penicillin allergic patients with cellulitis), cephalosporins, ciprofloxacin
o Pathology: Toxin. Pseudomembranous colitis.
o Rx: Oral metronidazole.
GI: Clostridium difficile diarrhoea.
659
Microbiology
Protein-only infectious agent. Rare transmissable spongiform encephalopathies in humans and animals resulting in rapid neuro-degeneration and death in months. Currently untreatable. If suspected be very careful handling lab samples!
Prion protein gene on Chr20, predominantly expressed in CNS.
Prion disease
660
Microbiology
CJD Rx?
Symptomatic: clonazepam – mycolonus: (Valproate, Levetiracetam, Piracetam)
Delaying prion ‘conversion’: Quinacrine, Pentosan, Tetracycline
661
Microbiology
14-3-3 protein +ve
CSF
Sporadic CJD
662
Microbiology
14-3-3 can be normal
CSF
Variant CJD
663
Microbiology
Serial EEG shows periodic triphasic changes
Normal/ highlighting basal ganglia
14-3-3 protein +ve
No mutations
Most cases 129 codon MM
Types 1- 3
1. Spongiform vacuolation 2. PrP amyloid plaques
Sporadic CJD
664
Microbiology
EEG - Non- specific slow waves
Posterior
thalamus highlighted on MRI-T2 (pulvinar sign)
14-3-3 can be normal
No mutations
ALL cases 129 codon MM
Type 4t from tonsillar biopsy (100% sens. + spec.)
1. PrPSC 4t detedtable in CNS + lymphoreticul ar tissue 2. Florid plaques
Variant CJD
665
Microbiology
Rapid, progressive dementia with myoclonus, cortical blindness, akinetic mutism and lower motor neuron signs
Mean onset is 45-75yrs and mean survival time = within 6/12 of symptoms starting
Sporadic CJD 80%
Either somatic PRNP mutation OR spontaneous conversion of PrPc to PRPSC and subsequent seeding
666
Microbiology
Either somatic PRNP mutation OR spontaneous conversion of PrPc to PRPSC and subsequent seeding
Sporadic CJD 80%
Rapid, progressive dementia with myoclonus, cortical blindness, akinetic mutism and lower motor neuron signs
Mean onset is 45-75yrs and mean survival time = within 6/12 of symptoms starting
667
Microbiology
Younger age of onset – typically 30yrs. Mean survival 14/12. Psychiatric symptoms to start (anxiety, paranoia, hallucinations) followed by the development of neurological symptoms (peripheral sensory symptoms, ataxia and myoclonus). Later symptoms include chorea, ataxia, dementia
vCJD (variant)
Exposure to bovine spongiform encephalopathy (BSE)
668
Microbiology
Exposure to bovine spongiform encephalopathy (BSE)
vCJD (variant)
Younger age of onset – typically 30yrs. Mean survival 14/12. Psychiatric symptoms to start (anxiety, paranoia, hallucinations) followed by the development of neurological symptoms (peripheral sensory symptoms, ataxia and myoclonus). Later symptoms include chorea, ataxia, dementia
669
Microbiology
Progressive cerebellar syndrome (death within 2yrs) following 45yr incubation Dementia is late or absent. Epidemic was in the 1950/60s
Kuru
Exposure to human prions from cannibalistic feasts
670
Microbiology
Exposure to human prions from cannibalistic feasts
Kuru
Progressive cerebellar syndrome (death within 2yrs) following 45yr incubation Dementia is late or absent. Epidemic was in the 1950/60s
671
Microbiology
Autosomal dominant (50 families in world)
Insomnia and paranoia progressing to
hallucinations and weight loss. Then a mute period. Death 1-18/12 after start of symptoms
Fatal Familial Insomnia
aka
Familial CJD, GSS, FFI, various atypical dementias
PRNP mutations
672
Microbiology
Autosomal dominant
Develops between 20-60yrs, mean survival = 5yrs
with dysarthria progressing to cerebellar ataxia ending in dementia
Gerstmann- Straussler- Scheinker syndrome
Familial CJD, GSS, FFI, various atypical dementias
PRNP mutations
673
Microbiology
Brucellosis, what morphology/gram
Gram-ve, aerobic bacilli (facultative intracellular), endemic worldwide.
Mode of transmission – Inhalation, Skin or mucus membrane contact.
From consumption of contaminated food (untreated milk/dairy products), animal
contact or environmental contamination. Also includes laboratory acquired.
Symptoms – Fever – Classically undulant fever (peaks in eve. normal by morn),
malaise, rigors, sweating, myalgia/arthralgia, tiredness (incubation 3-4/52)
Complications – endocarditis, osteomyelitis (occasionally meningoencephalitis)
Signs – arthritis, spinal tenderness, lymphadenopathy, splenomegaly, hepatomegaly,
epididymo-orchitis. Rarely – jaundice, CNS abnormalities, cardiac murmur, pneumonia.
Ix – Serology - anti-O-polysaccharide antibody. (Titres >1:160). WCC usually normal.
Leucocytosis rare, significant number of pts neutropaenic.
Rx – 4-6/52 Tetracycline or Doxycycline combined with Streptomycin. Or PO
doxycycline + rifampicin 8/52
674
Microbiology
Gram-ve, aerobic bacilli (facultative intracellular), endemic worldwide.
Mode of transmission – Inhalation, Skin or mucus membrane contact.
From consumption of contaminated food (untreated milk/dairy products), animal
contact or environmental contamination. Also includes laboratory acquired.
Symptoms – Fever – Classically undulant fever (peaks in eve. normal by morn),
malaise, rigors, sweating, myalgia/arthralgia, tiredness (incubation 3-4/52)
Complications – endocarditis, osteomyelitis (occasionally meningoencephalitis)
Signs – arthritis, spinal tenderness, lymphadenopathy, splenomegaly, hepatomegaly,
epididymo-orchitis. Rarely – jaundice, CNS abnormalities, cardiac murmur, pneumonia.
Ix – Serology - anti-O-polysaccharide antibody. (Titres >1:160). WCC usually normal.
Leucocytosis rare, significant number of pts neutropaenic.
Rx – 4-6/52 Tetracycline or Doxycycline combined with Streptomycin. Or PO
doxycycline + rifampicin 8/52
Brucellosis
675
Microbiology
Rx brucellosis?
Mode of transmission – Inhalation, Skin or mucus membrane contact.
From consumption of contaminated food (untreated milk/dairy products), animal
contact or environmental contamination. Also includes laboratory acquired.
Symptoms – Fever – Classically undulant fever (peaks in eve. normal by morn),
malaise, rigors, sweating, myalgia/arthralgia, tiredness (incubation 3-4/52)
Complications – endocarditis, osteomyelitis (occasionally meningoencephalitis)
Signs – arthritis, spinal tenderness, lymphadenopathy, splenomegaly, hepatomegaly,
epididymo-orchitis. Rarely – jaundice, CNS abnormalities, cardiac murmur, pneumonia.
Ix – Serology - anti-O-polysaccharide antibody. (Titres >1:160). WCC usually normal.
Leucocytosis rare, significant number of pts neutropaenic.
Rx – 4-6/52 Tetracycline or Doxycycline combined with Streptomycin. Or PO
doxycycline + rifampicin 8/52
676
Microbiology
Rhabdovirus
Rabies
677
Microbiology
Migrates to CNS (mths/yrs) – fatal encephalitis – Negri bodies = pathognomonic
Prodrome (fever, headache, sore throat) – acute encephalitis (hyperactive state)
IFA for rabies antigen in brain tissue.
Serology - neutralisation tests/ELISA for specific IgM.
Treatment – Rabies IgG post exposure
Rabies
678
Microbiology
Yersinia morphology/stain
gram-ve lactose fermenter
679
Microbiology
Bubonic plague – flea bites human – Swollen LN (Bubo) – dry gangrene
Pneumonic plague – Usually seen during epidemics, person-person spread
Treatment – Streptomycin, Doxycycline, Gentamicin, Chloramphenicol (in meningitis)
Plague – Yersinia pestis, gram-ve lactose fermenter. In rats, transmitted by fleas. Still seen in some American National Parks such as Yosemite. Dx: PCR
680
Microbiology
Excreted in dog/rat urine. Penetrates broken skin/swimming in contaminated water
Leptospirosis – Gram –ve, L interrogans, Obligate, aerobic, motile spirochaetes
681
Microbiology
Gram –ve, L interrogans, Obligate, aerobic, motile spirochaetes
Excreted in dog/rat urine. Penetrates broken skin/swimming in contaminated water.
High spiking temp/headache/conjunctival haemorrhages/jaundice, malaise, myalgia, meningism, carditis, renal failure, haemolytic anaemia (incubation 10-14/7)
Rx – Amoxicillin, erythromycin, doxycycline or ampicillin
Leptospirosis – Gram –ve, L interrogans, Obligate, aerobic, motile spirochaetes
682
Microbiology
Cutaneous – Painless round black lesions + rim of oedema
Pulmonary (Woolsorters disease) – Massive lymphadenopathy + mediastinal
haemorrhage, pleural effusion and resp. failure.
Anthrax - Bacillus anthracis (Rx. Cipro/doxy)
683
Microbiology
Early localized – Cyclical fevers, non-specific flu-like symptoms. Erythema chronicum
migrans (ECM) – ‘Bullseye Rash’
Early disseminated – Malaise, lymphadenopathy, hepatitis, carditis, arthritis
Late persistent – Arthritis, focal neurology, neuropsychiatric disturbance, ACA
(acrodermatitis chronic atrophicans)
Dx: Biopsy edge of ECM + ELISA for Lyme Abs
Treatment: Doxycycline 2-3/52, (also amoxicillin, cephalosporins). If CNS issues, IV
ceftriazone 2-4/52. Post Rx, few pts get ‘ME’ type symptoms.
Lyme disease - Borrelia burgdoferi (spirochaete). Arthropod-borne (Ixodes = tick)
684
Microbiology
Cattle/sheep infection, 2-5/52 post-infection – fever dry cough + fatigue + pleural
effusion and diarrhea – NO RASH!
Q fever - Coxiella burnetii (Rx.= doxy), looks like atypical pneumonia
685
Microbiology
Transmitted through bite of the sandfly (south & central America+ middle east)
Skin ulcer at site of bite – multiply in dermal macrophages – Heals after 1yr
leaving depigmented scar – May be single or multiple painless nodules which
grow + ulcerate, Type IV reaction
Cutaneous, eg: L. major, L. tropica
Leishmania – protozoa
686
Microbiology
Pts with immunodeficiency, Nodular skin lesions arise but do NOT ulcerate –
Lots of nodules, esp nose, Skin test–ve as immunodeficient
Diffuse cutaneous Leishmania – protozoa
687
Microbiology
Dermal ulcer same as cutaneous leishmaniasis
Months to yrs later – ulcers in mucous membranes of nose and mouth
What type of leishmania?
Muco-cutaneous, eg: L. braziliensis
688
Microbiology
Usually young malnourished child
o Abdo discomfort + distension/anorexia/wt. loss
o Leishmania donovani: invasion of reticuloendothelial system -> hepato-
splenomegaly, BM invasion. Later disfiguring dermal disease (PKDL).
Visceral = Kala Azar, eg: L. donovani, L. infantum (L. chagasi in S. America)
689
Microbiology
Subacute bacterial endocarditis. What is this caused by?
Low virulence strep
| Usually S.viridians
690
Microbiology
Acute bacterial endocarditis. What is this caused by?
```
Staph A
Strep progenies
HACEK
Haemophilus parainfluenza
Actinobacillus
Cardiobacterium
Eikenella
Kingella kingae
```
691
Microbiology
List the HACEK organisms that cause acute endocarditis.
What do they all have in common?
```
Haemophilus parainfluenza
Actinobacillus
Cardiobacterium
Eikenella
Kingella kingae
```
CULTURE NEGATIVE
692
Microbiology
IV Rx length for endocarditis
6 weeks IV
693
Microbiology
Orthomyxovirus
Influenza
694
Microbiology
What type of virus is Influenza
Orthomyxovirus
695
Microbiology
Influenza protein
Cleaves sialic acid residues exposing receptors on host cell, disrupts mucin barrier
NA – neuraminidase (sialidase) activity
696
Microbiology
Influenza protein
Binds sialic acid receptors, virus entry. Endosomal-viral envelope fusion = release
Virus strains named after this structure e.g. H5N1=HA5,NA1
HA – haemogglutinin activity: (Named for causing agglutination of RBCs/URT cells)
697
Microbiology
Mutation occur to HA/NA to give new strains of the virus
Antigenic Drift
698
Microbiology
Mutations causing complete change of HA/NA
Antigenic Shift
Can only occur with influenza A
There is trading of RNA segments between human and animal strains
699
Microbiology
Amantadine MoA
Amantadine (Influenza A only) – Targets M2 ion channel. BUT single AA mutation (S31N) in M2 = resistance (now in many ‘flu A strains incl. H1N1)
700
Microbiology
Oseltamivir (Tamiflu), Zanamivir (Relenza), Sialic acid – Effective only if given <48hrs after infection
What MoA
Neuraminidase inhibitors: Oseltamivir (Tamiflu), Zanamivir (Relenza), Sialic acid – Effective only if given <48hrs after infection
701
Microbiology
Guanosine analogue - blocks viral DNA extension through activation by viral thymidine kinase (TK) present in HSV. However CMV does not have this enzyme so aciclovir does not work.
Aciclovir
702
Microbiology
This antiviral does not work on CMV. Why?
Aciclovir
Guanosine analogue) blocks viral DNA extension through activation by viral thymidine kinase (TK) present in HSV. However CMV does not have this enzyme so aciclovir does not work.
703
Microbiology
CMV (and EBV, HHV-6). Nucleoside analogue. SE: BM suppression Treat CMV – Congenital, immunocompromised, pregnancy, HIV
Remember what CMV does? – RCHEP (Retinitis, colitis, hepatitis, encephalitis, pneumonitis). CMV cells –‘owls eye inclusions’
Ganciclovir
704
Microbiology
Pyrophosphate analogue, inhibits nucleic acid synthesis without requiring activation. Also used as prophylaxis post organ transplant.
Foscarnet
705
Microbiology
Nucleoside phosphonate, it is mainly used for Rx in CMV retinitis. Often used in treatment of non-herpes viral infections in the opportunistic post-transplant setting:
Eg: BK virus for BK nephropathy/BK cystitis/Adenovirus/PML (JC virus)
Cidofovir
706
Microbiology
Aciclovir MOA
Aciclovir (Guanosine analogue) blocks viral DNA extension through activation by viral thymidine kinase (TK) present in HSV. However CMV does not have this enzyme so aciclovir does not work
707
Microbiology
Ganciclovir MOA
Ganciclovir for CMV (and EBV, HHV-6). Nucleoside analogue. SE: BM suppression Treat CMV – Congenital, immunocompromised, pregnancy, HIV
CMV cells –‘owls eye inclusions’
708
Microbiology
Foscarnet MOA
Foscarnet: Pyrophosphate analogue, inhibits nucleic acid synthesis without requiring activation. Also used as prophylaxis post organ transplant.
709
Microbiology
Cidofovir MOA
Cidofovir - Nucleoside phosphonate, it is mainly used for Rx in CMV retinitis. Often used in treatment of non-herpes viral infections in the opportunistic post-transplant setting:
Eg: BK virus for BK nephropathy/BK cystitis/Adenovirus/PML (JC virus)
710
Microbiology
Rx steps in HSV
If you get herpes you need to act very fast......
AVF
```
Act
Acyclovir
Very
Valaciclovir
Fast
Famciclovir
```
711
Microbiology
Rx for HBV
Give your PET a TREAT if it has HEP B
Give you PET a treat if it has HEP B
o PegINF alpha 2a, Entecavir and tenofovir
Pegylated Interferon (INF) Alpha 2a (subcut) – Direct antiviral effect + upregulates
expression of MHC on cell surfaces
Nucleos(t)ide analogues
o Inhibitors of viral polymerase – Lamivudine, Adefovir dipivoxil, Entecavir (no resistance), Telbivudine
o Inhibitor of reverse transcriptase – Tenofovir
712
Microbiology
HCV Rx?
Give your HEP C a PR...
PR
PegINF 2b/2a
Ribavirin (RNA nucleoside analogue. Major S/E - Haemolytic anaemia)
713
Microbiology
Is hep C Rx more successful with hep C genotypes 1 OR 2+3
Genotypes 1 (40-50% of HCV UK burden), 4, 5, and 6 – Treatment less successful
Genotypes 2 and 3 – (40-50% of HCV UK burden) Treatment more successful
714
Microbiology
1. Denature
2. Primer annealing
3. Chain elongation (with Taq polymerase)
Stages of PCR
715
Microbiology
Risk in solid organ transplant if seropositive donor and seronegative recipient due to recipient virus exposure. Opposite risk in BM transplant if seronegative donor but seropositive recipient because the protective antibodies in the recipient are removed (with chemotherapy or radiotherapy) but not replaced by seronegative donor.
CMV
716
Microbiology
Causes post-transplant lymphoproliferative disease where control of proliferation of latently infected B cells is lost. In HIV patients; oral hairy leukoplakia and lymphomas. Tx: Reduce immunosuppression + Rituximab (anti-CD20 mAb)
EBV
717
Microbiology
Causes cancer in AIDS patients i.e. Kaposi Sarcoma – presence of spindle cells and KSHV proteins when biopsied. Also Castleman’s disease.
HHV 8
718
Microbiology
Spindle cells and KSHV proteins when biopsied
HHV 8
| Kaposi Sarcoma
719
Microbiology
Affects paediatric post-BMT patients. Weekly PCR surveillance. Tx: Reduce immunosuppression + Ribavirin.
Adenovirus
720
Microbiology
Graft rejection + similar Sx to CMV. Rx: Ganciclovir, Foscarnet/cidofovir.
HHV 6
721
Microbiology
Px: Unwell febrile patient with red hot swollen joint (50%: knee, unable to weightbear). Host inflammatory response damages joint.
Dx: Blood culture before Abx, joint aspirate (>50,000cells/mm3), inflammatory markers. Imaging shows effusion
Septic arthritis
Bugs: Staph aureus(46%), Streptococci (22%), less commonly various gram -ve organisms eg: E-Coli. Bug adheres to synovial membranes and proliferates in fluid.
722
Microbiology
Ax: Local or haematogenous spread. Brodie abscess (subacute) frank osteomyelitis
Bugs: Staphylococcus aureus
Px: Pain, fever, local swelling
Dx: MRI best imaging, bone biopsy for culture/histology
Rx: Antibiotics treat most cases. Second-line = Debridement. Remove sequestra and infected bone
Osteomyelitis
723
Microbiology
Ax: Local (wound infection); Systemic bacteraemia (eg UTI)
Bugs: Staphylococcus, Gram negatives eg Enterobacteriaceae
Px: Pain, failure of joint, sinus, patient complains joint was ‘never right’
Dx: Radiology – ‘loosening’, Joint aspirate – done with caution as risk of introducing
infection if joint is not infected.
Rx: Remove metalwork and revise joint replacement: single or two stage revision. Use
Abx-impregnated cement.
Prosthetic Joint Infection
724
Microbiology
The four mechanisms of antibiotic resistance – BEAT drug action
1. Bypass antibiotic step eg: MRSA
2. Enzyme mediated deactivation eg: β-lactamases
3. Accumulation prevention eg: tetracycline resistance
4. Target modification eg: Quinolone resistance
725
Microbiology
TORCH
(Toxoplasmosis, Other (HIV,HBV), Rubella, CMV, HSV)
726
Microbiology
Early onset sepsis (<48 hrs after birth) causes?
Group B streptococci, E. coli, Listeria
727
Microbiology
What is early onset sepsis?
Early onset sepsis (<48 hrs after birth): Group B streptococci, E. coli, Listeria
728
Microbiology
What is late onset sepsis?
Late-onset sepsis (>48 hrs after birth): Coagulase negative staph + GBS, E. coli, Listeria
729
Microbiology
Main causes late onset sepsis?
Late-onset sepsis (>48 hrs after birth): Coagulase negative staph + GBS, E. coli, Listeria
730
Microbiology
RFs for meningitis?
N. meningitidis: Complement deficiency, hyposplenism (susceptible to encapsulated organisms), hypogammaglobulinaemia
S. pneumoniae: Complement deficiency, hyposplenism, Immune defect (alcoholic), infection (pneumonia),entry #, previous head trauma w/ CSF leak
731
Microbiology
CSF
Glucose low; WCC high with polymorphs
Bacterial infection, ?turbid
732
Microbiology
CSF
Glucose normal; WCC high with polymorphs
Partially treated bacterial infection
733
Microbiology
CSF
Glucose normal; WCC high with mononuclear cells
Viral meningitis/encephalitis
734
Microbiology
Protein high; WCC high with mononuclear cells
Mycobacterium TB or cryptococcus
735
Microbiology
CSF can be normal in which other CNS infections
Cerebral abscess (Streptococci)
| Viral encephalitis (Herpes)
736
Microbiology
```
RNA virus
Acute – IgM (prev. infection or vaccination – IgG)
Faecal-oral
Acute - Anti-H_V IgM
(IgM persists up to 14w)
Supportive
2-6w incubation. Severe in elderly
```
Hep A
737
Microbiology
| RNA virus, which hepatitis(s)?
A+C
738
Microbiology
| dsDNA virus, which hepatitis(s)?
B
739
Microbiology
Acute <6mo and chronic. Latent virus can reactivate in IC patients.
Sexual, vertical, horizontal, blood products
ALT↑↑ AST↑ HB_Ag (infection or vaccine) HB_Ag(infectivity) HB_Ab (acute IgM chronic IgG)
PegIFN
α 2a Lamivudine T enofovir
Later fibrosis, cirrhosis, HCC.
2-6mo incubation
Ax with polyarteritis nodosa (vice versa)
Hep B
740
Microbiology
```
Acute, 80% progress to
Blood products
ALT
Anti H_V
Peg IFN α2b
Cirrhosis Cryoglobulin Ax
```
Hep C
741
Microbiology
Meaning of HBsAg?
infection or vaccine
742
Microbiology
Which HBAg means infection or vaccine in Hep B infection?
HBsAg
743
Microbiology
Meaning of HBeAg?
Infectivity
744
Microbiology
Meaning of HBcAg?
If acute = IgM
| If chronic = IgG
745
Microbiology
Which HBAg indicates infectivity?
HBeAg
746
Microbiology
Which HBAg indicates acute hep B infection?
IgM HBcAg
747
Microbiology
Which HBAg indicates chronic hep B infection?
IgG HBcAg
748
Microbiology
RNA virus that can only infect Hepatitis B patients.
Hep D
DNB
D NEEDS B
749
Microbiology
Resp/blood-borne transmission, 6-8 days incubation.
Symptoms: Asx; fever; malaise; erythema infectiosum ‘slapped cheek’, transient aplastic crisis (esp. those with sickle cell, spherocytosis)
Foetus: Infection <20w 3% risk hydrops fatalis, Tx = intrauterine transfusion. >20w no risk
Parvovirus B19
750
Microbiology
RNA virus. Resp transmission. Incubation 12-21 days
Symptoms: 20-50% have subclinical infection
Classical: picture of flu like symptoms followed by pinpoint macular-papular rash and lymphadenopathy (in adults.) Diagnosis via serology of saliva swabs
Rubella
751
Microbiology
Cataracts, glaucoma, heart disease, loss of hearing, retinopathy, splenomegaly, mental retardation and meningioencephalitis. 20% incidence of spontaneous abortion if infected before 8 wks.
If infected between 13-18wks may have hearing defects and occasionally retinopathy. However if >20 weeks at infection there is no documented risk.
Congenital Rubella Syndrome (CRS)
752
Microbiology
Risks of stillbirth (5x) and preterm delivery (3x). No congenital abnormalities. Recommendation - pregnant women are vaccinated
Influenza
753
Microbiology
Bacteria: Chlamydia trachomatis, Rickettsia, Coxiella (Q fever), Mycobacteria leprae, Protozoa: Toxoplasma, cryptosporidium, Leishmania spp,
Fungi including: pneumocystis jirovecii (PCP)
What do they all have in common?
Obligate Intracellular microbes
754
Histopathology
List causes of nephritic syndrome
1. ACUTE POSTINFECTIOUS (POST STREPTOCOCCAL) GN
2. IgA NEPHROPATHY (BERGER DISEASE)
3. RAPIDLY PROGRESSIVE (CRESCENTIC) GN
4. HEREDITARY NEPHRITIS (ALPORT’S SYNDROME)
5. THIN BASEMENT MEMBRANE DISEASE (BENIGN FAMILIAL HAEMATURIA)
755
Histopathology
Occurs 1-3 wks after streptococcal throat infection or impetigo (usually Group A
α-haemolytic strep = Strep pyogenes).
Glomerular damage thought to be due to immune complex deposition
Haematuria (red cells casts), proteinuria, oedema, HTN
● Bloods: ASOT titre ↑, C3 ↓
● Biopsy:
o Light microscope (LM): ↑cellularity of glomeruli
o Fluorescence Microscope (FM): granular deposits of IgG and C3 in GBM
o Electron Microscope (EM): Subendothelial humps
1. ACUTE POSTINFECTIOUS (POST STREPTOCOCCAL) GN
756
Histopathology
● Commonest GN worldwide
● Deposition of IgA immune complexes in glomeruli
● Presents 1-2 days after an URTI with frank haematuria
● Main symptoms are persistent or recurrent frank haematuria, or asymptomatic
microscopic haematuria. Other symptoms of nephritic syndrome are not prominent
● Can progress to ESRF
● Biopsy:
o FM: granular deposition of IgA and complement in mesangium
2. IgA NEPHROPATHY (BERGER DISEASE)
757
Histopathology
● Most aggressive GN – can cause ESRF within weeks.
● Presents as a nephritic syndrome, but oliguria and renal failure are more
pronounced
● Classification based on immunological findings:
o Type 1: Anti-GBM antibody
o Type 2: Immune complex
o Type 3: Pauci-immune / ANCA-associated
● Regardless of cause, all are characterised by presence of crescents in glomeruli
3. RAPIDLY PROGRESSIVE (CRESCENTIC) GN
758
Histopathology
What are the three types of RAPIDLY PROGRESSIVE (CRESCENTIC) GN
o Type 1: Anti-GBM antibody
o Type 2: Immune complex
o Type 3: Pauci-immune / ANCA-associated
759
Histopathology
Anti-GBM antibody
against COL4-A3 (collagen type IV)
Caused by: Goodpastures
syndrome. HLA- DRB1 association
Crescents on LM
Linear deposition of IgG in GBM
Lungs – pulmonary haemorrhage
What type of nephritic syndrome?
What subtype?
3. RAPIDLY PROGRESSIVE (CRESCENTIC) GN
o Type 1: Anti-GBM antibody
760
Histopathology
Immune complex
mediated
Caused by: SLE, IgA nephropathy,
post infectious GN
Crescents on LM
Granular (lumpy bumpy) IgG immune complex deposition on GBM/mesangium
What type of nephritic syndrome?
What subtype?
3. RAPIDLY PROGRESSIVE (CRESCENTIC) GN
o Type 2: Immune complex
761
Histopathology
Pauci-immune i.e. lack of anti-GBM or immune complex
Caused by: c-ANCA: Wegener’s
granulomatosis
p-ANCA: microscopic polyangiitis
Crescents on LM
Lack of/scanty significant immune complex deposition
Vasculitis – particularly presenting as skin rashes or pulmonary haemorrhage
What type of nephritic syndrome?
What subtype?
3. RAPIDLY PROGRESSIVE (CRESCENTIC) GN
o Type 3: Pauci-immune / ANCA-associated
762
Histopathology
● Hereditary glomerular disease caused by mutation in type IV collagen alpha 5 chain
● X linked
● Nephritic syndrome + sensorineural deafness + eye disorders (lens dislocation,
cataracts)
● Presents at 5-20yrs with nephritic syndrome progressing to ESRF
4. HEREDITARY NEPHRITIS (ALPORT’S SYNDROME)
763
Histopathology
● VERY RARELY A CAUSE OF NEPHRITIC SYNDROME – normally exclusively asymptomatic haematuria
● Diffuse thinning of GBM caused by mutation in type IV collagen alpha 4 chain
● Autosomal dominant
● Quite common – prevalence is ~5%
● Usually asymptomatic – incidentally diagnosed with microscopic haematuria
● Renal function usually normal
5. THIN BASEMENT MEMBRANE DISEASE (BENIGN FAMILIAL HAEMATURIA)
764
Histopathology
Damage to tubular epithelial cells → blockage of tubules by casts → reduced flow and haemodynamic changes → acute renal failure
Most common cause of acute renal failure.
Acute Tubular Injury (ATI) aka Acute Tubular Necrosis (ATN)
765
Histopathology
Histopathology: necrosis of short segments of tubules
Acute Tubular Injury (ATI) aka Acute Tubular Necrosis (ATN)
766
Histopathology
ATN causes?
Causes include:
o Ischaemia – burns, septicaemia
o Nephrotoxins – drugs (gentamicin, NSAIDs), radiographic contrast agents,
myoglobin, heavy metals
767
Histopathology
● Bacterial infection of the kidney, usually a result of ascending infection, most commonly caused by E. coli
● Presents with fever, chills, sweats, flank pain, renal angle tenderness and leukocytosis +/- frequency, dysuria and haematuria
● Leukocytic casts are seen in the urine
Acute pyelonephritis
768
Histopathology
● Chronic inflammation and scarring of the parenchyma caused by recurrent and persistent bacterial infection
● Can be due to:
o Chronic obstruction – posterior urethral valves, renal calculi o Urine reflux (= reflux nephropathy)
Chronic pyelonephritis and reflux nephropathy:
769
Histopathology
● A hypersensitivity reaction, usually to a drug (abx, NSAIDs, diuretics)
● Usually begins days after drug exposure
● Presents with: fever, skin rash, haematuria, proteinuria, eosinophilia
Acute interstitial nephritis
770
Histopathology
● Seen in elderly with long-term analgesic consumption (NSAIDs/paracetamol)
● Symptoms only occur late in disease: HTN, anaemia, proteinuria and haematuria
Chronic interstitial nephritis / Analgesic nephropathy:
771
Histopathology
Triad of:
▪ Microangiopathic haemolytic anaemia (MAHA)
▪ Thrombocytopaenia
▪ Sometimes renal failure
Pathophysiology: widespread fibrin deposition in vessels → formation of platelet-fibrin thrombi which damage passing platelets and RBCs → platelet and RBC destruction (i.e. thrombocytopenia and MAHA)
Haemolytic Uraemic Syndrome (HUS) and Thrombotic Thrombocytopaenic Purpura (TTP)
772
Histopathology
Pathophysiology: widespread fibrin deposition in vessels → formation of platelet-fibrin thrombi which damage passing platelets and RBCs → platelet and RBC destruction (i.e. thrombocytopenia and MAHA)
Haemolytic Uraemic Syndrome (HUS) and Thrombotic Thrombocytopaenic Purpura (TTP)
773
Histopathology
Usually affects children
Usually associated with diarrhoea caused by E.coli O157:H7 with outbreaks caused by children visiting petting zoos.
Can be ‘non-diarrhoea associated’ due to abnormal proteins in complement pathway/endothelium – can be familial
Thrombi confined to kidneys
↓plt → bleeding (petechiae, haematemesis, melena). MAHA → pallor and jaundice
Usually involves renal failure
● ↓Hb ↓plt
● Signs of haemolysis: ↑bilirubin, ↑reticulocytes, ↑LDH
● Fragmented RBCs on blood smear
● Coomb’s test negative (as not AIHA)
HUS
774
Histopathology
Usually affects adults
Thrombi occur throughout circulation, esp. in CNS
↓plt → bleeding (petechiae, haematemesis, melena). MAHA → pallor and jaundice
Usually no renal failure. Neuro symptoms (headache, altered consciousness, seizures, coma)
● ↓Hb ↓plt
● Signs of haemolysis: ↑bilirubin, ↑reticulocytes, ↑LDH
● Fragmented RBCs on blood smear
● Coomb’s test negative (as not AIHA)
TTP
775
Histopathology
A rapid loss of renal function manifesting as increased serum creatinine and urea. Complications include metabolic acidosis, hyperkalaemia, fluid overload, HTN, ↓Ca2+ and uraemia
Acute Renal Failure
776
Histopathology
Pre/intrinsic/post
Which is most common, in Acute RF
PRE-RENAL
● Most common cause of acute renal failure
● Caused by renal hypo-perfusion e.g. hypovolaemia, sepsis, burns, acute pancreatitis,
and renal artery stenosis.
777
Histopathology
List causes of pre-renal RF
PRE-RENAL
● Most common cause of acute renal failure
● Caused by renal hypo-perfusion e.g. hypovolaemia, sepsis, burns, acute pancreatitis,
and renal artery stenosis.
778
Histopathology
List causes of intrinsic-renal RF
RENAL
● Acute Tubular Necrosis (ATN): commonest renal cause of ARF.
● Acute glomerulonephritis.
● Thrombotic microangiopathy.
779
Histopathology
List causes of post-renal RF
POST-RENAL
● Obstruction to urine flow as a result of stones, tumours (primary & secondary), prostatic hypertrophy and retroperitoneal fibrosis
780
Histopathology
Progressive, irreversible loss of renal function characterized by prolonged symptoms and signs of uraemia (fatigue, itching, anorexia and if severe eventually confusion). Commonest causes in the UK;
● Diabetes (19.5%)
● Glomerulonephritis (15.3%)
● Hypertension & Vascular disease (15%)
● Reflux nephropathy (chronic pyelonephritis) (9.5%)
● Polycystic kidney disease (9.4%)
Chronic Renal Failure
781
Histopathology
Main causes of CKD?
● Diabetes (19.5%)
● Glomerulonephritis (15.3%)
● Hypertension & Vascular disease (15%)
● Reflux nephropathy (chronic pyelonephritis) (9.5%)
● Polycystic kidney disease (9.4%)
782
Histopathology
5 GFR classifications of CKD?
1
Kidney damage with normal renal function (often proteinuria)
>90
2
Mildly impaired
60-89
3
Moderately impaired
30-59
4
Severely impaired
15-29
5
Renal failure (generally requires replacement therapy)
<15 (or if being treated with renal replacement therapy)
783
Histopathology
Adult Polycystic Kidney Disease (APCKD) inheritance + genes?
Autosomal dominant inheritance. 85% due to mutations in PKD1 on chromosome 16 (encoding polycystin-1), remainder in PKD2 on chromosome 4 (encoding polycystin-2)
Accounts for 10% of cases of CKD
784
Histopathology
Autosomal dominant inheritance. 85% due to mutations in PKD1 on chromosome 16 (encoding polycystin-1), remainder in PKD2 on chromosome 4 (encoding polycystin-2)
Accounts for 10% of cases of CKD
Adult Polycystic Kidney Disease (APCKD)
785
Histopathology
Pathologic features: large multicystic kidneys with destroyed renal parenchyma, liver cysts (in PKD1) and berry aneurysms.
Clinical features: haematuria, flank pain, UTI. Clinical features are often due to cyst complications such cyst rupture, cyst infection and cyst haemorrhage.
Adult Polycystic Kidney Disease (APCKD)
786
Histopathology
Depending on site and intensity of immune complex deposition clinical presentation may be: isolated urinary abnormalities, acute renal failure, nephrotic syndrome or progressive chronic renal failure.
Lupus Nephritis
787
Histopathology
This type of renal carcinoma is most well differentiated
● Clear cell carcinoma – well differentiated
Risk factors: smoking, obesity, HTN, unopposed oestrogen, heavy metals, CKD Clinical features: costovertebral pain, palpable mass, haematuria
Paraneoplastic syndrome: polycythaemia, hypercalcaemia, HTN, Cushing’s syndrome, amyloidosis
788
Histopathology
This type of renal carcinoma is commonest in dialysis associated cystic disease
● Papillary carcinoma – commonest in dialysis-associated cystic disease
Risk factors: smoking, obesity, HTN, unopposed oestrogen, heavy metals, CKD Clinical features: costovertebral pain, palpable mass, haematuria
Paraneoplastic syndrome: polycythaemia, hypercalcaemia, HTN, Cushing’s syndrome, amyloidosis
789
Histopathology
On biopsy of this type of renal carcinoma you see pale, eosinophilic cells
● Chromophobe renal carcinoma – pale, eosinophilic cells
Risk factors: smoking, obesity, HTN, unopposed oestrogen, heavy metals, CKD Clinical features: costovertebral pain, palpable mass, haematuria
Paraneoplastic syndrome: polycythaemia, hypercalcaemia, HTN, Cushing’s syndrome, amyloidosis
790
Histopathology
Infection ascending from vagina and cervix up to uterus and tubes, leading to inflammation (endometritis, salpingitis) and the formation of adhesions.
Chlamydia trachomatis and Neisseria gonorrhoea are most common organisms in UK.
TB and schistosomiasis are common causes in some parts of the world.
Clinically: lower abdo pain, dyspareunia, vaginal bleeding/discharge, fever, adnexal tenderness, and cervical excitation
Complications:
● Fitz Hugh Curtis syndrome – RUQ from peri-hepatitis + violin string peri-hepatic adhesions
● Infertility
● ↑Risk of ectopic pregnancy
● Intestinal obstruction → bacteraemia
● Tubo-ovarian abscess
● Chronic pelvic pain
● Peritonitis
● Plical fusion
Pelvic Inflammatory Disease (PID / Salpingitis)
791
Histopathology
Presence of endometrial glands or stroma in abnormal locations outside the uterus e.g. ovaries, uterine ligaments, rectovaginal septum, Pouch of Douglas, pelvic peritoneum
3 theories of aetiology: regurgitant/implantation from retrograde menstrual flow of endometrial cells; metaplastic transformation of coelomic epithelial cells; vascular or lymphatic dissemination of endometrial cells
Ectopic tissue is functional, undergoing cyclical bleeding → pain, scarring and infertility
Clinically:
● Pelvic pain, dysmenorrhoea, deep dyspareunia, ↓fertility
● Cyclical PR bleeding, haematuria, bleeding from umbilicus (depending on site of endometrial deposits)
● Nodules/tenderness in vagina, posterior fornix or uterus; immobile uterus which is retroverted in advanced disease
Macroscopically:
● red-blue to brown nodules - “powder burns”
● “chocolate cysts” in ovaries (endometriomas)
Endometriosis
792
Histopathology
What are the 3 main theories surrounding endometriosis
3 theories of aetiology: regurgitant/implantation from retrograde menstrual flow of endometrial cells; metaplastic transformation of coelomic epithelial cells; vascular or lymphatic dissemination of endometrial cells
Ectopic tissue is functional, undergoing cyclical bleeding → pain, scarring and infertility
793
Histopathology
Similar to endometriosis; presence of ectopic endometrial tissue deep within the
myometrium
Clinically: heavy menstrual bleeding, dysmenorrhoea, and deep dyspareunia. Globular
uterus.
Adenomysosis
794
Histopathology
A benign tumour of smooth muscle origin
Most common tumour of female genital tract – occurring in 20% of women >35
Can occur intramural, submucosal or subserosal.
Oestrogen stimulation important: enlarge during pregnancy, regress post-menopause Macroscopically:
● Sharply circumscribed, discrete, round, firm, gray-white tumours. Size variable.
Microscopically:
● Bundles of smooth muscle cells
Clinically:
● Heavy menstrual bleeding, dysmenorrhoea, pressure effects (urinary frequency, tenesmus)
● Subfertility
● In pregnancy: red degeneration of fibroids (haemorrhagic infarction → severe abdo
pain), post-partum torsion
Benign to malignant transformation is rare (leiomyosarcoma)
Leiomyosarcomas likely arise de novo, usually occurring in post-menopausal women.
Leiomyoma (fibroid)
795
Histopathology
● Bundles of smooth muscle cells
● Sharply circumscribed, discrete, round, firm, gray-white tumours. Size variable.
Benign to malignant transformation is rare
Leiomyoma (fibroid)
796
Histopathology
Postmenopausal bleeding is endometrial cancer until proven otherwise
10% of women with postmenopausal bleeding will have malignancy. Staged with FIGO system
Subdivided into:
● ENDOMETRIOID – 80% (i.e. look similar to normal endometrial glands)
o Pathophysiology: related to oestrogen excess – usually in peri-menopausal women
o Risk factors:
▪ E2 excess: obesity, anovulatory amenorrhoea (e.g. PCOS), nulliparity,
early menarche, late menopause, tamoxifen
▪ DM, HTN
o Mainly adenocarcinomas (85%), but may show squamous differentiation ● NON-ENDOMETRIOID – 20%
o These include papillary, serous and clear cell. More aggressive.
o Pathophysiology: unrelated to estrogen excess; usually in elderly women with endometrial atrophy
Endometrial cancer
797
Histopathology
What are the two types of endometrial cancer?
● ENDOMETRIOID – 80% (i.e. look similar to normal endometrial glands)
o Pathophysiology: related to oestrogen excess – usually in peri-menopausal women
o Risk factors:
▪ E2 excess: obesity, anovulatory amenorrhoea (e.g. PCOS), nulliparity,
early menarche, late menopause, tamoxifen
▪ DM, HTN
o Mainly adenocarcinomas (85%), but may show squamous differentiation ● NON-ENDOMETRIOID – 20%
o These include papillary, serous and clear cell. More aggressive.
o Pathophysiology: unrelated to estrogen excess; usually in elderly women with endometrial atrophy
798
Histopathology
What is associated with VIN - vulval intraepithelial neoplasia?
● Dysplasia of epithelium; associated with HPV-16
799
Histopathology
● Dysplasia of epithelium; associated with HPV-16
● Usual type (warty, basaloid, mixed):
o women aged 35-55yrs
o associated with warty/basaloid SCC ● Differentiated type:
o older women
o associated with keratinizing SCC
o higher risk of malignant transformation than usual type
VIN
● Graded as VIN I, II and III
● Progression to invasive disease is lower than for CIN (~ 5%)
800
Histopathology
● Mainly squamous cell carcinoma; can arise from VIN (pre- malignant stage) or from other skin abnormalities (Paget’s of the vulva - adenocarcinoma in situ)
Vulval carcinoma
801
Histopathology
Most common type
Mimics tubal epithelium i.e. columnar epithelium
Psammoma bodies common most common malignancy affects women aged 30-40yrs
What type of ovarian epithelial tumour?
Serous cystadenoma
802
Histopathology
```
Mucin secreting cells, similar to
those of endocervical mucosa. OR intestinal type – metastatic from appendix in some cases → pseudomyxoma peritonei
No psammoma bodies
most common oestrogen-secreting tumour
affects younger women
```
What type of ovarian epithelial tumour?
Mucinous cystadenoma
803
Histopathology
Mimics endometrium – i.e. form tubular glands
Endometriosis is risk factor
What type of ovarian epithelial tumour?
Endometrioid
804
Histopathology
Abundant clear cytoplasm – intracellular glycogen Hobnail appearance malignant with poor prognosis
What type of ovarian epithelial tumour?
Clear cell
805
Histopathology
Female counterpart of testicular seminoma
rare, but the most common ovarian malignancy in young women sensitive to radiotherapy
What type of ovarian germ cell tumour?
Dysgerminoma
806
Histopathology
```
Shows differentiation toward somatic structures
Mature teratomas (dermoid cyst) 95% of teratomas: Benign; usually cystic;
Differentiation of germ cells into mature tissues (e.g. skin, hair, teeth, bone, cartilage); usually bilateral and asymptomatic. Immature teratomas: Malignant, usually solid; Contains immature, embryonal tissues secrete AFP
```
What type of ovarian germ cell tumour?
Teratoma
807
Histopathology
Secrete hCG malignant
What type of ovarian germ cell tumour?
Choriocarcinoma
808
Histopathology
No hormone production
50% associated with Meig’s syndrome (ascites + pleural effusion)
What type of ovarian sex chord tumour?
Fibroma (from cells of ovarian stroma)
809
Histopathology
Produce E2
Look for oestrogenic effects – irregular menstrual cycles, breast enlargement, endometrial/breast cancer
What type of ovarian sex chord tumour?
Granulosa-Theca cell tumour
810
Histopathology
Secrete androgens
Look for defeminisation (breast atrophy) and virilisation (hirsutism, deepened voice, enlarged clitoris)
What type of ovarian sex chord tumour?
Sertoli-Leydig cell tumour
811
Histopathology
The area where columnar epithelium transforms into squamous cells (=squamous metaplasia). This is a normal physiological process. This area is susceptible to malignant change
Transformation zone
812
Histopathology
CIN: Dysplasia at the TZ as a result of infection by
HPV 16 & 18
813
Histopathology
CIN: Dysplasia at the TZ as a result of infection by HPV 16 & 18.
Graded mild, moderate or severe dyskaryosis on cytology, but graded CIN 1-3 on histology (from biopsy).
What does CIN 1 mean?
CIN 1 = dysplasia confined to lower 1/3 of epithelium
60-90% of CIN 1 reverts to normal over 10-23 months 30% of CIN 3 progress to cervical cancer over 10 years
814
Histopathology
CIN: Dysplasia at the TZ as a result of infection by HPV 16 & 18.
Graded mild, moderate or severe dyskaryosis on cytology, but graded CIN 1-3 on histology (from biopsy).
What does CIN 1 mean?
CIN 2 = lower 2/3
60-90% of CIN 1 reverts to normal over 10-23 months 30% of CIN 3 progress to cervical cancer over 10 years
815
Histopathology
CIN: Dysplasia at the TZ as a result of infection by HPV 16 & 18.
Graded mild, moderate or severe dyskaryosis on cytology, but graded CIN 1-3 on histology (from biopsy).
What does CIN 1 mean?
CIN 3 = full thickness, but basement membrane intact
60-90% of CIN 1 reverts to normal over 10-23 months 30% of CIN 3 progress to cervical cancer over 10 years
816
Histopathology
CIN RFs
Early age at first intercourse, multiple partners, multiparity, smoking, HIV or immunosuppression
817
Histopathology
Usually arises from CIN
Most commonly squamous cell carcinoma (70-80%), but ~20% are adenocarcinomas, adenosquamous carcinomas and others.
Invasion through the basement membrane marks the change from CIN to carcinoma Clinically: post-coital bleeding, intermenstrual bleeding, postmenopausal bleeding, discharge, pain. Staged using FIGO system
Majority of the lesions are benign and common presenting symptoms include pain
(mastalgia/ mastodynia), palpable masses and/or nipple discharge.
Cervical carcinoma
818
Histopathology
Painful, red breast and fever
Almost all occur during lactation and breast-feeding as a result of staphylococcal infection via cracks in nipple. Involved breast tissue is necrotic and infiltrated by neutrophils.
Tx: continued expression of milk + antibiotics +/- surgical drainage
Acute mastitis
819
Histopathology
Mostly in smokers and not associated with lactation.
Histologically, keratinizing squamous epithelium extends deep into nipple duct orifices
Periductal mastitis
820
Histopathology
Occurs mainly in multiparous, 40-60yr old women.
Poorly defined palpable periareolar mass with thick, white nipple secretions. Caused by granulomatous inflammation and dilation of large breast ducts Mimics mammographic appearance of cancer
Cytology – proteinaceous material, inflammatory cells
Mammary Duct ectasia
821
Histopathology
Inflammatory reaction to damaged adipose tissue
Presents as painless breast mass/skin thickening/mammographic lesion Causes – trauma, radiotherapy, surgery
Fat necrosis
822
Histopathology
Increased number of acini per breast lobule (normally seen in pregnancy)
Adenosis
823
Histopathology
Unilateral or bilateral enlargement of the male breast
Indicator of hyperoestrogenism – alcohol, age, liver cirrhosis, functioning testicular tumour
Histology – Epithelial hyperplasia, finger like projections into ducts.
Gynaecomastia
824
Histopathology
Most common benign tumour, from stroma, often multiple and bilateral
Occurring at any age within the reproductive period, usually at 20-30yrs
Epithelium responsive to hormones therefore increase in size during pregnancy and calcify after menopause.
Spherical, freely mobile, variable size and rubbery.
Overgrowth of collagenous mesenchyme. “Shelling out” is curative
Fibroadenoma (‘breast mouse’)
825
Histopathology
Benign papillary tumour arising within the duct system of the breast. It can be within small terminal ductules (peripheral papillomas) or larger lactiferous ducts (central papillomas). Causes bloody discharge. No lump. Not seen on mammogram. Ix- galactogram
Duct papilloma
826
Histopathology
Benign sclerosing lesion – central scarring surrounded by proliferating glandular tissue in stellate pattern. Resembles carcinoma on mammogram.
Radial scar
827
Histopathology
Susceptibility genes for breast cancer
Susceptibility genes (12%) – BRCA1/BRCA2, also increased risk of ovarian, prostate and pancreatic malignancy. BRCA mutations cause a lifetime risk of invasive breast carcinoma of up to 85%.
828
Histopathology
RFs for breast Ca?
o Susceptibility genes (12%) – BRCA1/BRCA2, also increased risk of ovarian, prostate and pancreatic malignancy. BRCA mutations cause a lifetime risk of invasive breast carcinoma of up to 85%.
o Hormone exposure – early menarche, late menopause, late 1st live birth (pregnancy → terminal differentiation of milk-producing luminal cells, removing these from pool of potential cancer precursors), OCP/HRT
o Advancing age
o Family history
o Race (Caucasian>Afro-Caribbean>Asian>Hispanic) o Obesity, tobacco, alcohol
829
Histopathology
Presentation: hard fixed lump, Paget’s disease, peau d’orange, nipple retraction.
● Screening: 47 to 73yr old women invited every 3 years for mammography (looks for
abnormal areas of calcification or a mass within the breast)
Breast carcinoma
830
Histopathology
o Neoplastic epithelial proliferation limited to ducts/lobules by basement membrane
Which breast Ca?
● Carcinoma in situ (30%)
831
Histopathology
ALWAYS incidental finding on biopsy as no microcalcifications or stromal reactions. 20-40% bilateral. Cells lack adhesion protein E-cadherin. RF for subsequent invasive breast carcinoma.
Which breast Ca?
Lobular (LCIS)
832
Histopathology
Incidence increased dramatically since development of mammography. Appear as areas of microcalcification. 10% present with clinical symptoms. Much increased risk of progressing to invasive breast Ca. High, intermediate and low grade
Which breast Ca?
Ductal (DCIS)
833
Histopathology
Most common invasive carcinoma
Invasive breast carcinoma (80%) – malignant epithelial tumours which infiltrate within breast, capacity to spread to distant sites.
o They can be histologically subcategorised into ductal, lobular, tubular and mucinous.
o Invasive ductal = carcinoma that cannot be subclassified into another group. Most common
o Invasive lobular = cells aligned in single file chains/strands.
o Tubular carcinomas = well-formed tubules with low grade nuclei. Rarely palpable
as <1cm.
o Mucinous carcinoma cells produce abundant quantities of extracellular mucin
which dissects into surrounding stroma.
834
Histopathology
Breast carcinoma that cannot be subclassified into another group. Most common
Invasive breast carcinoma (80%) – malignant epithelial tumours which infiltrate within breast, capacity to spread to distant sites.
o They can be histologically subcategorised into ductal, lobular, tubular and mucinous.
o Invasive ductal = carcinoma that cannot be subclassified into another group. Most common
o Invasive lobular = cells aligned in single file chains/strands.
o Tubular carcinomas = well-formed tubules with low grade nuclei. Rarely palpable as <1cm.
o Mucinous carcinoma cells produce abundant quantities of extracellular mucin
which dissects into surrounding stroma.
835
Histopathology
Breast ca with cells aligned in single file chains/strands.
Invasive breast carcinoma (80%) – malignant epithelial tumours which infiltrate within breast, capacity to spread to distant sites.
o They can be histologically subcategorised into ductal, lobular, tubular and mucinous.
o Invasive ductal = carcinoma that cannot be subclassified into another group. Most common
o Invasive lobular = cells aligned in single file chains/strands.
o Tubular carcinomas = well-formed tubules with low grade nuclei. Rarely palpable
as <1cm.
o Mucinous carcinoma cells produce abundant quantities of extracellular mucin
which dissects into surrounding stroma.
836
Histopathology
Breast Ca with well-formed tubules with low grade nuclei. Rarely palpable
as <1cm.
Invasive breast carcinoma (80%) – malignant epithelial tumours which infiltrate within breast, capacity to spread to distant sites.
o They can be histologically subcategorised into ductal, lobular, tubular and mucinous.
o Invasive ductal = carcinoma that cannot be subclassified into another group. Most common
o Invasive lobular = cells aligned in single file chains/strands.
o Tubular carcinomas = well-formed tubules with low grade nuclei. Rarely palpable
as <1cm.
o Mucinous carcinoma cells produce abundant quantities of extracellular mucin
which dissects into surrounding stroma.
837
Histopathology
What is in the triple assessment?
Triple assessment: examination, radiological examination (mammography/USS/MRI), FNA & cytology
838
Histopathology
What receptors are tested in breast cancer?
All neoplastic lesions also assessed for oestrogen receptor, progesterone receptor and HER2 receptor status. ER/PR receptor positive associated with good prognosis because it predicts response to tamoxifen. HER 2 positive associated with bad prognosis
839
Histopathology
MoA of tamoxifen
● Tamoxifen = mixed agonist/antagonists of oestrogen at its receptor.
840
Histopathology
Herceptin/trastuzumab MoA
Herceptin/trastuzumab = monoclonal Ig to Her2 (direct toxic effect on myocardium,
must monitor LVEF.
841
Histopathology
Sheets of atypical cells with lymphocytic infiltrate. Stain positive for CK5/6/14
What breast cancer?
Basal-like carcinoma
842
Histopathology
Stain positive for CK5/6/14
What breast cancer?
Basal-like carcinoma
843
Histopathology
Arise from interlobular stroma (like fibroadenomas – can arise within existing
fibroadenomas) with increased cellularity and mitoses.
Present >50yrs as palpable mass
Low grade or high grade lesions. Mostly relatively benign, but can be aggressive therefore excised with wide local excision/mastectomy to limit local recurrence.
Mets very rare.
What breast cancer?
Phyllodes tumour
844
Histopathology
Sudden onset
FAST,
numbness, loss of vision, dysphagia (depends on territory)
Anterior vs. Posterior territory Commonest = MCA
Aspirin +/- dipyridamole Thrombolytics (if <3h from event) +/- carotid endarterectomy
Long term: treat HTN, ↓lipids, anticoag
Stroke
845
Histopathology
Symptoms last <24hrs, Amaurosis fugax, Carotid bruit
Any – characteristically embolic atherogenic debris from the carotid artery travels to the ophthalmic branch of internal carotid
Aspirin + dipyridamole
+/- carotid endarterectomy Long term: treat HTN, ↓lipids,
anticoag
TIA
846
Histopathology
50% due to HTN, onset is abrupt, can cause Charcot-bouchard microaneurysms (likely to rupture), common site= basal ganglia
Intraparenchymal haemorrhage
847
Histopathology
85% from ruptured berry aneurysms, most at internal carotid bifurcation, F>M, usually <50yrs, → thunderclap headache, vomiting and LoC, ↑in PKD, Ehler’s Danlos and Pts with Aortic Coarctation. Also associated with vascular abnormalities incl AV malformations, capillary telangiectasias, venous and cavernous angiomas, Ehlers Danlos.
Subarachnoid haemorrhage
848
Histopathology
Skull fracture, ruptured middle meningeal artery → rapid arterial bleed, lucid interval then LoC,
Extradural haemorrhage
849
Histopathology
Prev history of minor trauma → damaged bridging veins with slow venous bleed, often elderly/alcoholic, associated with brain atrophy, fluctuating consciousness
Subdural haemorrhage
850
Histopathology
Transient LoC and paralysis, recovery in hours or days
Concussion
851
Histopathology
Vegetative state, post traumatic dementia
What type of traumatic parenchymal injury
Diffuse axonal injury
852
Histopathology
When brain contacts skull +/- fracture
What type of traumatic parenchymal injury
Contusions
853
Histopathology
Traumatic brain injury:
What describes where the impact occurs
What describes opposite to region of impact
Coup= where impact occurs, contracoup= opposite to region of impact
854
Histopathology
6 types of herniation
Six types: Uncal, Central (transtentorial), Cingulate (subfalcine), Transcalvarial, Upward, Tonsillar.
855
Histopathology
Neonate - top bacterial causes meningitis?
GBS
E. Coli
Listeria
856
Histopathology
Neonate - top viral causes meningitis?
Echovirus
Coxsackie’s virus Mumps virus
HIV
857
Histopathology
1 month - 6 years - top bacterial causes meningitis?
Streptococcus pneumoniae (Haemophilus influenza)
858
Histopathology
Young adults and adolescents - top bacterial causes meningitis?
Neisseria Meningitidis Streptococcus pneumoniae
859
Histopathology
Elderly - top bacterial causes meningitis?
Streptococcus pneumoniae Gram –ve bacilli e.g. E coli
860
Histopathology
Main cause viral encephalitis
Causes include Herpes simplex 1, rabies
861
Histopathology
Most common primary tumours leading to brain mets?
Most common primaries are: lung, breast, malignant melanoma
| Well demarcated, solitary or multiple with surrounding oedema.
862
Histopathology
Brain tumour buzzwords:
Histopathology
meningioma
863
Histopathology
Brain tumour buzzwords:
Ventricular tumour, hydrocephalus
Ependymoma
864
Histopathology
Brain tumour buzzwords:
Indolent, childhood
pilocytic astrocytoma
865
Histopathology
Brain tumour buzzwords:
Soft, gelatinous, calcified
oligodendroma
866
Histopathology
loss of ability to carry out learned purposeful tasks
Apraxia
867
Histopathology
loss of ability to recognise object, people
Agnosia
868
Histopathology
Tau, beta-amyloid
Alzheimer’s disease
869
Histopathology
Alpha-synuclein, ubiquitin
Dementia with Lewy bodies
870
Histopathology
Tau
Corticobasal degeneration
Pick’s disease
Frontotemporal dementia linked to Chr 17
871
Histopathology
Generalised atrophy of the brain, widened sulci, narrowed gyri and enlarged ventricles (most marked in temporal and frontal lobes with loss of cholinergic neurons).
Alzheimer’s disease
Commonest cause of dementia, usually begins >50yrs, generalised atrophy of the brain, widened sulci, narrowed gyri and enlarged ventricles (most marked in temporal and frontal lobes with loss of cholinergic neurons).
Clinical diagnosis although PET and MRI may help. Senile plaques of beta-amyloid protein and neurofibrillary tangles of tau protein.
Rx is symptomatic: anti-cholinesterases, nAChR agonists, glutamate antagonists.
872
Histopathology
↓ stimulation of the motor cortex by the basal ganglia (caused by death of dopaminergic neurons in substantia nigra)
Idiopathic Parkinson’s Disease
Lewy bodies present in affected neurons (alpha synuclein protein is main component; mutations reported in familial PD)
873
Histopathology
Autoimmune demyelinating disease (remember myelin: produced by oligodendrocytes, wraps round axons, important for axon conduction)
Multiple Sclerosis
EMQ giveaway markers: Myelin Basic Protein and Proteo-lipid protein
874
Histopathology
MS plaques showing sharp margins of myelin loss
Multiple Sclerosis
EMQ giveaway markers: Myelin Basic Protein and Proteo-lipid protein
875
Histopathology
EMQ giveaway markers: Myelin Basic Protein and Proteo-lipid protein
Multiple Sclerosis
876
Histopathology
Degenerative neurological disorder charecterised by the features below that can present in a very similar manor to Parkinson’s but shows a poor response to Parkinson’s medication.
Shy Drager: Autonomic dysfuntion
Striatonigral: Difficulty with movement
Olivopontocerebellar: Difficulty with Balance and co-ordination
Multiple System Atrophy
877
Histopathology
Age related (post- menopause in females) or secondary to systemic disease/drugs
DEXA scan: T score > 2.5 SD below normal (1-2.5 = osteopaenia)
Histology - Loss of cancellous bone
Osteoporosis
878
Histopathology
↓dietary Vit D, ↓ sunlight, malabsorption of Vit D (GI causes), and genetic causes
↓bone
mineralization
Adults:
Bone pain/tenderness, proximal muscle weakness Children:
Bone pain, bowing tibia, rachitic rosary, frontal bossing, pigeon chest, delayed walking
XRAY Looser’s zones
(pseudo fractures) Splaying of metaphysis
Osteomalacia
879
Histopathology
Excess of unmineralized bone (osteoid
Osteomalacia
880
Histopathology
↔/↓Ca
↓ PO4 ↑ALP
Osteomalacia
881
Histopathology
↑Ca;
↓/↔ PO4; ↑/↔ ALP
Hyperparathyroidism (primary)
(Osteitis fibrosa cystica
(marrow fibrosis + cysts – aka Brown Tumour))
882
Histopathology
↔Ca;
↔PO4; ↑↑↑ALP
Paget’s
883
Histopathology
↓Ca;
↑PO4,
2o hyperPTH, metabolic acidosis
Renal Osteodystrophy
884
Histopathology
Brown’s tumours
Salt and pepper skull Subperiosteal bone resorption in phalanges
Hyperparathyroidism (primary)
885
Histopathology
Mixed lytic and sclerotic SKULL Osteoporosis circumscripta Cotton wool VERTEBRAE: Picture frame Ivory vertebra PELVIS: Sclerosis and lucency
Paget’s
| Disease
886
Histopathology
Huge osteoclasts
w > 100 nuclei Mosaic pattern of lamellar bone (like jigsaw puzzle)
Paget’s
| Disease
887
Histopathology
↑dietary purine intake, ETOH, diuretics, inherited metabolic abnormalities
Hot, swollen, red, exquisitely painful joint.
Tophus (s/c deposits of urate) is the pathognomonic lesion e.g. on pinna and hands.
Urate crystals, needle shaped
Negatively birefringent crystals
Gout
888
Histopathology
Acute attack: colchicine. Long term: allopurinol. Conservative: ↓ETOH and purine intake e.g. sardines, liver
Gout
889
Histopathology
Rx acute gout
Acute attack: colchicine. Long term: allopurinol. Conservative: ↓ETOH and purine intake e.g. sardines, liver
890
Histopathology
Rx pseudo gout
NSAIDs or intra-articular steroids
891
Histopathology
Calcium pyrophosphate crystals, rhomboid shaped
Pseudogout
892
Histopathology
Idiopathic
HyperPTH, DM, Hypothyroid, Wilsons
Hot swollen joint w/ effusion
Pseudogout
893
Histopathology
Positively birefringent
Pseudogout
894
Histopathology
Main cause osteomyelitis in adults
Adults – S. Aureus. Vertebrae, jaw (2o to dental abscess) and toes (2o to diabetic skin ulcer)
895
Histopathology
Main cause osteomyelitis in children
Children – Haemophilus influenza, Group B strep. Long bones
896
Histopathology
When do xray changes appear for osteomyelitis?
Presentation: pain, swelling and tenderness. General features of malaise, fever, chills, leukocytosis.
X-ray changes ~10 days post onset. Lytic destruction of bone.
Rare causes: TB (immunocompromised patients), syphilis (congenital or acquired)
897
Histopathology
Degenerative joint disease mainly affecting vertebrae, hips and knees. May see Heberden’s nodes (DIPJ) and Bouchard’s nodes (PIPJ)
Osteoarthritis
898
Histopathology
Clinical presentation: usually slowly progressing course. Symmetrical, small joints of hands and feet (sparing DIPJ), wrists, elbows, ankles and knees.
Characteristic deformities:
● Radial deviation of wrist and ulnar deviation of fingers.
● “swan neck” and “Boutonniere” deformity of fingers.
● “Z” shaped thumb
Rheumatoid arthritis
899
Histopathology
```
Adolescence
Knee (60%)
Histology
Malignant mesenchymal cells
ALP +ve
Elevated periosteum (Codman’s
triangle)
Sunburst appearance
```
Osteosarcoma
900
Histopathology
>40 yrs
Axial skeleton Femur/tibia/ pelvis
Malignant chondrocytes
Lytic lesion with fluffy calcification, Axial skeleton
Chondrosarcoma
901
Histopathology
```
<20yrs
Long bones, pelvis
Sheets of small round cells CD99 +ve
T 11:22 translocation
Onion skinning of periosteum
```
Ewing’s sarcoma
902
Histopathology
20-40yrs F>M
Knee- epiphysis
Osteoclast-type multinucleate giant cells on background of spindle/ovoid cells
Lytic/lucent lesions right up to articular surface
Giant cell (borderline malignancy)
903
Histopathology
Tibia/ Femur
Small benign bone forming lesion, night pain relieved by aspirin
Normal bone
Radiolucent nidus with sclerotic rim
Osteoid Osteoma
904
Histopathology
```
Head + neck
Bony outgrowths attached to normal bone
Gardner syndrome:
GI polyps + multiple _____ + epidermoid cysts
Normal bone
```
Osteoma
905
Histopathology
```
Hands 43% Ie Ends so often in the hands
Benign tumours of cartilage
Ollier’s syndrome =
multiple enchondromas
Maffuci’s syndrome =
multiple enchondromas + haemangiomas
Normal cartilage
Lytic lesion
Cotton wool calcification
Expansile, O ring sign
```
Enchondroma (Middle age)
906
Histopathology
Long bones
Cartilage capped bony outgrowth
Diaphyseal aclasis/ hereditary multiple exostoses =
multiple exostoses + short stature + bone deformities
Cartilage capped bony outgrowth
Well defined bony protuberance from bone
Osteochondroma (=exostosis)
| Adolescent
907
Histopathology
```
Femur
A bit of bone is replaced by fibrous
tissue
Albright syndrome =
polyostotic dysplasia + café au lait spots + precocious puberty
Chinese letters (misshapen
bone trabeculae)
Soap bubble osteolysis
Shepherd’s crook
deformity
```
Fibrous dysplasia
| F>M Middle age
908
Histopathology
Humerus or femur
Fluid filled unilocular
Lytic well defined
Simple Bone cyst
909
Histopathology
Similar to osteoid osteoma
Speckled mineralisation
Osteoblastoma
910
Histopathology
↑ in S. corneum / ↑keratin
Hyperkeratosis
911
Histopathology
nuclei in S. corneum
Parakeratosis
912
Histopathology
↑ in s. spinosum
Acanthosis
913
Histopathology
↓ cohesions between keratinocytes
Acantholysis
914
Histopathology
Intercellular edema
Spongiosis
915
Histopathology
linear pattern of melanocyte proliferation within epidermal basal cell layer (reactive or neoplastic)
Lentiginous
916
Histopathology
```
Histology
ACUTE:
● Spongiosis
● Inflammatory infiltrate in
dermis
● Dilated dermal
capillaries
CHRONIC:
● Acanthosis
● Crusting, scaling
```
Atopic + contact dermatitis
917
Histopathology
Infants: face, scalp
Older: flexural areas
If chronic - lichenification
Persists into adulthood in those with FHx of atopy
Atopic dermatitis
918
Histopathology
Type IV hypersensitivity – e.g. to nickel, rubber Erythema, swelling, pruritis
Commonly affects ear lobes and neck (from jewellery), wrist (leather watch straps), feet (from shoes)
Contact dermatitis
919
Histopathology
Inflammatory reaction to a yeast - Malassezia Infants: cradle cap (large yellow scales on scalp) Young adults: mild erythema, fine scaling, mildly pruritic- affects face, eyebrow, eyelid, anterior chest, external ear
Seborrhoeic dermatitis
920
Histopathology
Salmon pink plaques with silver scale affecting extensor aspects of knees, elbows and scalp.
Rubbing them causing pin-point bleeding (Auspitz’ sign)
Koebner phenomenon – lesions form at sites of trauma
Cells in psoriatic plaque have increased proliferation rate
Chronic plaque psoriasis
Histo: Parakeratosis, loss of granular layer, clubbing of rete ridges giving “test tubes in a rack” appearance; Munro’s microabscesses
921
Histopathology
Lesions form at sites of trauma
Cells in psoriatic plaque have increased proliferation rate
Koebner phenomenon
Chronic plaque psoriasis
Histo: Parakeratosis, loss of granular layer, clubbing of rete ridges giving “test tubes in a rack” appearance; Munro’s microabscesses
922
Histopathology
Rubbing them causing pin-point bleeding
Auspitz’ sign
Chronic plaque psoriasis
Histo: Parakeratosis, loss of granular layer, clubbing of rete ridges giving “test tubes in a rack” appearance; Munro’s microabscesses
923
Histopathology
Histo: Parakeratosis, loss of granular layer, clubbing of rete ridges giving “test tubes in a rack” appearance; Munro’s microabscesses
Chronic plaque psoriasis
924
Histopathology
“rain-drop” plaque distribution, often in children, usually seen 2 weeks post-Strep throat
Guttate psoriasis
925
Histopathology
severe widespread psoriasis, often systemic symptoms, can be limited to hands and feet = palmo-plantar psoriasis
Erythrodermic/pustular psoriasis
926
Histopathology
Nail changes in psoriasis
POSH
```
o Nail changes:
▪ Pitting
▪ Onycholysis
▪ Subungual Hyperkeratosis
o Arthritis (5-10%)
```
927
Histopathology
```
o Nail changes:
▪ Pitting
▪ Onycholysis
▪ Subungual Hyperkeratosis
o Arthritis (5-10%)
```
Nail changes in psoriasis
928
Histopathology
Lesions are “pruritic, purple, polygonal, papules and plaques” with a mother-of-pearl sheen, and fine white network on their surface called Wickam’s striae
Usually on inner surfaces of wrists; can also affect oral mucous membrane where the lesions have lacy appearance
Aetiology unknown
Histo: hyperkeratosis with saw-toothing of rete ridges and basal cell degeneration
Lichen Planus
929
Histopathology
Histo: hyperkeratosis with saw-toothing of rete ridges and basal cell degeneration
Lichen Planus
930
Histopathology
```
Classically causes annular target lesions, most commonly on extensor surfaces of hands and feet. It causes pleomorphic lesions and there can be a combination of macules, papules, urticarial weals, vesicles, bullae and petechiae.
Causes:
● Infections:
○ HSV
○ mycoplasma
● Drugs:
○ Sulphonamides ○ NSAIDs
○ Allopurinol
○ Penicillin
○ Phenytoin
```
Erythema Multiforme
931
Histopathology
WHAT INFECTIONS CAUSE Erythema Multiforme
```
● Infections:
○ HSV
○ mycoplasma
● Drugs:
○ Sulphonamides ○ NSAIDs
○ Allopurinol
○ Penicillin
○ Phenytoin
```
932
Histopathology
WHAT drugs CAUSE Erythema Multiforme
```
● Infections:
○ HSV
○ mycoplasma
● Drugs:
○ Sulphonamides ○ NSAIDs
○ Allopurinol
○ Penicillin
○ Phenytoin
```
933
Histopathology
Wickam’s striae
Lichen Planus
934
Histopathology
Associated with coeliac
IgA Abs bind to basement membrane → subepidermal bulla
Itchy vesicles on extensor
surfaces of elbows, buttocks
Dermatitis
| herpetiformis
935
Histopathology
Histology:
Microabscesses which
coalesce to form
subepidermal bullae Neutrophil & IgA deposits at tips of dermal papillae
What skin rash?
Dermatitis
| herpetiformis
936
Histopathology
IgG Abs bind to hemidesmosomes of basement membrane → subepidermal bulla
Large tense bullae on erythematous base. Often on forearms, groin and axillae. ELDERLY.
Bullae do not rupture as easily as pemphigus
PemphigoiD - Bullae are Deep
937
Histopathology
Subepidermal bulla with eosinophils
Linear deposition of IgG along basement membrane
What skin rash?
PemphigoiD - Bullae are Deep
938
Histopathology
IgG Abs bind to desmosomal proteins → intraepidermal bulla
Bullae are easily ruptured. Found on skin AND mucosal membranes
PemphiguS - Bullae are Superficial
939
Histopathology
```
Histology
Intraepidermal bulla
Netlike pattern of
intercellular IgG deposits
Acantholysis
```
What skin rash?
PemphiguS - Bullae are Superficial
940
Histopathology
Rough plaques, waxy, “stuck on” appear in middle age / the elderly
Seborrhoeic Keratosis
BENIGN
941
Histopathology
Rough, sandpaper like, scaly lesions on sun-exposed areas
SPAIN
Solar elastosis Parakeratosis Atypia/dysplasia Inflammation
Not full thickness
Actinic (Solar/Senile) Keratosis
PREMALIGNANT
942
Histopathology
Rapidly growing dome shaped nodule which may develop a necrotic, crusted centre.
Grows over 2-3 weeks and clears spontaneously
Similar histology to SCC – hard to differentiate
Keratoacanthoma
PREMALIGNANT
943
Histopathology
Intra-epidermal squamous cell carcinoma in situ
Flat, red, scaly patches on sun- exposed areas
Full thickness atypia/dysplasia
Basement membrane intact – i.e. not invading the dermis
Bowen’s Disease
PREMALIGNANT
944
Histopathology
When Bowen’s has spread to involve dermis
Similar clinical features to Bowen’s but may ulcerate
Atypia/dysplasia throughout epidermis, nuclear crowding and spreading through basement membrane into dermis
Squamous cell carcinoma
945
Histopathology
Aka “rodent” ulcer
Slow growing tumour; rarely metastatic but locally destructive
Pearly surface, often with telangiectasia
Mass of basal cells pushing down into dermis
Palisading (nuclei align in outermost layer)
Basal cell carcinoma
946
Histopathology
o Histo: atypical melanocytes; initially grow horizontally in epidermis (radial growth phase); then grow vertically into dermis (vertical growth phase); vertical growth produces “buckshot appearance” (=Pagetoid cells)
o Breslow thickness = most important prognostic factor
● Malignant – melanoma
947
Histopathology
Occurs on sun exposed areas of elderly caucasians, flat, slowly growing black lesion
What subtype of melanoma?
Lentigo maligna melanoma
948
Histopathology
irregular borders with variation in colour
What subtype of melanoma?
Superficial spreading malignant melanoma
949
Histopathology
can occur on all sites, more common in the younger age group.
What subtype of melanoma?
Nodular malignant melanoma
950
Histopathology
occurs on the palms, soles and subungual areas
What subtype of melanoma?
Acral Lentiginous melanoma
951
Histopathology
Dermatological emergency; sheets of skin detachment (<10% body surface area in SJS and > 30% in TEN)
Nikolsky sign positive; mucosal involvement prominent
Commonly caused by drugs (e.g. sulfonamide antibiotics, anticonvulsants)
Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
952
Histopathology
Differentiation between Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
(<10% body surface area in SJS and > 30% in TEN)
Dermatological emergency; sheets of skin detachment (<10% body surface area in SJS and > 30% in TEN)
Nikolsky sign positive; mucosal involvement prominent
Commonly caused by drugs (e.g. sulfonamide antibiotics, anticonvulsants)
953
Histopathology
Salmon pink rash appears first (=herald patch) followed by oval macules in Christmas tree distribution.
Appears after viral illness.
Remits spontaneously
Pityriasis Rosea
954
Histopathology
```
Autoimmune multi-
system disorder
Type III hypersensitivity reaction
↑ in classical complement deficiencies
Can be drug- induced
↑in AfroC. F>M
```
HLA DR3 (or 2)
SLE
955
Histopathology
SLE antibodies
ANA (95%)
| ● Anti dsDNA ● Anti-Sm Drug-induced Anti-histone
956
Histopathology
ANA (95%)
● Anti dsDNA ● Anti-Sm Drug-induced Anti-histone
SLE antibodies
957
Histopathology
LE bodies
Kidney – see Renal CNS – small vessel angiopathy
Spleen – onion skin lesions
Heart – Libman- Sack Endocarditis
SLE
958
Histopathology
4 of 11 ACR criteria
(SOAP BRAIN MD)
Serositis
Oral ulcers Arthritis Photosensitivity Blood disorders (AIHA, ITP, leucopenia)
Renal involvement ANA +ve
Immune phenomena (dsDNA, anti-Sm, Antiphospholipid Ab)
Neuro symptoms Malar rash Discoid rash
SLE
959
Histopathology
Autoimmune multi-system
disorders
HLA DR5 & DRw8
CREST and diffuse scleroderma
960
Histopathology
↑collagen in skin and organs. Onion skin thickening of arterioles
Limited scleroderma (=CREST)
961
Histopathology
↑collagen in skin and organs. Onion skin thickening of arterioles
+
Inflammation within or around muscle fibres
Diffuse scleroderma
Skin changes can occur anywhere
Widespread organ involvement
Associated with pulmonary fibrosis
962
Histopathology
Anti Scl-70 Fibrillarin
RNA pol I, II, III PM-Scl
Diffuse scleroderma
Skin changes can occur anywhere
Widespread organ involvement
Associated with pulmonary fibrosis
963
Histopathology
Diffuse scleroderma antibodies
Anti Scl-70 Fibrillarin
| RNA pol I, II, III PM-Scl
964
Histopathology
Anti-centromere
CREST
965
Histopathology
CREST antibody
Anti-centromere
966
Histopathology
Autoimmune
inflammatory disorder of muscle +/- skin
Associated with underlying malignancy
Polymyositis & Dermatomyositis
967
Histopathology
Polymyositis & Dermatomyositis
antibodies
Anti Jo-1
| =tRNA synthetase
968
Histopathology
Endomysial inflamm. infiltrate
Anti Jo-1
Polymyositis
969
Histopathology
‘drop out’ of capillaries and myofibre damage
Anti Jo-1
Dermatomyositis
970
Histopathology
```
Proximal muscle weakness
↑CK & abnormal EMG
DM has cutaneous features:
(1) Heliotrope rash (2) Gottron papules
Associated w. pulmonary fibrosis
```
Polymyositis
| Dermatomyositis
971
Histopathology
Large Vessel vasculitides
Takayasu’s arteritis
| Temporal arteritis
972
Histopathology
=”Pulseless” disease
↑ in Japanese women
Vascular symptoms: Absent pulse, bruits, claudication
Takayasu’s arteritis
973
Histopathology
Elderly; scalp tenderness, temporal headache, Jaw claudication, blurred vision
↑ESR
Overlap with polymyalgia rheumatica
Histo: Granulomatous transmural inflammation + giant cells + skip lesions
Temporal arteritis
974
Histopathology
Medium Vessel vasculitides
Polyarteritis nodosa (PAN)
Kawasaki’s disease
Buerger’s disease (Thrombangitis obliterans)
975
Histopathology
Renal involvement is main feature
Can involve other organs but spares lungs 30% have underlying Hep B Microaneurysms on angiography
Polyarteritis nodosa (PAN)
976
Histopathology
Children < 5yrs
Fever > 5 days
Rash – red palms and soles with later desquamation Conjunctivitis
Inflammation of lips, mouth or tongue (strawberry tongue) Cervical LNs
Coronary arteries may be involved with aneurysm formation
Kawasaki’s disease
977
Histopathology
Heavy smokers, usually men < 35 years
Inflammation of arteries of extremities – usually tibial and radial Pain; ulceration of toes, feet, fingers
Angiogram: corkscrew appearance from segmental occlusive lesions
Buerger’s disease (Thrombangitis obliterans)
978
Histopathology
List small vessel vasculitides
```
Wegener’s granulomatosis
Churg Strauss
Microscopic polyangiitis
Henoch
Schonlein Purpura
```
979
Chemical Pathology
Total body water
60%
980
Chemical Pathology
total number of particles in solution - measured with an osmometer, units = mmol/kg.
Osmolality
981
Chemical Pathology
calculated, units = mmol/l
Osmolarity
982
Chemical Pathology
2(Na+ + K+) + urea + glucose
Osmolarity
983
Chemical Pathology
Osmolarity equation
Osmolarity = 2(Na+ + K+) + urea + glucose
984
Chemical Pathology
normal range for serum osmolality
normal range for serum osmolality is 275 – 295 mmol/kg
985
Chemical Pathology
275 – 295 mmol/kg
normal range for serum osmolality is 275 – 295 mmol/kg
986
Chemical Pathology
Sx hyponatraemia
o nausea and vomiting (<136mmol/l),
o confusion (<131mmol/l)
o seizures, non-cardiogenic pulmonary oedema (<125mmol/l) o coma(<117mmol/l) and eventual death
987
Chemical Pathology
o nausea and vomiting (<136mmol/l),
o confusion (<131mmol/l)
o seizures, non-cardiogenic pulmonary oedema (<125mmol/l) o coma(<117mmol/l) and eventual death
Sx hyponatraemia
988
Chemical Pathology
How do you define whether it is true hyponatraemia using serum osmolality?
True hyponatraemia = low osmolality
If normal: Spurious
Drip arm sample Ethanol
Pseudohyponatraemia (hyperlipidaemia/ paraproteinaemia)
If high: Glucose/mannitol infusion
989
Chemical Pathology
Hypervolaemic hyponatraemia causes?
3 failures
HF
Renal Failure
Liver failure (cirrhosis)
990
Chemical Pathology
What type of hyponatraemia?
3 failures
HF
Renal Failure
Liver failure (cirrhosis)
Hypervolaemic hyponatraemia
991
Chemical Pathology
Hypervolaemic hyponatraemia causes?
3 failures
HF
Renal Failure
Liver failure (cirrhosis)
992
Chemical Pathology
Rx of hypervolaemic hponatraemia
3 failures
HF
Renal Failure
Liver failure (cirrhosis)
FLUID RESTRICT
993
Chemical Pathology
Causes of Euvolaemic hyponatraemia?
Euvolaemic
- Endocrine
SIADH
Glucocorticoid insufficiency (Addisons)
Hypothyroidism
994
Chemical Pathology
What type of hyponatraemia?
SIADH
Glucocorticoid insufficiency (Addisons)
Hypothyroidism
Euvolaemic
- Endocrine
SIADH
Glucocorticoid insufficiency (Addisons)
Hypothyroidism
995
Chemical Pathology
Ix for euvolaemic hyponatraemia?
Euvolaemic
- Endocrine
SIADH - urine and serum osmolality
Glucocorticoid insufficiency (Addisons) - synACTHen
Hypothyroidism - TFTs
996
Chemical Pathology
Causes of hypovolaemic hyponatraemia
Diarrhoea
Vomiting
Diuretics
Salt losing nephropathy
997
Chemical Pathology
Rx of hypovolaemic hyponatraemia?
Volume replacement with 0.9% saline
998
Chemical Pathology
At what rate should sodium be replaced?
Why is this?
Serum Na must NOT be corrected > 8-10 mmol/L in the first 24 hours
Risk of osmotic demyelination (central pontine myelionlysis)
quadriplegia, dysarthria, dysphgia, seizures, coma, death
999
Chemical Pathology
How do you distinguish between renal and non renal causes of hypovolaemic hyponatraemia?
Urinary sodium:
> 20 = Renal
Diuretics, Addison’s, Salt-losing nephropathies (kidney is failing to reabsorb sodium so water lost as well
< 20 = Non-renal
Vomiting, Diarrhoea, Excess sweating, Third space losses (ascites, burns) . Kidney is doing its job and holding onto sodium
1000
Chemical Pathology
How do you distinguish between renal and non renal causes of hypervolaemic hyponatraemia?
> 20 = Renal
AKI, CKD (kidneys not retaining sodium)
< 20 = Non-renal
Cardiac Failure, Cirrhosis, Inappropriate IV fluid.
1001
Chemical Pathology
SIADH causes
Malignancy - small cell lung cancer (most common), pancreas, prostate, lymphoma
(ectopic secretion)
CNS disorders - meningoencephalitis, haemorrhage, abscess (pretty much any CNS pathology
Chest disease - TB, pneumonia, abscess
Drugs - opiates, SSRIs, carbamazepine, proton pump inhibitors
Treatment: Fluid restriction and treat the cause, demeclocycline and tolvaptan are able to induce a state of diabetes insipidus that may help to correct the SIADH although the cost is probibitive.
1002
Chemical Pathology
Symptoms = thirst--> confusion--> seizures + ataxia--> coma
Symptoms of hypernatraemia
1003
Chemical Pathology
Symptoms of hypernatraemia
Symptoms = thirst--> confusion--> seizures + ataxia--> coma
1004
Chemical Pathology
Causes of hypovolaemic hyponatraemia (where water is lost more than sodium)
GI loss: Vomiting, Diarrhoea
Skin loss: Excessive sweating, Burns Renal loss:
Loop diuretics
Osmotic diuresis (glucose, mannitol), following initial
hyponatraemia
1005
Chemical Pathology
GI loss: Vomiting, Diarrhoea
Skin loss: Excessive sweating, Burns Renal loss:
Loop diuretics
Osmotic diuresis (glucose, mannitol), following initial
hyponatraemia
What type of hypernatraemia?
hypovolaemic
1006
Chemical Pathology
Causes of euvolaemic hypernatraemia
Respiratory (tachypnoea)
| Skin (sweating, fever) Renal (diabetes insipidus)
1007
Chemical Pathology
Respiratory (tachypnoea)
Skin (sweating, fever) Renal (diabetes insipidus)
What type of hypernatraemia?
Euvolaemic
1008
Chemical Pathology
Causes of hypervolaemic hypernatraemia
Mineralocorticoid excess (Conn’s Syndrome) Hypertonic saline
1009
Chemical Pathology
Mineralocorticoid excess (Conn’s Syndrome) Hypertonic saline
What type of hypernatraemia?
Hypervolaemic
1010
Chemical Pathology
Lack of/No ADH
Causes: surgery, trauma, tumours
Cranial Diabetes Insipidus
1011
Chemical Pathology
Receptor defect – insensitivity to ADH
Treatment with thiazide diuretics (bizzare!) Causes:
o Inherited channelopathies o Lithium, demeclocycline o Hypercalcaemia
Nephrogenic Diabetes Insipidus
1012
Chemical Pathology
What is the result of a fluid deprivation test for nephrogenic DI
Diagnosis: 8hr fluid deprivation test
Normal: Urine concentration ↑ >600mOsmol/kg
Primary polydipsia: Urine concentrates >400-600mOsmol/kg
Cranial DI: urine concentrates only after giving desmopressin
Nephrogenic DI: low concentration urine after desmopressin
1013
Chemical Pathology
What is the result of a fluid deprivation test for cranial DI
Diagnosis: 8hr fluid deprivation test
Normal: Urine concentration ↑ >600mOsmol/kg
Primary polydipsia: Urine concentrates >400-600mOsmol/kg
Cranial DI: urine concentrates only after giving desmopressin
Nephrogenic DI: low concentration urine after desmopressin
1014
Chemical Pathology
What is the result of a fluid deprivation test for psychogenic polydispia
Diagnosis: 8hr fluid deprivation test
Normal: Urine concentration ↑ >600mOsmol/kg
Primary polydipsia: Urine concentrates >400-600mOsmol/kg
Cranial DI: urine concentrates only after giving desmopressin
Nephrogenic DI: low concentration urine after desmopressin
1015
Chemical Pathology
What is the result of a fluid deprivation test for NORMAL person
Diagnosis: 8hr fluid deprivation test
Normal: Urine concentration ↑ >600mOsmol/kg
Primary polydipsia: Urine concentrates >400-600mOsmol/kg
Cranial DI: urine concentrates only after giving desmopressin
Nephrogenic DI: low concentration urine after desmopressin
1016
Chemical Pathology
What does urine specific gravity mean?
Urine specific gravity: Some exam questions will give you a specific gravity from a urine dipstick. The normal range is 1.000 to 1.030. if it is high, then there are more solutes (high osmolality), and vice-versa if it is low.
1017
Chemical Pathology
The predominant intracellular cation (only 2% extracellular), maintained by active pumping from ECF
K+
1018
Chemical Pathology
4 classes of hypokalaemia causes
1. GI loss
2. Renal loss
Hyperaldosterism, excess cortisol
Increased sodium delivery to distal nephron (thiazide and loop diuretics)
Osmotic diuresis
3. Redistribution into the cells
Insulin, beta-agonists, metabolic alkalosis (see box below)
4. Rare causes
Rare tubular acidosis type 1 & 2, hypomagnesaemia
1019
Chemical Pathology
Which types of renal tubular acidosis cause hypokalaemia?
1+2
Type 1: most severe, distal failure of H+ excretion and subsequent acidosis and
hypokalemia (failed hydrogen potassium pumping)
Type 2: milder, proximal failure to reabsorb bicarbonate, leads to acidosis and
hypokalaemia
Type 4: aldosterone deficiency or resistance (acidosis and hyperkalaemia)
1020
Chemical Pathology
Causes of hyperkalamia
Excessive Intake:
Oral (fasting)
Parenteral
Stored blood transfusion
```
Transcellular Movement (ICF>ECF):
Acidosis
Insulin shortage (DKA)
Tissue damage/catabolic state (rhabdomyolysis)
```
Decreased excretion
```
Acute Renal Failure (oliguric phase)
CRF (late)
K - sparing diuretics (spironolactone)
Mineralocorticoid deficiency (Addison's)
NSAIDs, ACEi, ARBs
```
1021
Chemical Pathology
Rx hyperkalaemia?
0mls 10% calcium gluconate, 100mls 20% dextrose and 10 units insulin. Salbutamol is a useful adjunct as well. Always treat the cause.
1022
Chemical Pathology
Causes of metabolic acidosis?
MUDPILES
```
Methanol
Uraemia
DKA
Paracetamol
Isonizid
Lactic acidosis
Ethanol/ethylene glycol
Salicylates
```
1023
Chemical Pathology
(Na+ + K+) – (Cl- + HCO3
Normal range = 14 - 18mmol/l
anion gap
Normal range = 14 - 18mmol/l
Difference between total concentration of principal cations and principal anions = Concentration of unmeasured anions in the plasma
1024
Chemical Pathology
Anion gap equation
Normal range = 14 - 18mmol/l
(Na+ + K+) – (Cl- + HCO3
Normal range = 14 - 18mmol/l
Difference between total concentration of principal cations and principal anions = Concentration of unmeasured anions in the plasma
1025
Chemical Pathology
Mnemonic for elevated anion gap metabolic acidosis
KULT
Ketoacidosis (DKA, alcoholic, starvation)
Uraemia (renal failure)
Lactic Acidosis
Toxins (ethylene glycol, methanol, paraldehyde, salicylate
1026
Chemical Pathology
Osmolality (measured) – Osmolarity (calculated)
Osmolar Gap
Normal osmolar gap = < 10
An elevated osmolar gap provides indirect evidence for the presence of an abnormal
solute
The osmolar gap is increased by extra solutes in the plasma (e.g. ethylene glycol, ethanol, methanol, mannitol)
Helpful in differentiating the cause of an elevated anion gap metabolic acidosis
1027
Chemical Pathology
Markers of synthetic liver function?
clotting
albumin
glucose
1028
Chemical Pathology
Markers of liver cell damage
AST ALP ALT GGT Bilirubin
1029
Chemical Pathology
AST:ALT = 2:1
Alcoholic liver disease
1030
Chemical Pathology
Alcoholic liver disease AST:ALT ratio?
2:1
1031
Chemical Pathology
Viral liver disease AST:ALT ratio?
AST:ALT = <1:1
1032
Chemical Pathology
AST:ALT = <1:1
Viral liver disease
1033
Chemical Pathology
Elevated GGT?
Alcohol use (chron)
Also bile duct disease and metastases. Used to confirm hepatic source of ↑ALP
1034
Chemical Pathology
Symptoms (neuro-visceral only) - abdo pain, seizures, psych disturbances, nausea &
vomiting, tachycardia, hypertension, sensory loss, muscle weakness, constipation,
urinary incontinence. NO cutaneous manifestations due to absence of porphyrinogens
Acute Intermittent Porphyria (AIP)
HMB (Hydroxymethylbilane) synthase deficiency
1035
Chemical Pathology
Inheritance of Acute Intermittent Porphyria (AIP)
Autosomal dominant inheritance
HMB (Hydroxymethylbilane) synthase deficiency
1036
Chemical Pathology
What is deficient in Acute Intermittent Porphyria (AIP)
HMB (Hydroxymethylbilane) synthase deficiency
1037
Chemical Pathology
HMB (Hydroxymethylbilane) synthase deficiency
Acute Intermittent Porphyria (AIP)
1038
Chemical Pathology
Precipitating factors in ALA + PBG in urine (“Port wine urine”)
```
o ALA synthase inducers (steroids, ethanol, barbiturates)
o Stress (infection, surgery)
o Reduced caloric intake and endocrine factors (e.g. premenstrual)
```
1039
Chemical Pathology
ALA + PBG in urine (“Port wine urine”)
ALA + PBG in urine (“Port wine urine”)
1040
Chemical Pathology
ALA + PBG in urine (“Port wine urine”) investigations
ALA + PBG in urine (“Port wine urine”)
1041
Chemical Pathology
ALA + PBG in urine (“Port wine urine”) investigations
ALA + PBG in urine (“Port wine urine”)
1042
Chemical Pathology
Acute Intermittent Porphyria (AIP) Rx
Treatment – avoid precipitating factors, analgesia, IV carbohydrate/ haem arginate
1043
Chemical Pathology
Name the two acute porphyries with SKIN LESIONS
Hereditary coproporphyria (HCP) and Variegate porphyria (VP)
Autosomal dominant
HCP-
Symptoms – neurovisceral + skin lesions
Raised porphyrins in faeces or urine
1044
Chemical Pathology
Name the three NON ACUTE prophyrias with SKIN LESIONS ONLY
Skin lesions ONLY
Congenital Erythopoietic porphyria (CEP)
Erythropoietic protoporphyria (EPP)
Porphyria Cutanea Tarda (PCT)
1045
Chemical Pathology
Photosensitivity, burning, itching oedema following sun exposure
Erythropoietic protoporphyria (EPP)
1046
Chemical Pathology
Inherited/ acquired
Uroporphyrinogen decarboxylase deficiency
Symptoms (cutaneous) – Vesicles (crusting, pigmented, superficial scarring) on sun
exposed sites
Diagnosis - ↑ urinary uroporphyrins + coproporphyrins + ↑ferritin
Treatment – avoid precipitants (alcohol, hepatic compromise), phlebotomy
Porphyria Cutanea Tarda (PCT)
1047
Chemical Pathology
↑TSH ↓T4
Hypothyroidism
1048
Chemical Pathology
↑TSH ↔T4
Treated hypothyroidism or subclinical hypothyroidism (look for assoc hypercholesterolaemia)
1049
Chemical Pathology
↑TSH ↑T4
TSH secreting tumour or thyroid hormone resistance
1050
Chemical Pathology
↓TSH ↑T4 or ↑T3
Hyperthyroidism
1051
Chemical Pathology
↓TSH ↔T3 and T4
Subclinical hyperthyroidism. This may progress to primary hypothyroidism, especially if the patient is anti-TPO antibody positive
1052
Chemical Pathology
List the whether H/L/N for TSH + T4
Hypothyroidism
↑TSH ↓T4
1053
Chemical Pathology
List the whether H/L/N for TSH + T4
Treated hypothyroidism or subclinical hypothyroidism (look for assoc hypercholesterolaemia)
↑TSH ↔T4
1054
Chemical Pathology
List the whether H/L/N for TSH + T4
TSH secreting tumour or thyroid hormone resistance
↑TSH ↑T4
1055
Chemical Pathology
List the whether H/L/N for TSH + T4
Hyperthyroidism
↓TSH ↑T4 or ↑T3
1056
Chemical Pathology
List the whether H/L/N for TSH + T4
Subclinical hyperthyroidism. This may progress to primary hypothyroidism, especially if the patient is anti-TPO antibody positive
↓TSH ↔T3 and T4
1057
Chemical Pathology
List the whether H/L/N for TSH + T4
Central hypothyroidism (hypothalamic/pituitary disorder)
↓TSH ↓T4
1058
Chemical Pathology
List the whether H/L/N for TSH + T4
Sick euthyroidism (with any severe illness). The body tries to shut down metabolism as the thyroid gland has reduced output
↑(later ↓)TSH ↓T3 and ↓ T4
1059
Chemical Pathology
List the whether H/L/N for TSH + T4
? assay interference, changes in TBG, amiodarone
↔TSH, abnormal T4
1060
Chemical Pathology
↔TSH, abnormal T4
? assay interference, changes in TBG, amiodarone
1061
Chemical Pathology
↑(later ↓)TSH ↓T3 and ↓ T4
Sick euthyroidism (with any severe illness). The body tries to shut down metabolism as the thyroid gland has reduced output
1062
Chemical Pathology
↓TSH ↓T4
Central hypothyroidism (hypothalamic/pituitary disorder)
1063
Chemical Pathology
High Uptake hyperparathyroidism
Graves disease: 40 - 60%, F>M (9:1), autoantibodies ++, high uptake on isotope scan (with Tc99)
Toxic multinodular goitre: 30 - 50%, high uptake
Toxic adenoma: 5%, ‘hot nodule’ on isotope scan (1 area of uptake)
1064
Chemical Pathology
Graves disease: 40 - 60%, F>M (9:1), autoantibodies ++, high uptake on isotope scan (with Tc99)
Toxic multinodular goitre: 30 - 50%, high uptake
Toxic adenoma: 5%, ‘hot nodule’ on isotope scan (1 area of uptake)
High Uptake hyperparathyroidism
1065
Chemical Pathology
Low Uptake hyperparathyroidism
```
Subacute De Quervains thyroiditis: self-limiting post viral painful goiter. Initially hyperthyroid, then hypothyroid
Postpartum thyroiditis (like De Quervain’s but postpartum)
```
1066
Chemical Pathology
Autoimmune hypothyroidism
Primary atrophic hypoT: diffuse lymphocytic infiltration & atrophy. No goiter so small thyroid. No known antibodies detected yet
Hashimotos thyroiditis: Plasma cell infiltration & goitre. Elderly females. May be initial ‘Hashitoxicosis’. ++ Autoantibody titres (anti TPO/TG)
1067
Chemical Pathology
Non- Autoimmune hypothyroidism
Iodine deficiency (common worldwide)
Post thyroidectomy/radioiodine
Drug induced – antithyroid drugs, lithium, amiodarone
1068
Chemical Pathology
Hyperthyroid Rx
Hyperthyroid – depends on aetiology. Low uptake – symptomatic – betablockers, NSAIDs for dequervains. High uptake – BB + antithyroid therapy – carbimazole/propylthiouracil (propylthiouracil rarely used now due to risks of aplastic anaemia). Can be used in block and replace or titrate to TSH. Can also use radioiodine or surgery.
1069
Chemical Pathology
Most common thyroid neoplasia?
Papillary
>60% of cases, 30-40y, surgery +/- radioiodine, Thyroxine (to ↓TSH). May see psammoma bodies on histology, these patients have a very good prognosis.
1070
Chemical Pathology
>60% of cases, 30-40y, surgery +/- radioiodine, Thyroxine (to ↓TSH). May see psammoma bodies on histology, these patients have a very good prognosis.
Papillary thyroid carcinoma
1071
Chemical Pathology
25%, Middle age, well differentiated but spreads early, Surgery + RI + thyroxine
Which thyroid carcinoma?
Follicular
1072
Chemical Pathology
5% originates in parafollicular “C” cells – linked to MEN2. Produce calcitonin
Which thyroid carcinoma?
Medullary
1073
Chemical Pathology
5% MALT origin. Risk factor: chronic Hashimotos (as lots of lymphocytes that proliferate), good prognosis
Which thyroid carcinoma?
Lymphoma
1074
Chemical Pathology
Rare. Elderly. Poor response to any treatment.
Which thyroid carcinoma?
Anaplastic
1075
Chemical Pathology
Pituitary tumour – “Cushing’s disease” (85%) Adrenal tumour (10%) Ectopic ACTH- producing tumour (5%)
Iatrogenic steroid use
Cushing’s
Low dose dexamethasone
(0.5mg)
High dose dexamethasone (2 mg).
Low dose dex will fail to suppress cortisol in all of these, but high dose will succeed in pituitary cushings
1076
Chemical Pathology
Causes Addison’s
Autoimmune
TB
Tumour mets
Adrenal haemorrhage (meningococcus) Amyloidosis
1077
Chemical Pathology
↑K
↓ Na+ + ↓ glucose Postural hypotension Skin pigmentation Lethargy Depression
Addison’s
SynACTHen
1078
Chemical Pathology
Rx Addisons
Hormone replacement – hydrocortisone/ fludrocortison if primary adrenal lesion
1079
Chemical Pathology
Aldosterone : Renin Ratio. Raised aldosterone low renin
Uncontrollable hypertension ↑ Na+
↓ K+
Conn’s
Adrenal tumour
Aldosterone antagonists/potassium sparing diuretics – Spironolactone, eplerenone, amiloride
1080
Chemical Pathology
Adrenal medulla tumour = ↑ Adrenaline
Hypotension Arrhythmias
Death if untreated
Plasma and 24h urinary metadrenaline measurement/ catecholamines & VMA
Phaeo
1081
Chemical Pathology
Phaeo Rx
Alpha blockade, beta blockade then surgery when blood pressure well controlled.
1082
Chemical Pathology
Signs toxicity. What drug?
Ataxia and
nystagmus
Phenytoin
At high levels liver
becomes saturated surge in blood levels
Omit / reduce
dose
1083
Chemical Pathology
Signs toxicity. What drug?
Arrythmias, heart block, confusion, xanthopsia (seeing yellow)
Digoxin
Levels increased with Hypokalaemia. Reduce dose in renal failure and in elderly
Digibind aka Digoxin immune Fab
1084
Chemical Pathology
Signs toxicity. What drug?
Tremor (early), lethargy, fits, arrhythmia, renal failure
Lithium
Excretion impaired by hyponatraemia, ↓renal func and diuretics
RF may need haemodialysis
1085
Chemical Pathology
Signs toxicity. What drug?
Tinnitus, deafness, nystagmus, renal failure
Gentamicin
Mostly use single daily dosing. Monitor peak and trough level before next dose
Omit / reduce dose
1086
Chemical Pathology
Signs toxicity. What drug?
Arrythmias, anxiety, tremor, convulsions
Theophyline
Variation t1/2; eg 4hrs smokers 8hrs non- smokers, 30hrs liver disease.
Level ↑ by erythromycin, cimetidine and phenytoin
Omit / reduce dose
1087
Chemical Pathology
45% ionised (free – biologically active form)
50% bound to albumin, therefore affected by albumin level – use corrected
calcium
Calcium
Normal plasma range: 2.2 - 2.6mmol/l
1088
Chemical Pathology
PTH actions
↑tubular 1α hydroxylation of vitamin D (25(OH)D)
Mobilises calcium from bone
↑ renal calcium reabsorption
↑ renal phosphate excretion
1089
Chemical Pathology
1,25 (OH)2vitD (Calcitriol) actions
↑ Calcium and phosphate absorption from the gut
| Bone remodeling
1090
Chemical Pathology
Primary hyperparathyroidism:
List results for Ca, PO4, PTH, ALP, vit D
- ALSO AETIOLOGY?
Ca - high
PTH high (or inappropriately N)
PO4 low
ALP normal/high
Vit D = N
Aetiology: Increase of PTH. (80% parathyroid adenoma)
1091
Chemical Pathology
Ca - high
PTH high (or inappropriately N)
PO4 low
ALP normal/high
Vit D = N
Primary hyperparathyroidism
Aetiology: Increase of PTH. (80% parathyroid adenoma)
1092
Chemical Pathology
Secondary hyperparathyroidism:
List results for Ca, PO4, PTH, ALP, vit D
- ALSO AETIOLOGY?
Ca - low (or inappropriately N)
PTH high
PO4 (high) - failed renal excretion
ALP high
Vit D = L/N - failed renal conversion
Aetiology - Renal osteodystrophy
1093
Chemical Pathology
Ca - low (or inappropriately N)
PTH high
PO4 (high) - failed renal excretion
ALP high
Vit D = L/N - failed renal conversion
Secondary hyperparathyroidism
Aetiology - Renal osteodystrophy
1094
Chemical Pathology
Tertiary hyperparathyroidism:
List results for Ca, PO4, PTH, ALP, vit D
- ALSO AETIOLOGY?
Ca - high
PTH high
PO4 low
ALP N/high
Vit D = N
Aetiology - Autonomous PTH secretion post renal transplant
1095
Chemical Pathology
Ca - high
PTH high
PO4 low
ALP N/high
Vit D = N
Tertiary hyperparathyroidism
Aetiology - Autonomous PTH secretion post renal transplant
1096
Chemical Pathology
Low levels of PTH. 10: DeGeorge syn 20: Post thyroid surgery
Hypoparathyroidism
1097
Chemical Pathology
hypoparathyroidism:
List results for Ca, PO4, PTH, ALP, vit D
- ALSO AETIOLOGY?
```
Ca - low
PO4 - high
PTH - Low
ALP - N/low
Vit D - N
```
Low levels of PTH. 10: DeGeorge syn 20: Post thyroid surgery
1098
Chemical Pathology
```
Ca - low
PO4 - high
PTH - Low
ALP - N/low
Vit D - N
```
hypoparathyroidism:
Low levels of PTH. 10: DeGeorge syn 20: Post thyroid surgery
1099
Chemical Pathology
Rickets/osteomalacia:
List results for Ca, PO4, PTH, ALP, vit D
- ALSO AETIOLOGY?
```
Ca - low
PO4 - low
PTH - high
ALP - high
Vit D - low
```
1100
Chemical Pathology
Symptoms: perioral paraesthesia, carpopedal spasm, neuromuscular excitability (Trousseau’s and Chvostek’s sign)
Hypocalcaemia
1101
Chemical Pathology
Rx calcium
Treatment:
Mild: give calcium
Chronic Kidney Disease: alfacalcidol Severe: 10% calcium gluconate IV
1102
Chemical Pathology
Stones (renal) Bones (pain) Groans (psych) Moans (abdo pain) Polyuria
Muscle weakness
Hypercalcaemia
1103
Chemical Pathology
Rx hypercalcaemia
Treatment:
Correct dehydration Bisphosphonates
Correct cause eg chemo for cancer
1104
Chemical Pathology
Calcium stone causes
Results from:
| Hyperoxaluria (increased intake, absorption etc) Hypercalciuria (increased intake, renal leak)
1105
Chemical Pathology
Rx calcium stones
Preventative management: avoid dehydration, reduce oxalate intake, maintain Ca intake, thiazides hypocalciuric, citrate (alkalinise urine)
1106
Chemical Pathology
Radioopaque“staghorn stone
Triple phosphate“Struvite”
1107
Chemical Pathology
Name two radiolucent stones
Uric acid
Cysteine
Indinavir
1108
Chemical Pathology
high serum levels in acute pancreatitis (usually >10x upper limit of normal)
Amylase
1109
Chemical Pathology
Most widely used as a marker of muscle damage
Creatine Kinase: Most widely used as a marker of muscle damage (CK-MM = skeletal muscle, CK-MB (1&2) = cardiac muscles.)
1110
Chemical Pathology
Causes of raised CK?
Raised levels due to:
Physiological: Afro-Caribbean (<5x upper limit of normal)
Pathological: Duchenne Muscular Dystrophy (>10xULN), MI (>10xULN), Statin
related myopathy, Rhabdomyolysis
1111
Chemical Pathology
present in high concentrations in liver, bone, intestine and placenta.
Alkaline Phosphatase
1112
Chemical Pathology
Causes of raised ALP:
Physiological: Pregnancy (3rd trimester), Childhood (during growth spurt) Pathological:
o >5x ULN = Bone (Pagets, osteomalacia), Liver (Cholestasis, Cirrhosis) o <5x ULN = Bone (tumours, fractures, osteomyelitis), Liver (infiltrative
disease, hepatitis)
1113
Chemical Pathology
When do you measure troponin?
Troponin I/T = myocardial injury biomarker
Measure at 6 hours and then at 12 hours post onset of chest pain (100% Se and 98% Sp at 12-24 hours). Remains elevated for 3 – 10 days
1114
Chemical Pathology
quantity of enzyme that catalyses 1uMol of substrate in a minute (at a given temp and pH)
1 I/U
1115
Chemical Pathology
AD: LDLR, apoB, PCSK9 AR: LDLRAP1
Familial hypercholesteraemia (type II)
Primary Hypercholesteraemia
1116
Chemical Pathology
CETP deficiency
Familial hyperα-lipoproteinaemia
Primary Hypercholesteraemia
1117
Chemical Pathology
ABC G5 & G8
Phytosterolaemia
Primary Hypercholesteraemia
1118
Chemical Pathology
Lipoprotein lipase or apoC II def
Familial Type I
| Primary Hypertriglyceridaemia
1119
Chemical Pathology
apoA V def (sometimes)
Familial Type V
| Primary Hypertriglyceridaemia
1120
Chemical Pathology
↑synthesis of TG
Familial Type IVPrimary Hypertriglyceridaemia
1121
Chemical Pathology
MTP def
Aβ-lipoproteinaemia
Hypolipidaemia
Hypolipidaemia
1122
Chemical Pathology
Truncated apoB protein
Hypoβ-lipoproteinaemia
| Hypolipidaemia
1123
Chemical Pathology
HDL def
Tangier Disease
| Hypolipidaemia
1124
Chemical Pathology
apoA-I mutations (sometimes)
Hypoα-lipoproteinaemia
| Hypolipidaemia
1125
Chemical Pathology
Binds LDLR and promotes its degradation
PCSK9
Loss of function mutation of PCSK9 low LDL levels
1126
Chemical Pathology
What 5 diseases are screened on Guthrie
```
1969 – Phenylketonuria
1970 – Congenital hypothyroidism
2004 – Cystic Fibrosis
2006 – Sickle cell disease
2009 – Medium Chain AcylCoA dehydrogenase Deficiency
```
1127
Chemical Pathology
Phenylanine hydroxylase deficiency
Phenylketonuria
1128
Chemical Pathology
Dysgenesis/Agenesis of thyroid
Congenital Hypothyroidism
1129
Chemical Pathology
Acylcarnitine levels
Medium Chain AcylCoA dehydrogenase Deficiency
1130
Chemical Pathology
High urea, ketones
Metabolic acidosis
Treat with low protein diet, acylcarnitine and haemofiltration
Often have funny smells due to the organic acids
Organic adicaemias
Group 1 –
accumulation of toxins
1131
Chemical Pathology
High ammonia (>200uM) leading to encephalopathy and developmental delay Respiratory alkalosis
Vomiting?diarrhoea
Treat with low protein diet (stops urea formation)
Urea cycle disorders 9 in total, includes ornithine transcarbamylase deficiency
Group 1 –
accumulation of toxins
1132
Chemical Pathology
High phenylalanine, blue eyes and fair hair/skin Retardation
MSUD apparently causes sweaty feet...
Aminoacidopathies Includes PKU and maple- syrup urine disease
Group 1 –
accumulation of toxins
1133
Chemical Pathology
Hypoglycaemia and lactic acidosis Hepatomegaly, developmental delay Hepatoblastoma risk high
Treat with regular CHO
Glycogen storage disorders
Includes Von Gierke’s
Group 2- reduced energy stores
1134
Chemical Pathology
Increased Gal-1-phosphate levels cause cataracts
Hypoglycaemia, neonatal conjugated jaundice Test urine reducing agents
Treat with low lactose/galactose diet
Galactossaemia
Group 2- reduced energy stores
1135
Chemical Pathology
Hypoglycaemia, cardiomyopathy, rhabdomyolysis
Low ketones!
Screened with blood acylcarnitine Test urine organic acids
Treat with regular carbohydrate
Fatty acid oxidation disorders
Includes MCADD
Group 2- reduced energy stores
1136
Chemical Pathology
Poor feeds, seixuresa
Retinopathy
Hepatomegaly and mixed hyperbiliribinaemia
Peroxisomal disorders Cannot catabolise very long fatty acids or make bile acids
Group 3- large molecule synthesis (all dysmorphic)
1137
Chemical Pathology
Measure serum transferrins
Lead to retardation and nipple inversion
Glycosylation disorders
Group 3- large molecule synthesis (all dysmorphic)
1138
Chemical Pathology
Very slow progressing
Neuroregression, hepatosplenomegaly Cardiomyopathy
Test urine mucooligopolysaccharides and WBC enzyme levels
Lysosomal disorders Include Tay Sachs disease
Group 4 – defects in large molecule metabolism
1139
Chemical Pathology
Involve the CNS, muscle and heart High lactate and CK
Muscle biopsy diagnostic
Various: MELAS, Kearn’s Sayre, POEMS
Group 5 - mitochondrial
1140
Chemical Pathology
Fasting glucose >7, Oral glucose tolerance test >11.1 or random glucose >11.1,
HbA1C >48
Diabetes
1141
Chemical Pathology
Diabetes values
Fasting glucose >7, Oral glucose tolerance test >11.1 or random glucose >11.1,
HbA1C >48
1142
Chemical Pathology
random or oral glucose tolerance test >7.8 but <11.1
Impaired glucose tolerance.
1143
Chemical Pathology
Impaired glucose tolerance test
random or oral glucose tolerance test >7.8 but <11.1
1144
Chemical Pathology
fasting glucose >6.1 but <7.0
impaired fasting glucose
1145
Chemical Pathology
impaired fasting glucose results
fasting glucose >6.1 but <7.0
1146
Chemical Pathology
Hyperinsulinaemic hypoglycaemia causes
Hyperinsulinaemic hypoglycaemia – Iatrogenic insulin, sulfonylurea excess, insulinoma
1147
Chemical Pathology
Hypoinsulinaemic hypoglycaemia causes
+ve ketones – Alcohol binge no food, Pituitary insufficiency, Addison’s, liver failure
-ve ketones – Non pancreatic neoplasms – fibrosarcomata, fibromata
1148
Chemical Pathology
Common problems in low birth weight:
```
Respiratory distress syndrome
Retinopathy of prematurity
Intraventricular haemorrhage
Patent ductus arteriosus
Necrotizing enterocolitis – inflammation of bowel wall – necrosis and perforation
```
1149
Chemical Pathology
Functional maturity of glomerular filtration rate only by two years old
Low GFR for surface area
Less reabsorption than adult due to short proximal tubule
o Although usually adequate for small filtered load
Reduced concentrating ability due to short loops of Henle and distal collecting ducts
Persistant sodium loss due to distal tubule being relatively aldosterone-insensitive
Paediatric kidney
1150
Chemical Pathology
High insensible (uncontrollable) water loss due to:
o High surface area to body weight ratio
o Skin blood flow is increased
o Metabolic/respiratory rate is higher than adults
o Transepidermal fluid loss (skin less of a good barrier as it’s immature)
Hypernatraemia is common in the first 2 weeks of life, although can be a marker of dehydration or an overly-concentrated milk formula
Kids
1151
Chemical Pathology
the volume of plasma that can be completed cleared of a marker substance in a unit of time
Clearance
Gold standard measure of GFR = inulin. But requires steady state infusion and difficult to assay so it is reserved for research purposes only.
1152
Chemical Pathology
Indications for dialysis as an emergency:
1. Pulmonaryoedema
2. Refractoryhyperkalaemia
3. Metabolicacidosis
4. Uraemic encephalopathy
5. Also some drug toxicity (lithium for example)
1153
Chemical Pathology
Renal failure consequences
1]Progressive failure of homeostatic function -Acidosis
-Hyperkalaemia
2]Progressive failure of hormonal function
-Anaemia (loss of EPO synthesis)
-Renal Bone Disease (secondary hyperparathyroidism due to low Vit D) 3]Cardiovascular disease
-Vascular calcification and subsequent atherosclerosis (biggest mortality in CKD)
-Uraemic cardiomyopathy 4]Uraemia and Death
1154
Haematology
Acanthocytes (Spur/spike cells)
RBCs show many spicules
Abetalipoproteinaemia, liver disease, hyposplenism
1155
Haematology
RBCs show many spicules
Abetalipoproteinaemia, liver disease, hyposplenism
Acanthocytes (Spur/spike cells)
1156
Haematology
Basophilic RBC stippling
Accelerated erythropoiesis or defective Hb synthesis, small dots at the periphery are seen (rRNA)
Lead poisoning, megaloblastic anaemia, myelodysplasia, liver disease, haemoglobinopathy e.g. thalassaemia
1157
Haematology
Accelerated erythropoiesis or defective Hb synthesis, small dots at the periphery are seen (rRNA)
Lead poisoning, megaloblastic anaemia, myelodysplasia, liver disease, haemoglobinopathy e.g. thalassaemia
Basophilic RBC stippling
1158
Haematology
Burr cells (Echinocyte)
Irregularly shaped cells
Uraemia, GI bleeding, stomach carcinoma
1159
Haematology
Irregularly shaped cells
Uraemia, GI bleeding, stomach carcinoma
Burr cells (Echinocyte)
1160
Haematology
Heinz bodies
Inclusions within RBCs of denatured Hb
Glucose-6-phosphate dehydrogenase deficiency, chronic liver disease
1161
Haematology
Inclusions within RBCs of denatured Hb
Glucose-6-phosphate dehydrogenase deficiency, chronic liver disease
Heinz bodies
1162
Haematology
Howell-Jolly bodies
Basophilic (purple spot) nuclear remnants in RBCs
Post-splenectomy or hyposplenism (e.g. sickle cell disease, coeliac disease, congenital, UC/Crohn's, myeloproliferative disease, amyloid) Megaloblastic anaemia, hereditary spherocytosis
1163
Haematology
Basophilic (purple spot) nuclear remnants in RBCs
Post-splenectomy or hyposplenism (e.g. sickle cell disease, coeliac disease, congenital, UC/Crohn's, myeloproliferative disease, amyloid) Megaloblastic anaemia, hereditary spherocytosis
Howell-Jolly bodies
1164
Haematology
Leucoerythroblastic (myelophthisic) anaemia
Marrow infiltration- nucleated RBCs and primitive WBCs into peripheral blood
Marrow infiltration i.e. myelofibrosis, malignancy
1165
Haematology
Marrow infiltration- nucleated RBCs and primitive WBCs into peripheral blood
Marrow infiltration i.e. myelofibrosis, malignancy
Leucoerythroblastic (myelophthisic) anaemia
1166
Haematology
Pelger Huet Cells
Hyposegmented neutrophil
Congenital (lamin B Receptor mutation)
| Acquired (myelogenous leukaemia and myelodysplastic syndromes)
1167
Haematology
Hyposegmented neutrophil
Congenital (lamin B Receptor mutation)
Acquired (myelogenous leukaemia and myelodysplastic syndromes)
Pelger Huet Cells
1168
Haematology
Polychromasia (sign of reticulocytes)
Red Blood cells of multiple colours (particularly grey-blue), due to differing amounts of Hb in RBC
Premature/inappropriate release from BM
1169
Haematology
Red Blood cells of multiple colours (particularly grey-blue), due to differing amounts of Hb in RBC
Premature/inappropriate release from BM
Polychromasia (sign of reticulocytes)
1170
Haematology
Reticulocytes
Immature RBCs (mesh-like network of ribosomal RNA becomes visible with certain stains i.e. new methylene blue)
↑in haemolytic anaemias ↓aplastic anaemia, chemo
1171
Haematology
Immature RBCs (mesh-like network of ribosomal RNA becomes visible with certain stains i.e. new methylene blue)
↑in haemolytic anaemias ↓aplastic anaemia, chemo
Reticulocytes
1172
Haematology
Right shift
Hypermature white cells - hypersegmented polymorphs (>5 lobes to nucleus)
Megaloblastic anaemia, uraemia, liver disease
1173
Haematology
Hypermature white cells - hypersegmented polymorphs (>5 lobes to nucleus)
Megaloblastic anaemia, uraemia, liver disease
Right shift
1174
Haematology
Rouleaux formation
Red cells stacked on each other
Chronic inflammation, paraproteinaemia, myeloma
1175
Haematology
Red cells stacked on each other
Chronic inflammation, paraproteinaemia, myeloma
Rouleaux formation
1176
Haematology
Schistocytes
Fragmented parts of RBCs – typically irregularly shaped, jagged and asymmetrical
Microangiopathic anaemia, e.g. DIC, haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, pre-eclampsia
1177
Haematology
Fragmented parts of RBCs – typically irregularly shaped, jagged and asymmetrical
Microangiopathic anaemia, e.g. DIC, haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, pre-eclampsia
Schistocytes
1178
Haematology
Spherocytes
Sphere shaped RBC
Hereditary spherocytosis, Autoimmune Haemolytic Anaemia
1179
Haematology
Sphere shaped RBC
Hereditary spherocytosis, Autoimmune Haemolytic Anaemia
Spherocytes
1180
Haematology
Stomatocytes
Central pallor is straight or curved rod-like shape. RBCs appear as ‘smiling faces’ or ‘fish mouth’
Hereditary stomatocytosis, high alcohol intake, liver disease
1181
Haematology
Central pallor is straight or curved rod-like shape. RBCs appear as ‘smiling faces’ or ‘fish mouth’
Hereditary stomatocytosis, high alcohol intake, liver disease
Stomatocytes
1182
Haematology
Target cells (codocyte)
Bull’s-eye appearance in central pallor
Liver disease, hyposplenism, thalassaemia, IDA
1183
Haematology
Bull’s-eye appearance in central pallor
Liver disease, hyposplenism, thalassaemia, IDA
Target cells (codocyte)
1184
Haematology
Low MCV (microcytic anaemia) (FAST)
Fe-deficiency anaemia
Anaemia of chronic disease
Sideroblastic anaemia
Thalassaemia (in the absence of anaemia)
1185
Haematology
```
Normal MCV (normocytic anaemia)
BARP HAH
```
```
Bone marrow failure
Acute blood loss
Renal failure
Pregnancy
Hypothyroidism
Anaemia of chronic disease
Haemolysis
```
1186
Haematology
High MCV (macrocytic anaemia) (FATRBC)
Fetus (pregnancy)
Antifolates (e.g. phenytoin)
Thyroid (hypothyroidism)
Reticulocytosis (release of larger immature cells e.g. with haemolysis)
B12 or folate deficiency
Cirrhosis (Alcohol excess or liver disease)
Myelodysplastic syndromes
1187
Haematology
Signs: Koilonychia, atrophic glossitis, angular cheilosis, post-cricoid webs (Plummer- Vinson syndrome), brittle hair and nails.
IDA
Causes: Bleeding until proven otherwise.
1188
Haematology
Blood film: Microcytic, hypochromic, anisocytosis (varying size), poikilocytosis (shape) pencil cells.
IDA
Causes: Bleeding until proven otherwise.
1189
Haematology
Cytokine driven inhibition of red cell production
Anaemia of Chronic Disease
- Inflammatory markers like IFNs, TNF and IL1 reduce EPO receptor production (and thus EPO synthesis) by kidneys.
- Iron metabolism is dysregulated. IL6 and LPS stimulate the liver to make hepcidin, which decreases iron absorption from gut (by inhibiting transferrin) and also causes iron accumulation in macrophages
In renal failure: not cytokine driven but due to EPO deficiency.
Causes:
Chronic infection (e.g. TB, osteomyelitis) Vasculitis
Rheumatoid arthritis
Malignancy etc.
1190
Haematology
Anaemia of Chronic Disease definition
Cytokine driven inhibition of red cell production
- Inflammatory markers like IFNs, TNF and IL1 reduce EPO receptor production (and thus EPO synthesis) by kidneys.
- Iron metabolism is dysregulated. IL6 and LPS stimulate the liver to make hepcidin, which decreases iron absorption from gut (by inhibiting transferrin) and also causes iron accumulation in macrophages
In renal failure: not cytokine driven but due to EPO deficiency.
Causes:
Chronic infection (e.g. TB, osteomyelitis) Vasculitis
Rheumatoid arthritis
Malignancy etc.
1191
Haematology
ACD pathogenesis
- Inflammatory markers like IFNs, TNF and IL1 reduce EPO receptor production (and thus EPO synthesis) by kidneys.
- Iron metabolism is dysregulated. IL6 and LPS stimulate the liver to make hepcidin, which decreases iron absorption from gut (by inhibiting transferrin) and also causes iron accumulation in macrophages
In renal failure: not cytokine driven but due to EPO deficiency.
Causes:
Chronic infection (e.g. TB, osteomyelitis) Vasculitis
Rheumatoid arthritis
Malignancy etc.
1192
Haematology
Ferritin H/L/N in ACD?
Ferritin (intracellular protein, iron store) is high in ACD: Fe sequestered in macrophage to deprive invading bacteria of Fe (unless the patient has co-existing iron deficiency anaemia)
1193
Haematology
Ineffective erythropoiesis → iron loading (bone marrow) causing haemosiderosis (endocrine, liver and cardiac damage due to iron deposition)
Sideroblastic Anaemia
Diagnosis: Ring sideroblasts seen in the marrow (erythroid precursors with iron deposited in mitochondria in a ring around the nucleus).
Causes: myelodysplastic disorders, following chemotherapy, irradiation, alcohol excess, lead excess, anti-TB drugs or myeloproliferative disease.
Treatment: Remove the cause and Pyridoxine (vitamin B6 promotes RBC production).
1194
Haematology
Diagnosis: Ring sideroblasts seen in the marrow (erythroid precursors with iron deposited in mitochondria in a ring around the nucleus).
Sideroblastic Anaemia
Ineffective erythropoiesis → iron loading (bone marrow) causing haemosiderosis (endocrine, liver and cardiac damage due to iron deposition)
Causes: myelodysplastic disorders, following chemotherapy, irradiation, alcohol excess, lead excess, anti-TB drugs or myeloproliferative disease.
Treatment: Remove the cause and Pyridoxine (vitamin B6 promotes RBC production).
1195
Haematology
Causes: myelodysplastic disorders, following chemotherapy, irradiation, alcohol excess, lead excess, anti-TB drugs or myeloproliferative disease.
Treatment: Remove the cause and Pyridoxine (vitamin B6 promotes RBC production)
Sideroblastic Anaemia
Ineffective erythropoiesis → iron loading (bone marrow) causing haemosiderosis (endocrine, liver and cardiac damage due to iron deposition)
Diagnosis: Ring sideroblasts seen in the marrow (erythroid precursors with iron deposited in mitochondria in a ring around the nucleus).
1196
Haematology
CAUSES MEGALOBLASTIC MACROCYTIC ANAEMIA?
Megaloblastic: B12 deficiency, folate deficiency, cytotoxic drugs.
1197
Haematology
CAUSES NON-MEGALOBLASTIC MACROCYTIC ANAEMIA?
Non-megaloblastic: Alcohol (most common cause of macrocytosis without anaemia), reticulocytosis (e.g. in haemolysis), liver disease, hypothyroidism, and pregnancy.
1198
Haematology
Hypersegmented polymorphs, leucopenia, macrocytosis, anaemia, thrombocytopenia.
Megaloblastic blood film = Hypersegmented polymorphs, leucopenia, macrocytosis,
1199
Haematology
b12 dietary sources
Source: Meat and dairy products (we have large body stores)
1200
Haematology
Causes of b12 deficiency
Dietary (e.g. vegans) Malabsorption:
o Stomach (lack of intrinsic factor which is produced by gastric parietal cells) → Pernicious anaemia, post gastrectomy
o Terminal ileum (absorption) due to ileal resection, Crohn's disease, bacterial overgrowth, tropical sprue and tapeworms.
1201
Haematology
Mouth: Glossitis, angular cheilosis
Neuropsychiatric: Irritability, depression, psychosis, dementia.
Neurological: Paraesthesiae, peripheral neuropathy (loss of vibration and
proprioception first, absent ankle reflex, spastic parapereisis, SACD of spinal cord)
Vitamin B12
Source: Meat and dairy products (we have large body stores) Causes of deficiency:
Dietary (e.g. vegans) Malabsorption:
o Stomach (lack of intrinsic factor which is produced by gastric parietal cells) → Pernicious anaemia, post gastrectomy
o Terminal ileum (absorption) due to ileal resection, Crohn's disease, bacterial overgrowth, tropical sprue and tapeworms.
1202
Haematology
Autoimmune atrophic gastritis → achlorhydria and lack of gastric intrinsic factor
Most common cause of a macrocytic anaemia in Western countries (Usually >40yrs)
Specific tests: Parietal cell antibodies (90%), Intrinsic factor antibodies (50%), Schilling
test (outdated)
Treatment: Replenish stores with IM hydroxocobalamin (B12)
Pernicious anaemia:
1203
Haematology
Dietary sources of folate
Source: DIET - green vegetables, nuts, yeast & liver, synthesized by gut bacteria (low body stores, cannot produce de novo)
Treatment: Give oral folic acid. If cause of anaemia is not known then folic acid must not be given, as this will exacerbate the neuropathy of B12 deficiency
1204
Haematology
Causes of folate deficiency:
Poor diet
Increased demand: pregnancy or ↑ cell turnover (haemolysis, malignancy,
inflammatory disease and renal dialysis).
Malabsorption: coeliac disease, tropical sprue.
Drugs: alcohol, anti-epileptics (phenytoin), methotrexate, trimethoprim.
Treatment: Give oral folic acid. If cause of anaemia is not known then folic acid must not be given, as this will exacerbate the neuropathy of B12 deficiency
1205
Haematology
```
↑bilirubin (unconjugated)
↑urobilinogen
↑LDH
Reticulocytosis (↑ MCV and polychromasia)
May have pigmented gallstones
```
All Haemolytic Anaemias
1206
Haematology
↑ free plasma Hb
↓haptoglobin (binds free Hb)
Haemoglobinuria (dark red urine)
Methaemalbuminaemia (Haem + albumin in blood)
Intravascular or Extravascular haemolytic anaemia?
Intravascular
1207
Haematology
Sx of intravascular haemolytic anaemia?
↑ free plasma Hb
↓haptoglobin (binds free Hb)
Haemoglobinuria (dark red urine)
Methaemalbuminaemia (Haem + albumin in blood)
1208
Haematology
Sx of extravascular haemolytic anaemia?
Splenomegaly
1209
Haematology
Splenomegaly
Intravascular or Extravascular haemolytic anaemia?
extravascular
1210
Haematology
Acquired causes of haemolytic anaemia?
Immune:
Autoimmune – warm or cold
Alloimmune – haemolytic transfusion reactions
Non-immune:
Mechanical e.g, metal valves, trauma
PNH, MAHA
Infections (i.e. Malaria), Drugs
1211
Haematology
Inherited causes of haemolytic anaemia?
Membrane Defect:
Hereditary spherocytosis
Hereditary elliptocytosis
Enzyme Defect:
G6PD deficiency
Pyruvate kinase deficiency
Haemoglobinopathies;
Sickle Cell Disease
Thalassaemias
1212
Haematology
Autosomal dominant - FHx to aid diagnosis (25% recessive or de novo!)
Spectrin or ankyrin deficiency (membrane proteins)
Susceptibility to effect of parvovirus B19 and develop gallstones
Extravascular haemolysis - splenomegaly
Diagnosis: spherocytes, ↑osmotic fragility (lysis in hypotonic solutions), [-ve DAT (Coombs) – not autoimm Ab mediated], flow cytometry
Treatment: Splenectomy, Folic acid
Hereditary spherocytosis
1213
Haematology
Spectrin or ankyrin deficiency (membrane proteins)
Hereditary spherocytosis
1214
Haematology
Diagnosis: spherocytes, ↑osmotic fragility (lysis in hypotonic solutions), [-ve DAT (Coombs) – not autoimm Ab mediated], flow cytometry
Hereditary spherocytosis
1215
Haematology
Rx Hereditary spherocytosis
Treatment: Splenectomy, Folic acid
1216
Haematology
Hereditary spherocytosis inheritance
Autosomal dominant - FHx to aid diagnosis (25% recessive or de novo!)
1217
Haematology
Almost all forms are autosomal dominant – spectrin mutations
o Except for Hereditary Pyropoikilocytosis (erythrocytes are abnormally
sensitivity to heat) – autosomal recessive (small print)
Severity ranges from hydrops foetalis to asymptomatic
Erythrocytes are elliptical in shape
Hereditary elliptocytosis:
1218
Haematology
Almost all forms are autosomal dominant – spectrin mutations
Hereditary elliptocytosis
1219
Haematology
Hereditary elliptocytosis inheritance
autosomal dominant
1220
Haematology
Recessive – heterozygous +/- malaria protection
South East Asian Ovalocytosis
1221
Haematology
Commonest RBC enzyme defect – X linked
Prevalent in areas of malarial endemicitiy i.e. African, Mediterranean and Middle
Eastern populations
Attacks - rapid anaemia and jaundice, with bite cells and Heinz bodies (blue deposits,
oxidized Hb).
Precipitated by oxidants as G6PD helps RBCs make glutathione which protects them
from oxidant damage - drugs (usually 2-3 days after starting) (e.g. primaquine, sulfonamides, aspirin), broad beans (within 1 day of eating)(favism), acute stressors, moth balls, acute infection
Diagnosis: Enzyme assay ~2- 3 months after a crisis: young RBCs may have sufficient enzyme so results may appear normal
Intravascular haemolysis: dark urine
Treatment: Avoid precipitants; transfuse if severe, genetic screening (rare subtypes
give chronic haemolysis for which splenectomy is a good treatment)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
1222
Haematology
Attacks - rapid anaemia and jaundice, with bite cells and Heinz bodies (blue deposits,
oxidized Hb).
Glucose-6-phosphate dehydrogenase (G6PD) deficiency:
1223
Haematology
Diagnosis: Enzyme assay ~2- 3 months after a crisis: young RBCs may have sufficient enzyme so results may appear normal
Glucose-6-phosphate dehydrogenase (G6PD) deficiency:
1224
Haematology
Autosomal recessive (but autosomal dominant has been observed with the disorder)
Clinical features: can be severe neonatal jaundice, splenomegaly, haemolytic anaemia
Treatment: most do not require treatment (can incl blood transfusion or splenectomy)
Pyruvate Kinase Deficiency
1225
Haematology
Inheritance pyruvate kinase
Autosomal recessive (but autosomal dominant has been observed with the disorder)
1226
Haematology
Mutation in sickle cell
Single base mutation; GAG → GTG. Glu → Val at codon 6 of β chain → HbS instead
of HbA.
Sickle cell anaemia manifests at 3-6mths (coincides with decreasing fetal Hb (HbF))
↓O2 tension HbS polymerisation sickling
1227
Haematology
HbSS vs HbAS
Sickle cell anaemia - Hb SS - severe
Sickle cell trait HbAS – usually asymptomatic except under stress (e.g cold, exercise)
Sickle cell anaemia manifests at 3-6mths (coincides with decreasing fetal Hb (HbF))
↓O2 tension HbS polymerisation sickling
1228
Haematology
o Sickle-haemoglobin C disease – HbSC: one HbS inherited from one parent, and one HbC (defective b chain) inherited from the other
o Sickle β thalassaemia – HbS/β: one HbS from one parent, β thalassaemia trait/ β0 from other. Sickle β0 similar in severity to HbSS
Rarer forms SCD
Sickle cell anaemia manifests at 3-6mths (coincides with decreasing fetal Hb (HbF))
↓O2 tension HbS polymerisation sickling
1229
Haematology
Inheritance sickle cell disease
Autosomal recessive
Sickle cell anaemia manifests at 3-6mths (coincides with decreasing fetal Hb (HbF))
↓O2 tension HbS polymerisation sickling
1230
Haematology
Childhood repercussions of sickle cell
Child – strokes, splenomegaly + splenic crises, dactylitis
1231
Haematology
Teenage repercussions of sickle cell
Teens – impaired growth, gallstones, psych, priapism
1232
Haematology
Adult repercussions of sickle cell
Adult – hyposplenism, CKD, retinopathy, pulomary hypertension
1233
Haematology
Diagnosis: sickle cells and target cells on blood film, sickle solubility test, Hb electrophoresis, Guthrie test (birth) to aid prompt pneumococcal prophylaxis (+FHx)
SCD
1234
Haematology
Diagnosis of SCD
Diagnosis: sickle cells and target cells on blood film, sickle solubility test, Hb electrophoresis, Guthrie test (birth) to aid prompt pneumococcal prophylaxis (+FHx)
1235
Haematology
Rx SCD
Treatment: Analgesia for painful crises, Folic acid, Penicillin V, pneumovax, HIB vaccine, Hydroxycarbamide, carotid Doppler monitoring in early childhood with prophylactic exchange transfusion if turbulent carotid flow.
1236
Haematology
Unbalanced Hb synthesis→ unmatched globins precipitate→ haemolysis and ineffective erthyropoiesis
Thalassaemia
1237
Haematology
↑HbA2 and HbF
β Thalassaemia:
1238
Haematology
Point mutations – ↓ β-chain synthesis (spectrum of disease), excess α-chains
β Thalassaemia:
1239
Haematology
Skull bossing, maxillary hypertrophy, hairs on end skull X-ray Hepatosplenomegaly
β Thalassaemia:
1240
Haematology
3-6mths severe anaemia,
FTT, hepatosplenomegaly (extramedullary erythropoiesis), bony
deformity, severe anaemia + heart failure
Which β Thalassaemia
β- thalassaemia major (homozygous) → 3-6mths severe anaemia,
FTT, hepatosplenomegaly (extramedullary erythropoiesis), bony
deformity, severe anaemia + heart failure
1241
Haematology
Moderate anaemia, splenomegaly,
bony deformity, gallstones
Which β Thalassaemia
β- thalassaemia intermedia → Moderate anaemia, splenomegaly,
| bony deformity, gallstones
1242
Haematology
Asymptomatic carrier, mild anaemia
Which β Thalassaemia
o β- thalassaemia minor (heterozygous) → Asymptomatic carrier, mild anaemia
1243
Haematology
Diagnosis of β Thalassaemia
Diagnosis: Hb electrophoresis (Guthrie at birth)
1244
Haematology
Rx of β Thalassaemia
Treatment: blood transfusions and desferrioxamine to stop iron overload, plus folic acid
1245
Haematology
Deletions - reduced α-chain synthesis, excess β-chains
4 α genes, severity depends on number deleted
α- Thalassaemia:
o α- thalassaemia trait (1/2 deleted) → Asymptomatic, mild anaemia o HbH disease (3 deleted) → Moderate anaemia, splenomegaly
o Hydrops Foetalis (4 deleted) → Incompatible with life
1246
Haematology
How many alpha globin genes exist?
4 α genes, severity depends on number deleted
o α- thalassaemia trait (1/2 deleted) → Asymptomatic, mild anaemia o HbH disease (3 deleted) → Moderate anaemia, splenomegaly
o Hydrops Foetalis (4 deleted) → Incompatible with life
1247
Haematology
1/2 alpha genes deleted?
o α- thalassaemia trait (1/2 deleted) → Asymptomatic, mild anaemia o HbH disease (3 deleted) → Moderate anaemia, splenomegaly
o Hydrops Foetalis (4 deleted) → Incompatible with life
1248
Haematology
3 alpha genes deleted?
o α- thalassaemia trait (1/2 deleted) → Asymptomatic, mild anaemia o HbH disease (3 deleted) → Moderate anaemia, splenomegaly
o Hydrops Foetalis (4 deleted) → Incompatible with life
1249
Haematology
4 alpha genes deleted?
o α- thalassaemia trait (1/2 deleted) → Asymptomatic, mild anaemia o HbH disease (3 deleted) → Moderate anaemia, splenomegaly
o Hydrops Foetalis (4 deleted) → Incompatible with life
1250
Haematology
37oC
IgG
Positive Coombs test
Blood film - spherocytes
Warm (WAIHA)– most common
1251
Haematology
<37oC
IgM
Positive Coombs test
Often with Raynaud's
Cold Agglutinin Disease
1252
Haematology
Causes of warm (WAIHA)?
Mainly primary idiopathic
| Lymphoma, CLL, SLE, methyldopa
1253
Haematology
Causes of cold agglutinin disease (CAIHA)?
Primary idiopathic
Lymphoma,
Infections: EBV, mycoplasma
1254
Haematology
Rx of WAIHA?
Steroids
Splenectomy
Immunosuppression
1255
Haematology
Rx of CAIHA?
Treat underlying condition
Avoid the cold
Chlorambucil (chemo)
1256
Haematology
Acquired loss of protective surface GPI markers on RBCs (platelets + neutrophils) → complement-mediated lysis → chronic intravascular haemolysis especially at night.
Paroxysmal nocturnal haemoglobinuria:
1257
Haematology
Acquired loss of protective surface GPI markers on RBCs (platelets + neutrophils) → complement-mediated lysis → chronic intravascular haemolysis especially at night.
Morning haemoglobinuria, thrombosis (+Budd- Chiari syndrome – hepatic v thromb).
Paroxysmal nocturnal haemoglobinuria:
1258
Haematology
```
Treatment: iron/folate supplements, prophylactic vaccines/antibiotics. Expensive
monoclonal antibodies (eculizumab) that prevents complement from binding RBCs
```
Paroxysmal nocturnal haemoglobinuria
1259
Haematology
Paroxysmal nocturnal haemoglobinuria Rx?
```
Treatment: iron/folate supplements, prophylactic vaccines/antibiotics. Expensive
monoclonal antibodies (eculizumab) that prevents complement from binding RBCs
```
1260
Haematology
mechanical RBC destruction (forced through fibrin/plt mesh in damaged vessels) → schistocytes
Microangiopathic Haemolytic Anaemia (MAHA)
1261
Haematology
Causes: HUS, TTP, DIC, pre-eclampsia, eclampsia. Rx – usually plasma exchange
Microangiopathic Haemolytic Anaemia (MAHA)
1262
Haematology
Microangiopathic Haemolytic Anaemia (MAHA) causes
Causes: HUS, TTP, DIC, pre-eclampsia, eclampsia. Rx – usually plasma exchange
1263
Haematology
MAHA, fever, renal impairment, neuro abnormalities, thrombocytopenia (classic pentad of symps).
o TTP: Thrombotic thrombocytopenic purpura.
ADAMTS13
1264
Haematology
Caused by E. Colitoxin damages endothelial cellsfibrin mesh and RBC damageimpaired renal function + microangiopathic haemolytic anaemia. Diarrhoea, renal failure, no neuro problems, children and elderly.
o HUS: Haemolytic uraemic syndrome.
1265
Haematology
Causes of acquired ↓Platelet function
ie normal number
Aspirin, Cardiopulmonary bypass
| Uraemia
1266
Haematology
Causes of Congenital ↓Platelet function
ie normal number
Storage pool disease
| Thrombasthenia (glycoprotein deficiency)
1267
Haematology
Thrombocytopenia (norm plt count 150- 400x109 g/l)
↓production
Bone marrow failure
1268
Haematology
Thrombocytopenia (norm plt count 150- 400x109 g/l)
↑destruction
Auto-Immume Thrombocytopenic Purpura
(AITP) – formally idiopathic (ITP)
Drugs e.g. heparin, DIC, HUS, TTP
1269
Haematology
```
Children (2-6 yrs)
M=F
Infection before
Abrupt onset
<20k platelet count
2 - 6 weeks duration
Common, usually self limiting
```
Acute ITP
1270
Haematology
```
Adults
3:1 F:M
Abrupt or indolent onset
Plt count <50k
Long term duration (associated with autoimmune ocnfitions, CLL, HIV)
Needs IVIG, steroids, splenectomy
```
Chronic ITP
1271
Haematology
Factor VIII deficiency
o X-linked recessive affecting 1/10,000 males
o Presentation: often early in life or prolonged bleeding after surgery/trauma
o Diagnosis: ↑APTT, normal PT and ↓ factor VIII assay.
o Severity: related to factor level
eg.sev<1%,mod1-5%,mild5-25%
o Management: Avoid NSAIDs and IM injections, desmopressin (vWF release
which is VIII carrier), factor VIII concentrates as replacement which is life long
Haemophilia A
1272
Haematology
o Diagnosis: ↑APTT, normal PT and ↓ factor VIII assay.
Haemophilia A
1273
Haematology
o Management: Avoid NSAIDs and IM injections, desmopressin (vWF release
which is VIII carrier), factor VIII concentrates as replacement which is life long
Haemophilia A
1274
Haematology
Haemophilia A – inheritance
o X-linked recessive affecting 1/10,000 males
1275
Haematology
Factor IX deficiency o X-linked recessive affecting 1/50,000 males
o Clinically like haemophilia A.
o Management: Factor IX concentrates
Haemophilia B (Christmas disease)
1276
Haematology
o Several types – quantitative (deficiency) vs. qualitative
o ↓ platelet function and ↓ factor VIII (vWF carries factor VIII in circulation)
o Mostly autosomal dominant affecting 1/10,000
o Presentation: often bleeding indicative of platelet disorders (i.e. mucocutaneous
bleeding) but can also include bleeding indicative of coagulation disorders
o Diagnosis:↑APTT, ↑bleedingtime, ↓FactorVIII, ↓vWF Ag.
Normal INR & plts
o Management: Desmopressin, VWF and Factor VIII concentrates
Von Willebrand's disease
1277
Haematology
o Diagnosis:↑APTT, ↑bleedingtime, ↓FactorVIII, ↓vWF Ag.
Von Willebrand's disease
1278
Haematology
o ↓ platelet function and ↓ factor VIII (vWF carries factor VIII in circulation)
Von Willebrand's disease
1279
Haematology
Von Willebrand's disease inheritance?
AD
| 1/10000
1280
Haematology
o Widespread activation of coagulation
o Clotting factors and platelets are consumed → ↑ risk of bleeding
o Causes: Malignancy, sepsis, trauma, obstetric complications, toxins. o Low plts, low fibrinogen, high FDP/D-Dimer, long PT/INR.
o Treat the cause and give transfusions, FFP, platelets, cryo etc.
Disseminated intravascular coagulation (DIC):
1281
Haematology
o ↓ synthesis of II, V, VII, IX, X, XI and fibrinogen o ↓ absorption of vitamin K
o Abnormalities of platelet function.
Liver disease:
1282
Haematology
Vitamin K needed for synthesis of what?
o Vit K needed for synthesis of Factors II, VII, IX and X
o And Protein C/S (this is why warfarin may be pro-coagulant initially)
o Causes: Warfarin, vitamin K malabsorption/malnutrition, Abx therapy, biliary obstruction
o Treatment: IV vitamin K or FFP for acute haemorrhage.
1283
Haematology
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden – 5% caucasian pop, resistance to protein C
Prothrombin G20210A
Lupus anticoagulant
Coag excess – VIII (10%), II (2%), fibrinogen
Inherited VTE RFs
1284
Haematology
Rx VTE
LMWH (175 units/kg) and Warfarin or Apixaban/Rivaroxaban (DOACs)
LMWH stopped once INR in therapeutic range (2.5) general (with DOACs LMWH can
be stopped immediately)
1st VTE with known cause – 3 months oral anticoagulant
Cancer VTE – 3-6months LMWH
1st VTE unknown cause – 3-6months anticoagulation, possibly lifelong
1st VTE in thrombophilic patient – 3 months anticoagulation, possibly lifelong
Recurrent VTE – lifelong warfarin
TEDS to prevent postphlebitic syndrome
1285
Haematology
Potentiates antithrombin III which inactivates thrombin, and factors 9, 10, 11
Heparin
1286
Haematology
Which heparin requires monitoring?
LMWH: given SC once daily, does not require monitoring (except late pregnancy and
renal failure)
Unfractionated heparin (used if renal impairment): given IV, loading dose then infusion,
monitor APTT
Antidote: protamine sulphate
Side effects are Bleeding and Heparin induced thrombocytopenia (HIT) and
osteoporosis with long-term use. (HIT and osteoporosis more common with UFH)
1287
Haematology
Antidote: protamine sulphate
Heparin
1288
Haematology
Inhibits the reductase enzyme responsible for regenerating the active form of vitamin K and therefore inhibits the synthesis of factors 2, 7, 9, 10 and proteins C, S and Z
Warfarin
1289
Haematology
Warfarin reversal
Reversal: IV vitamin K/ factor concentrates
Risk of teratogenicity
Reversal: IV vitamin K/ factor concentrates
Dose adjusted to maintain INR in therapeutic range
Risk of teratogenicity
1290
Haematology
1st episode DVT or PE, atrial fibrillation (2-3), cardiomyopathy, symptomatic inherited thrombophilia, mural thrombus, cardioversion
Target INR
2.5
1291
Haematology
Recurrent DVT or PE, mechanical prosthetic valve (2.5-3.5), coronary artery graft thrombosis, antiphospholipid syndrome
Target INR
3.5
1292
Haematology
Warfarin
INR 5-8, no bleeding
What do you do?
Withhold few doses, reduce maintenance. Restart when INR
| <5.
1293
Haematology
Warfarin
INR 5 – 8, minor bleeding
What do you do?
Stop warfarin. Vit K slow IV. Restart when INR <5.
1294
Haematology
warfarin
INR >8, no bleed/minor bleed
What do you do?
Stop warfarin. Vitamin K (oral/IV) no bleeding/if risk factors for bleeding or minor bleeding. Check INR daily.
1295
Haematology
Major bleeding, (including intracranial haemorrhage) warfarin
What do you do?
Stop warfarin. Give prothrombin complex concentrate. If unavailable, give FFP. Also give vitamin K IV.
1296
Haematology
Neoplastic process of bone marrow (BM) and blood “Acute” thus rapidly progressing and fatal
Immature blasts > 20% BM cells
Acute Leukaemia (ALL and AML)
1297
Haematology
```
Acute Leukaemia (ALL and AML)
How many blast cells needed?
```
Immature blasts > 20% BM cells
1298
Haematology
Ionising radiation - radiotherapy
Cytotoxic drugs - chemotherapy
Benzene
Pre-leukaemic disorders, e.g: Myelodysplastic syndromes (MDS)/Myeloproliferative
disorders (MPD)
Down’s: significantly increased risk of AML/ALL
Neonates: often (30%) develop transient abnormal myelopoeisis; resembles
AML but resolves spontaneously and completely after few weeks
AML/ALL causes
1299
Haematology
```
Lymphadenopathy +++
CNS involvement +++
Testicular enlargement
Thymic enlargement (mediastinum)
CHILDREN
```
ALL
1300
Haematology
Who gets AML?
Adulthood (risk increases with age) and under-2s (infant peak)
1301
Haematology
M3 AML subtype?
M3: Acute promyelocytic leukaemia – prone to DIC
1302
Haematology
M4 AML subtype?
M4+5: Monoblasts/monocytes - Skin / gum infiltration + hypokalaemia
1303
Haematology
```
High WCC (blasts)
Lymphocytes (or precursors) +++ Flow cytometry:
CD34 = precursor/stem cells CD3 = T lymphocytes
CD19 = B lymphocytes
```
ALL
1304
Haematology
ALL flow cytometry markers
```
High WCC (blasts)
Lymphocytes (or precursors) +++ Flow cytometry:
CD34 = precursor/stem cells CD3 = T lymphocytes
CD19 = B lymphocytes
```
1305
Haematology
Auer rods
AML
1306
Haematology
```
High WCC (blasts)
Auer rods and granules Flow cytometry:
CD34 = precursor/stem cells MPO = Myeloid cells
```
AML
1307
Haematology
AML flow cytometry markers
```
High WCC (blasts)
Auer rods and granules Flow cytometry:
CD34 = precursor/stem cells MPO = Myeloid cells
```
1308
Haematology
Remission induction: Chemo agents often given with steroids Consolidation: High dose multi drug chemotherapy
CNS treatment
Maintenance: 2 years in girls and adults, 3 years in boys
Consider allo-Stem Cell Transplant
Supportive: Blood products, ABx, Allopurinol, fluid, electrolytes – to prevent tumour lysis syndrome
ALL Rx
1309
Haematology
What are the 3 ALL Rx steps?
1. Remission induction: Chemo agents often given with steroids
2. Consolidation: High dose multi drug chemotherapy
CNS treatment
3. Maintenance: 2 years in girls and adults, 3 years in boys
Consider allo-Stem Cell Transplant
Supportive: Blood products, ABx, Allopurinol, fluid, electrolytes – to prevent tumour lysis syndrome
1310
Haematology
ATRA Rx
Which subtype of AML?
M3
1311
Haematology
2 Rx steps in AML?
Remission induction: Chemo agents often given with steroids Consolidation: High dose multi drug chemotherapy
1312
Haematology
A myeloproliferative disease (others discussed later)
Middle-aged (40 to 60); median survival 3-5 years.
Often diagnosed on routine bloods (large number of differentiated neutrophils) 95% remission rate with imatinib
O/E: splenomegaly - often massive
Chronic Myeloid Leukaemia
1313
Haematology
MASSIVE splenomegaly
Chronic Myeloid Leukaemia
1314
Haematology
Ph+ve (Philadelphia chromosome) in 80% = chromosomal translocation (9;22) PCR for BCR-ABL (Philadelphia Ch) fusion gene
Monitor disease and therapeutic response
WBC, Neutrophils 50-500
Hypercellular BM with spectrum of immature (e.g. myelocytes) and mature granulocytic cells in the blood
AML
1315
Haematology
What is the chronic phase of AML?
What is the Rx?
<5% blasts in BM/blood, WBC slowly increases over years (indolent)
Rx = Imatinib (BCR-ABL tyrosine kinase inhibitor) or dasatinib/nilotinib for resistance;
extremely effective and well tolerated.
1316
Haematology
What is the accelerated phase of AML?
What is the Rx?
>10% blasts in BM/blood
| Increasing manifestations, such as splenomegaly, lasting up to a year Less responsive to therapy
1317
Haematology
What is the blast phase of AML?
What is the Rx?
>20% blasts in BM/blood
Resembles acute leukaemia; timeframe = months (+/- WL, lethargy, night sweats) Treatment similar to AML, possibly with allogeneic SCT for young pts.
1318
Haematology
May be asymptomatic, often diagnosed on routine bloods (80% cases)
Symmetrical painless lymphadenopathy
BM failure - anaemia & thrombocytopenia symptoms, recurrent infections (50% deaths) Weight loss, low grade fever, night sweats
Hepatomegaly & splenomegaly (less prominent)
Associated with autoimmunity (Evan’s Syndrome) – AIHA, ITP
Can progress to a form of lymphoma (DLBC, see later) – Richter’s transformation
Chronic Lymphocytic Leukaemia
1319
Haematology
High WBC with lymphocytosis >5 (high % of WBC composed of lymphocytes, small mature)
Low serum Ig
Smear cells (remember SMEAR CLLs) – seen on blood film Ix
Abnormal BM – lymphocytic replacement
CLL
1320
Haematology
SMEAR cells
CLL
1321
Haematology
In a CLL patient you see:
LDH raised, CD38 +ve, 11q23 deletion
What does this imply?
LDH raised, CD38 +ve, 11q23 deletion = bad prognosis
1322
Haematology
In a CLL patient you see:
Hypermutated Ig gene, Low ZAP-70 expression, 13q14 deletion
What does this imply?
Hypermutated Ig gene, Low ZAP-70 expression, 13q14 deletion = good prognosis
1323
Haematology
```
Stage A
High WBC
<3 groups of enlarged lymph nodes
Usually no treatment required Stage B
>3 groups of enlarged lymph nodes Stage C
Anaemia or thrombocytopenia
```
Binet Staging A, B & C
1324
Haematology
Binet Staging A, B & C, what is in each?
```
Stage A
High WBC
<3 groups of enlarged lymph nodes
Usually no treatment required Stage B
>3 groups of enlarged lymph nodes Stage C
Anaemia or thrombocytopenia
```
1325
Haematology
Many patients benefit from watchful waiting if they are asymptomatic with slowly progressive disease
1st line: p53 deletion = alemtuzumab otherwise = clinical trial or chlorambucil
CLL Rx
1326
Haematology
CLL Rx
Many patients benefit from watchful waiting if they are asymptomatic with slowly progressive disease
1st line: p53 deletion = alemtuzumab otherwise = clinical trial or chlorambucil
1327
Haematology
M>F; bimodal age incidence – 20-29 year olds and >60 year olds
EBV-associated
Spreads contiguously to adjacent lymph nodes; often involves single LN group
Hodgkins Lymphoma
1328
Haematology
Asymmetrical painless lymphadenopathy +/- obstructive/mass effect symptoms “B-symptoms”
o Fever >38. Classical Pel-Ebstein fever (cyclical 1-2wk) seen in a minority o Drenching sweats at night
o Weight loss >10% in 6 months unintentional
Pain in affected nodes after alcohol
Hodgkins Lymphoma
1329
Haematology
Tissue diagnosis: LN or BM biopsy - cells stain with CD15 & CD30
Hodgkins Lymphoma
1330
Haematology
Hodgkins Lymphoma
What do BM cells stain for?
Tissue diagnosis: LN or BM biopsy - cells stain with CD15 & CD30
1331
Haematology
bi-nucleate/multinucleate (‘owl eyed’) cell on a
background of lymphocytes & reactive cells
Reed-Sternberg cell – Hodgkins
1332
Haematology
Reed-Sternberg cell
Hodgkins
1333
Haematology
Subtypes: nodular sclerosing (most common), mixed cellularity, lymphocyte rich,
lymphocyte depleted, nodular lymphocyte predominant (not classical HL)
HL
1334
Haematology
List Hodgkins subtypes
Subtypes: nodular sclerosing (most common), mixed cellularity, lymphocyte rich,
lymphocyte depleted, nodular lymphocyte predominant (not classical HL)
1335
Haematology
Stage 1 – one LN region (LN region can include spleen)
Stage 2 – two or more LN regions on the same side of the diaphragm Stage 3 – two or more LN regions on opposite sides of the diaphragm Stage 4 – extranodal sites (liver, BM)
A: No constitutional symptoms B: Constitutional symptoms
Hodgkins staging
1336
Haematology
Hodgkins staging
Stage 1 – one LN region (LN region can include spleen)
Stage 2 – two or more LN regions on the same side of the diaphragm Stage 3 – two or more LN regions on opposite sides of the diaphragm Stage 4 – extranodal sites (liver, BM)
A: No constitutional symptoms B: Constitutional symptoms
1337
Haematology
Treatment - prognosis excellent, especially in the young
1. Combinationchemotherapy–
o Used in most cases
o ABVD: Adriamycin, bleomycin, vinblastine and dacarbazine o 2-4 cycles in stage 1/2, 6-8 cycles in stage 3/
2. Radiotherapy–
o Often used alongside chemo in bulky areas
3. IntensivechemoandautologousSCT– o Relapsed patients
HL Rx
1338
Haematology
HL Rx
Treatment - prognosis excellent, especially in the young
1. Combination chemotherapy–
o Used in most cases
o ABVD: Adriamycin, bleomycin, vinblastine and dacarbazine o 2-4 cycles in stage 1/2, 6-8 cycles in stage 3/
2. Radiotherapy–
o Often used alongside chemo in bulky areas
3. Intensive chemo and autologousSCT– o Relapsed patients
1339
Haematology
Similarities: painless lymphadenopathy, often involving multiple sites,
constitutional symptoms, no pain after alcohol
Staging as per Hodgkin’s
Non-Hodgkin’s Lymphoma (80%)
1340
Haematology
Children and young adults Aggressive
Large “epithelioid” lymphocytes t(2;5)
Alk-1 protein expression
Which T cell lymphoma?
Anaplastic large cell lymphoma
1341
Haematology
Large “epithelioid” lymphocytes
Which T cell lymphoma?
Anaplastic large cell lymphoma
Children and young adults Aggressive
Large “epithelioid” lymphocytes t(2;5)
Alk-1 protein expression
1342
Haematology
Middle-aged and elderly Aggressive
Large T-cells
Which T cell lymphoma?
Peripheral T-Cell Lymphoma
1343
Haematology
Caribbean and Japanese HTLV-1 infection, aggressive
Which T cell lymphoma?
Adult T cell leukaemia/lymphoma
1344
Haematology
Associated with longstanding coeliac disease
Which T cell lymphoma?
Enteropathy-associated T cell lymphoma (EATL)
1345
Haematology
Associated with mycosis fungoides
Which T cell lymphoma?
Cutaneous T Cell Lymphoma
1346
Haematology
“Starry sky” appearance
Burkitt’s
1347
Haematology
Most common malignancy in equatorial Africa EBV-associated Characteristic jaw involvement and abdominal masses
All very aggressive, fast growing
t(8;14) translocation c-myc oncogene overexpression Rapidly responsive to Rx
Which B cell lymphoma?
Endemic Burkitt’s
All very aggressive, fast growing
t(8;14) translocation c-myc oncogene overexpression Rapidly responsive to Rx
1348
Haematology
Found outside Africa EBV-associated Jaw less commonly involved
All very aggressive, fast growing
t(8;14) translocation c-myc oncogene overexpression Rapidly responsive to Rx
Sporadic Burkitt’s
All very aggressive, fast growing
t(8;14) translocation c-myc oncogene overexpression Rapidly responsive to Rx
1349
Haematology
Non-EBV-associated HIV/post transplant patients
All very aggressive, fast growing
t(8;14) translocation c-myc oncogene overexpression Rapidly responsive to Rx
Immunodeficiency Burkitt’s
All very aggressive, fast growing
t(8;14) translocation c-myc oncogene overexpression Rapidly responsive to Rx
1350
Haematology
Rx burkitts
Chemotherapy (rituximab (anti CD20 - found on B cells) & leukaemia protocol) or SCT
1351
Haematology
Middle aged and elderly
Aggressive Richter’s transformation Other lymphomas occur secondary to this
“Sheets of large lymphoid cells”
Diffuse Large B-cell (DLBC)
1352
Haematology
“Sheets of large lymphoid cells”
Diffuse Large B-cell (DLBC)
1353
Haematology
Rx for
Diffuse Large B-cell (DLBC)
Rituximab-CHOP Auto-SCT for relapse
1354
Haematology
Middle-aged, M>F Aggressive Disseminated at presentation Median survival 3-5 years
t(11;14) translocation Cyclin D1 deregulation
“Angular nuclei”
Mantle cell lymphoma
1355
Haematology
t(11;14) translocation
Cyclin D1 deregulation
“Angular nuclei”
Mantle cell lymphoma
1356
Haematology
What translocation is Mantle cell lymphoma
t(11;14) translocation
1357
Haematology
Rx for Mantle cell lymphoma
Rituximab-CHOP Auto-SCT for relapse
1358
Haematology
t(8;14) translocation c-myc oncogene
Burkitt’s
1359
Haematology
Burkitt’s translocation
t(8;14)
1360
Haematology
Indolent
Mostly incurable Median survival 12-15 yrs
t(14:18) translocation
“Follicular
pattern” “Nodular appearance”
Follicular
1361
Haematology
Follicular Rx
Watch and wait
| Rituximab CVP
1362
Haematology
Follicular lymphoma
t(14:18) translocation
1363
Haematology
Marginal zone NHL Middle-aged Chronic antigen stimulation:
H. pylori
Sjogren’s syndrome
parotid lymphoma
Mucosal associated lymphoid tissue (MALT)
1364
Haematology
Rx MALT
Remove antigenic stimulus e.g. H. pylori triple therapy, Chemotherapy
1365
Haematology
neoplasia of plasma cells (effector B cells antibodies) of BM Production of monoclonal immunoglobulin - “paraprotein”
IgG most common
Middle-Aged to Elderly
Increased incidence in Afro-Caribbeans
Multiple Myeloma
1366
Haematology
Clinical features (CRAB):
Calcium high – thirst, moans, groans, stones, bones
Renal failure (plus amyloidosis and nephrotic syndrome) Anaemia (+pancytopenia)
Bones: pain, osteoporosis, osteolytic lesions, fractures
e.g. wedge compression, pepper pot skull + Hyperviscosity syndrome
Multiple Myeloma
1367
Haematology
Multiple Myeloma signs
Clinical features (CRAB):
Calcium high – thirst, moans, groans, stones, bones
Renal failure (plus amyloidosis and nephrotic syndrome) Anaemia (+pancytopenia)
Bones: pain, osteoporosis, osteolytic lesions, fractures
e.g. wedge compression, pepper pot skull + Hyperviscosity syndrome
1368
Haematology
Dense narrow band on serum electrophoresis (compared with broad band in polyclonal)
Rouleaux on blood film (RBC stacking)
Multiple Myeloma
1369
Haematology
ESR very high
>10% plasma cells in BM
Multiple Myeloma
1370
Haematology
```
Dense narrow band on serum electrophoresis (compared with broad band in polyclonal)
Rouleaux on blood film (RBC stacking)
Bence-Jones protein in urine
ESR very high
>10% plasma cells in BM
```
Multiple Myeloma
1371
Haematology
Multiple Myeloma Rx
Supportive for CRAB symptoms inc, bispohosphonates Options:
o Auto-SCT – curative, best for younger patients
o Bortezomib – new agent, used with dex and cyclophosphamide o Thalidomide/lenalidomide
1372
Haematology
```
IgG/IgA <30g/l
<10% clonal plasma
cells
No treatment needed
Small transformation rate
No symptoms
```
MGUS
Smouldering MM
OR
Multiple myeloma
MGUS
```
MGUS
IgG/IgA <30g/l
<10% clonal plasma
cells
No treatment needed
Small transformation rate
```
```
Smouldering MM
IgG/IgA >30g/l
>10% clonal plasma
cells
No symptoms
No treatment needed Higher transformation rate
```
```
Multiple Myeloma
IgG/IgA >30g/l
Any clonal plasma cell
population
CRAB Sx
Hypogammaglobulinaem ia
Occult bone disease Hyperviscosity Cytopenia
Treatment needed
```
1373
Haematology
```
IgG/IgA >30g/l
>10% clonal plasma
cells
No symptoms
No treatment needed Higher transformation rate
```
MGUS
Smouldering MM
OR
Multiple myeloma
Smouldering MM
```
MGUS
IgG/IgA <30g/l
<10% clonal plasma
cells
No treatment needed
Small transformation rate
```
```
Smouldering MM
IgG/IgA >30g/l
>10% clonal plasma
cells
No symptoms
No treatment needed Higher transformation rate
```
```
Multiple Myeloma
IgG/IgA >30g/l
Any clonal plasma cell
population
CRAB Sx
Hypogammaglobulinaem ia
Occult bone disease Hyperviscosity Cytopenia
Treatment needed
```
1374
Haematology
```
IgG/IgA >30g/l
Any clonal plasma cell
population
CRAB Sx
Hypogammaglobulinaem ia
Occult bone disease Hyperviscosity Cytopenia
Treatment needed
```
MGUS
Smouldering MM
OR
Multiple myeloma
Multiple Myeloma
```
MGUS
IgG/IgA <30g/l
<10% clonal plasma
cells
No treatment needed
Small transformation rate
```
```
Smouldering MM
IgG/IgA >30g/l
>10% clonal plasma
cells
No symptoms
No treatment needed Higher transformation rate
```
```
Multiple Myeloma
IgG/IgA >30g/l
Any clonal plasma cell
population
CRAB Sx
Hypogammaglobulinaem ia
Occult bone disease Hyperviscosity Cytopenia
Treatment needed
```
1375
Haematology
Elderly men
A low-grade NHL; lymphoplasmacytoid cells produce monoclonal serum IgM that
infiltrates the LNs/BM
Weight loss, fatigue, hyperviscosity syndrome (visual problems, confusion, CCF,
muscle weakness)
Treatment: plasmapheresis for hyperviscosity; chlorambucil,
cyclophosphamide and other chemo
Waldenstrom’s Macroglobinaemia (Lymphoplasmacytoid Lymphoma - LPL)
1376
Haematology
Ig light chains = paraprotein deposition of abn proteinaceous subst in tissues
Diagnosed via congo-red stain apple green birefringence
o New diagnostic test is the SAP scan at the national amyloidosis centre at the Royal Free
Presents with macroglossia, carpal tunnel syndrome, peripheral neuropathy, HF, RF
Treatment = chemo / auto-SCT
Systemic Amyloidosis
1377
Haematology
Presents with macroglossia, carpal tunnel syndrome, peripheral neuropathy, HF, RF
Systemic Amyloidosis
1378
Haematology
Diagnosed via congo-red stain apple green birefringence
Systemic Amyloidosis
1379
Haematology
Ig light chains = paraprotein deposition of abn proteinaceous subst in tissues
Systemic Amyloidosis
1380
Haematology
A low-grade NHL; lymphoplasmacytoid cells produce monoclonal serum IgM that
infiltrates the LNs/BM
Waldenstrom’s Macroglobinaemia (Lymphoplasmacytoid Lymphoma - LPL)
1381
Haematology
A heterogeneous group of progressive disorders featuring ineffective proliferation and differentiation of abnormally maturing myeloid stem cells.
Characterised by: peripheral cytopenia; qualitative abnormalities of cell maturation; risk of AML transformation.
By definition all patients have <20% blasts (>20% blasts = acute leukaemia)
Myelodysplastic Syndromes
1382
Haematology
BM failure and cytopenias – infection, bleeding, fatigue
Hypercellular BM
Defective cells:
o RBCs e.g. ring sideroblasts (abn nucleated blast surrounded by iron granule ring) o WBCs – hypogranulation, Pseudo-Pelger-huet anomaly (hyposegmented neutro) o Platelets – micromegakaryocytes, hypolobated nuclei
In the exam – use an ‘investigative approach’ to pick out clues that lead to classification
Myelodysplastic Syndromes
1383
Haematology
o RBCs e.g. ring sideroblasts (abn nucleated blast surrounded by iron granule ring)
o WBCs – hypogranulation, Pseudo-Pelger-huet anomaly (hyposegmented neutro)
o Platelets – micromegakaryocytes, hypolobated nuclei
Myelodysplastic Syndromes
1384
Haematology
MDS prognostic score
Depends on International Prognostic Scoring System (IPSS): BM blast %; karyotype; degree of cytopenia.
1385
Haematology
o Mortality rule of 1/3: 1/3 die from infection, 1/3 bleeding and 1/3 acute leukaemia.
1386
Haematology
MDS subtype
Blood: Anaemia, no blasts
BM: Erythroid dysplasia with <5% blasts
Refractory anaemia (RA)
1387
Haematology
MDS subtype
Blood: Anaemia, no blasts
BM: Erythroid dysplasia with >15% ringed sideroblasts
Refractory anaemia with ringed sideroblasts (RA +RS)
1388
Haematology
MDS subtype
Blood: Cytopenia in ≥ 2 cell lines
BM: Dysplasia in >10% cells in ≥ 2 cell lines
Refractory cytopenia with multilineage dysplasia (RCMD)
1389
Haematology
MDS subtype
Blood: Cytopenia in ≥ 2 cell lines
BM: Dysplasia in >10% cells in ≥ 2 cell lines and >15% ringed sideroblasts
Refractory cytopaenia with multilineage dysplasia and ringed sideroblasts (RCMD + RS)
1390
Haematology
MDS subtype
Blood: Cytopenias, <5% blasts, no Auer rods
BM: Dysplasias, 5-9% blasts
Refractory anaemia with excess blasts – 1 (RAEB I)
1391
Haematology
MDS subtype
Blood: Cytopenias or 5-19% blasts or Auer rods
BM: Dysplasias, 10-19% blasts or Auer rods
Refractory anaemia with excess blasts – 2 (RAEB II)
1392
Haematology
MDS subtype
Blood: Anaemia, normal or increased platelets
BM: Megakaryocytes with hypolobated nuclei and <5% blasts
MDS with 5q deletion
1393
Haematology
MDS subtype
Blood: Complex - cytopenias, no blasts, no Auer rods
BM: Complex - myeloid or megakaryocytic dysplasia, <5% blasts
Myelodysplasia Syndrome Unclassified
1394
Haematology
The inability of BM to produce adequate blood cells
Haemopoeitic stem cell numbers are reduced in BM trephines (hypocellular BM)
Aplastic Anaemia
1395
Haematology
Causes of aplastic anaemia?
Primary:
o Idiopathic (70%) – vast majority unexplained pathology
o Inherited (10%) – see below
Secondary (10-15%) – due to malignant infiltration, radiation, drugs incl. chemo, viruses,
AI e.g. SLE
Management:
Supportive – transfusions, Abx, iron chelation
Drugs – to promote marrow recovery – growth factors and oxymethalone (androgen)
Immunosuppressants – idiopathic AA
SCT
1396
Haematology
```
Autosomal recessive. Pancytopenia
Presents at 5-10yrs
Skeletal abnormalities (radii, thumbs), renal malformations, microopthalmia, short
stature, skin pigmentation
MDS (~30%), AML risk (10% progress)
```
Fanconi Anaemia (cf Fanconi Syndrome = renal)
1397
Haematology
X-linked. Chromosome instability (telomere shortening)
Skin pigmentation, nail dystrophy, oral leukoplakia (triad) + BM failure
Dyskeratosis Congenita
1398
Haematology
Autosomal recessive. Primarily neutrophilia +/- others
Skeletal abnormalities, endocrine and pancreatic dysfunction, hepatic impairment,
short stature
AML risk
Schwachman-Diamond Syndrome
1399
Haematology
Pure red-cell aplasia; normal WCC and platelets
Presents at 1yr/neonatal
Dysmorphology
Diamond-Blackfan Syndrome
1400
Haematology
"Philadelphia Chromosome positive"
Myeloproliferative Disorders
Chronic Myeloid Leukemia (CML)
1401
Haematology
A group of conditions characterized by clonal proliferation of one or more haemopoietic component i.e. increased production of mature cells.
Myeloproliferative Disorders
1402
Haematology
"Philadelphia Chromosome negative"
Myeloproliferative Disorders
```
Polycythemia vera (PV) Myelofibrosis (MF)
Essential thrombocytosis (ET)
```
Ph –ive associated with JAK2 mutations, particularly PRV (>95%).
1403
Haematology
Raised red cell mass, Hb, red cell count and packed cell volume
Polycythaemia
Primary causes:
Polycythaemia vera
Familial polycythaemia Secondary causes (EPO):
Disease states (renal Ca), high altitude, chronic hypoxia
1404
Haematology
List primary and secondary causes of Polycythaemia
Primary causes:
Polycythaemia vera
Familial polycythaemia Secondary causes (EPO):
Disease states (renal Ca), high altitude, chronic hypoxia
1405
Haematology
Red cell mass normal but plasma volume reduced
Dehydration, burns, vomiting, diarrhoea, cigarette smoking
Relative (Pseudo) Polycythaemia
1406
Haematology
An MPD where erythroid precursors dominate the BM. Incidence rises with age. Point mutations: JAK2 (V617F). Independent of normal mechanisms of regulation.
Polycythaemia Rubra Vera (PRV)
1407
Haematology
Hyperviscosity / hypervolaemia / hypermetabolism
Blurred vision, headache
Plethoric (“red nose”), gout, thrombosis and stroke, retinal vein engorgement,
erythromelagia
Splenomegaly
Histamine release > aquagenic pruritis (contact with water) and peptic ulcers
Polycythaemia Rubra Vera (PRV)
1408
Haematology
Polycythaemia Rubra Vera (PRV) Rx
Venesection
| Hydroxycarbamide (maintenance), aspirin
1409
Haematology
Raised Hb, HCT; also possibly platelets, WCC (neutrophils & basophils)
Low serum EPO
Polycythaemia Rubra Vera (PRV)
1410
Haematology
A MPD where myeloproliferationfibrosis of BM or replacement with collagenous tissue Primary (idiopathic) vs secondary following PRV, ET, leukaemia etc).
Myelofibrosis
Blood film – tear-drop poikilocytes (dacrocyte), leukoerythroblasts (primitive cells)
BM – fibrosis, “dry tap”
1411
Haematology
Pancytopaenia-related symptoms
Extramedullary haematopoeisis - hepatomegaly, massive splenomegaly, WL, fever
Can present with Budd-Chiari syndrome
Which MPD?
Myelofibrosis
A MPD where myeloproliferationfibrosis of BM or replacement with collagenous tissue Primary (idiopathic) vs secondary following PRV, ET, leukaemia etc).
Blood film – tear-drop poikilocytes (dacrocyte), leukoerythroblasts (primitive cells)
BM – fibrosis, “dry tap”
1412
Haematology
Blood film – tear-drop poikilocytes (dacrocyte), leukoerythroblasts (primitive cells)
BM – fibrosis, “dry tap”
Myelofibrosis
1413
Haematology
Rx of myelofibrosis
Support with blood products, in some cases - splenectomy
| Hydroxycarbamide, thalidomide, steroids and SCT also used.
1414
Haematology
An MPD where megakaryocytes dominate the BM 50% associated with JAK2
Essential Thrombocythaemia (or thrombocytosis)
Incidental finding in 50%
Venous and arterial thrombosis (stroke & MI), gangrene and haemorrhage
Erythromelalgia
Splenomegaly, dizziness, headaches, visual disturbances
Investigations
Platelet count >600x109
Blood film – large platelets and megakaryocyte fragments
Increased BM megakaryocytes (not reactive)
Treatment
Aspirin
Anagrelide – reduce formation of plts from megakaryocytes
Hydroxycarbamide
1415
Haematology
Incidental finding in 50%
Venous and arterial thrombosis (stroke & MI), gangrene and haemorrhage
Erythromelalgia
Splenomegaly, dizziness, headaches, visual disturbances
Essential Thrombocythaemia (or thrombocytosis)
1416
Haematology
Platelet count >600x109
Blood film – large platelets and megakaryocyte fragments
Increased BM megakaryocytes (not reactive)
Essential Thrombocythaemia (or thrombocytosis)
1417
Haematology
Rx Essential Thrombocythaemia (or thrombocytosis)
Aspirin
Anagrelide – reduce formation of plts from megakaryocytes
Hydroxycarbamide
1418
Haematology
When should you give RBCs?
o Treat Iron/Folate/B12 deficiency first unless active bleeding
o For transfusion dependent patients use a threshold 70-90g/l (depends on
what level patient gets symptomatic)
o Higher threshold of up to 100g/l for patients with ACS
o Only transfuse one unit at a time unless active bleeding
1419
Haematology
When should you give platelets?
o Consumptive disorders e.g. TTP, DIC, HIT
Do not transfuse unless actively bleeding (plts will be destroyed) o Reduced production e.g. leukaemias
Transfuse when <10bn/litre
Higher threshold of 20 in sepsis
o Pre-procedure: Various thresholds depending on procedure.
1420
Haematology
When should you give FFP?
o Use Vit K first
Blood Transfusions
When to transfuse
o Do not use unless patient is bleeding or undergoing a procedure e.g. LP
1421
Haematology
Which Ig can cross the placentae?
Only IgG can cross placenta
Ab most often responsible is anti-D, therefore always transfuse RhD negative blood
to RhD negative women of childbearing age
Other Ab: anti-c, anti-K, IgG ABO
1422
Haematology
Prevention of anti-D formation
In women who are RhD negative
Give mother intra-muscular anti-D Ig when she is at high risk of feto-maternal
haemorrhage
Routine antenatal prophylaxis at 28 and 34 weeks
During pregnancy if sensitising event occurs (abortion, miscarriage, abdo
trauma, ECV, amniocentesis etc.) At delivery if baby is RhD positive
1423
Haematology
Transfusion reaction includes mild fever or urticarial rash only. What Ddx?
```
FEBRILE NON HAEMOLYTIC (fever)
MILD ALLERGIC (urticaria
```
1424
Haematology
Transfusion reaction includes SIGNIFICANT change in obs/shock/collapse
```
ABO incompatibility (bleeding /dark urine)
Severe allergic reaction (swelling / wheeze)
```
1425
Haematology
Transfusion reaction includes SIGNIFICANT change in obs/shock/collapse AND FEVER
Bacterial infection of unit
1426
Haematology
Transfusion reaction includes SIGNIFICANT change in obs/shock/collapse AND RAISED CVP
TACO
