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Haematology Flashcards

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1
Q

what causes RBC production?

A

Tissue hypoxia -> EPO kidneys -> bone marrow ->RBC production

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2
Q

describe staining of erythrocyte?

A

has mesangial mRNA-stain blue (loses this within 2-3 days)

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3
Q

what is myelofibrosis?

A

scarring of bone marrow-splenomegaly as hematopoiesis reverts back to spleen

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4
Q

where does prenatal hematopoiesis take place?

A

yolk sac
liver
spleen
bone marrow

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5
Q

describe erythropoiesis

A

in bone marrow: pluripotenti hematopoietic stem cell -> proerythoblast ->erythroblast ->reticulocyte
in blood: reticulocyte-> erythrocyte

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6
Q

describe the symptoms of tissue hypoxia?

A

Brain-sleepy, fatigue
Heart – decreased work capacity, tachycardia, pump failure
Lung-dyspnea, respiratory reserve declines
Skeletal muscle-weakness, fatigue

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7
Q

what are the signs and symptoms of anaemia?

A

headache, dizziness, fatigue, chest pain, SOB, pallor, tachycardia, murmurs

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8
Q

what are the potential causes of anaemia?

A 
Hematuria
Prregnancy
Nutritional deficiency
GI pathologies
Menorrhagia
Haemorrhoids 
Hook worms
Iron deficiency
Red cell maturation disorders
Hemolytic anaemia
Acute bleeding 
Marrow damage
Inflammation
Neoplasia
Chronic disease
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9
Q

how is a diagnosis of anaemia made?

A

History
Examination
Laboratory (Depends on history-family history, clinical findings, ethnicity, morbidity, previous treatments, base line laboratory results)
Interpret clinical findings

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10
Q

describe microcytic anaemia?

A

Low MCV

Ferritin (either deficient- establish cause or ferritin normal-anaemia of chronic disease or hemoglobinopathy)

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11
Q

describe normocytic anaemia?

A

Normal MCV
Reticulocyte count
-High-hemolysis or blood loss
-Low-anemia of chronic disease, renal failure, marrow failure

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12
Q

describe macrocytic anaemia?

A

High MCV

Measure B12 and folate

  • Normal-obvious cause or cause not obvious so consider bone marrow
  • Low-establish cause
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13
Q

what are the dietary sources of iron?

A

red meat, certain vegetables (spinach, brocholi, iron fortified cereals.
Haem iron in meat
Non haem iron in dairy products, eggs, legumes

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14
Q

describe iron absorption?

A

Can only lose iron from bleeding
Gastric acid keeps iron soluble and iin ferrous state
Duodenum
Mucosal cells regulate quantitiy of iron absorbed

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15
Q

what are the issues with iron excess?

A

injury to organs

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16
Q

what are the signs and symptoms of iron deficiency?

A 
Hair loss
Depressed
SOB
Tired/fatigue
Restless legs syndrome
Headaches
Cold
brittle nails
Need to give iron treatment for 4-6 months
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17
Q 
describe the levels of 
1. Hb
2. other Fe functions
3. stores (SF)
in mild deficiency
A
  1. normal
  2. normal/low
  3. normal/low
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18
Q 
describe the levels of 
1. Hb
2. other Fe functions
3. stores (SF)
in marginal deficiency
A
  1. normal
  2. low
  3. low
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19
Q 
describe the levels of 
1. Hb
2. other Fe functions
3. stores (SF)
in severe deficiency
A
  1. low
  2. low
  3. low
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20
Q

describe the progressive depletion of iron stores?

A

normal-> depletion of iron stores -> iron deficiency erythropoiesis ->iron deficiency anaemia

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21
Q

how are iron levels measured?

A

Serum iron level (transferrin bound ferric iron)
Total iron binding capacity (measure of transferrin protein)
Percentage transferring saturation
Serum ferritin
Bone marrow iron stores
Plasma transferrin receptor

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22
Q

what are the causes of iron deficiency?

A 
Increased physiological demand
Blood loss
Malabsorption
Dietary deficiency
Increased demand or decreased intake/absorption
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23
Q

what are the risk factors for iron deficiency?

A

Dietary factors
Demographic factors
Social/physical factors

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24
Q

describe how a diagnosis of iron deficiency anaemia is made?

A

Microcytic hypochromic anaemia
Serum iron decreased
TIBC increased
Percentage transferrin saturation decreased
Serum ferritin decreased
Absent bone marrow haemosiderin
Reduced Hb, MCV, MCH, MCHC, serum ferritin, serum iron, TSA.blood film,

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25
how can a source of blood loss be found?
``` FOB Upper GI endoscopy Colonoscopy Small bowel enema Capsular entroscopy (if other investigations negative) Gynae referral Blood loss from urinary tract? No value for barium meal/enema studies to ascertain cause of GI blood loss-NOT ROUTINE ```
26
what is the management for iron deficiency?
``` Diet Personal care Manage blood loss Oral iron parenteral iron blood transfusion ```
27
describe the use or oral iron?
Non enteric coated (preferable) Replace iron deficit in total, correct anaemia and MCV, replenish iron stores Failure: poor compliance, excessive loss, poor absorption, coeliac disease, underlying inflammation, malignancy, combined deficiency, wrong diagnosis
28
describe the use of parenteral iron?
Iron dextran –cosmofer Iron sucrose – venofer Ferric carboxymaltose – ferinject Iron isomaltoside 1000 – monofer (PREFFERED) Indications: oral iron intolerance, GI upset eg crohns or UC, extensive small bowel resection, severe IDA 3rd trimester pregnancy, pre EPO in CRF
29
what are the causes of macrocytic anaemia?
B12 deficiency, folate deficiency, liver disease, alcohol excess, hypothyroidism, drugs
30
what are the types of macrocytic anaemia?
megaloblastic | non megaloblastic
31
what are the causes of megaloblastic macrocytic anaemia?
Vitamin B12 deficiency Folate deficiency Drugs-methotrexate, zidovudine, metformin (decreases B12 absorption)
32
what are the causes of non-megaloblastic macrocytic anaemia?
Alcohol abuse Liver disease Myelodysplasia hypothyroidism
33
what are the investigations for macrocytic anaemia?
- Endoscopy-Gastric biopsy (b12), buodenal biopsy (folate) - Bone marrow-Mds, aplastic anaemia, myeloma - Folate deficiency-Autoantibody screen for coeliac - B12 deficiency-Auto antibodies (GPC, IF), diacopac, gastrin assay - Macrocytosis-B12, folate, LFT, TFT, reticulocyte count, EP
34
what are the sources of b12?
Basic structure can only be synthesized by bacteria and human body convert to various forms Sources-everything that walks, swims or flies but nothing that grows out of the ground
35
why is b12 important?
Key to normal functions of brain, CNS, and blood Involved in DNA synthesis Sub acute combined degeneration: patchy loss of myelin in posterior and lateral columns, weakness, glove and stocking paresthesia, vision disturbances, mental disturbances, bilateral spastic paresis.
36
what are the causes of b12 deficiency?
``` Diet Malabsorption (gastric, intestinal) Drugs (H2 receptor antagonists, PPI, metformin Vegan, poor diet PA gastrectomy Crohns Stagnant loop Ileal resection ```
37
what is needed for b12 absorption?
``` intrinsic factor (parietal cells) intrinsic factor is a glycoprotein. vitamin b12 combines with intrinsic factor to form a complex that can resist GIT enymes and is absorbed in the terminal ileum by pinocytosis. it is transported to the liver where it is stored ```
38
what is the treatment for B12 deficiency if there are no neurological symptoms?
Initially 1mg 3x a week for 2 weeks then 1mg every 3 months
39
what is the treatment for B12 deficiency if there are neurological symptoms?
Initially 1mg on alternate days until no further improvement then 1mg every 2 months
40
what are the side effects of B12 injections (hydroxocobalamin)?
Nausea, headache, dizziness, fever, hypersensitivity reactions (rash and pruritis), injection site pain, hypokalaemia during initial treatment
41
what is the role of folic acid?
``` Water soluble (B9, Bc) DNA synthesis, DNA repair, cofactor in biological reactions, rapid cell growth ```
42
describe the features of folic acid deficiency/
``` Macrocytic anaemia Diarrhoeas Fatigue and tiredness Bald, swollen tongue Mental onfusion, forgetfulness, cognitive disability Neural tubular defects in embryos ```
43
what are the causes of folate deficiency?
``` Diet Malabsorption Increased demand eg pregnancy Increased loss Drugs (anticonvulsants, sulphasalazine, metformin, methotrexate, triamterene, barbiturates) Increased requirements ```
44
what is the treatment of folate deficiency?
Oral folic acid 5mg daily Prophylaxis in pregnancy
45
describe the features of heamoglobin s?
Participation in molecular polymerization of deoxy-Hb Erythrocytes of heterozygous (sickle cell trait) individuals have been shown to resist invasion by malarial parasites which improves protection against plasmodium falciparum
46
describe sickle cell crisis/
``` More likely to have a sickle crisis during anaesthesia Vaso-occlusive crisis Painful crisis Sequestration crisis Infections ```
47
what is the treatment for sickle cell crisis?
Hydration Analgesia Antibiotics Blood transfusion
48
what are the classifications of thalassemia?
``` Thalssemia major Thalassemia trait Hb-H disease Hydrops fetalis Silent carrier ```
49
what is thalassemia?
Hereditary anaemias due to mutations affecting synthesis of Hb In beta thalassaemia there is a deficient synthesis of beta globin Alpha thalassaemia-deficienct synthesis of alpha globin Reduced synthesis of one of two globin polypeptides leads to deficient haemoglobin accumulation, resulting in hypochromic and microcytic red cells
50
what is thalassemia trait?
mild and clinically significant anaemia that apparently protects individuals from malaria, and therefore through natural selection it has become extremely common in some parts of the world
51
how is a laboratory diagnosis of thalassemia made?
``` FBC- low MCV, high RBC-test for HBA2 and HBF Ante natal screening Partner screening for ante natal clinic FBC on parents following positive newborn screening Family screening Iron status check Hb electrophoresis Hb column chromatography Newborn blood screening at 5-8 days ```
52
what are the types of haematological malignancies?
- Lymphoid-derived from neoplastic lymphocytes - Myeloid-derived from neoplastic neutrophil precursors (in bone marrow) - Both types present with similar symptoms, non specific
53
give examples of myeloid malignancies?
``` Acute myeloid leukaemias Myelodysplastic disorders Chronic myeloid leukaemia Juvenile chronic myeloid leukaemia Polycythemia rubra vera Essential thrombocythaemia chronic myelomonocytic leukaemia Myelofibrosis Myeloproliferative neoplasm unspecified Hypereosinophilic syndromes Systemic mastocytosis Paroxysmal haemoglobinuria ```
54
give examples of lymphoid malignancies?
``` Diffuse large B cell lymphoma Follicular lymphoma Hodgkin lymphoma Mantle cell lymphoma Burkitts lymphoma Acute lymphoblastic leukemia Chronic lymphocytic leukemia Hairy cell leukaemia Waldenstroms macroglobulinaemia Large granular lymphocytic leukaemia Marginal zone lymphomas Myeloma Other plasma dyscrasias AL amyloidosis Heavy and light chain deposition diseases Peripheral T cell lymphoma Anaplastic large cell lymphoma Mycosis fungiodes Sezary syndrome ```
55
describe the presentation of lymphoma?
Incidental finding of raised WCC Lymphadenopathy (usually painless, lump in neck or groin, slowly getting bigger) Sweats (pathological=drenching sweats often at night to point where they have to change clothes) Pruritis (itching)-hodgin lymphoma Weight loss (pathological=loss of 10% or more unintentionally) splenomegaly
56
describe the presentation of myeloid disorders?
Weight loss Fatigue Splenomegaly Intermittent spiking fevers
57
what blood results are typically seen in bone marrow failure?
``` Hb- anaemia MCV raised Neutropenia Thrombocytopenia Abnormal white cells –blood films ```
58
describe infections seen in patients with haematological maignancies?
Increased risk for patients with haematological malignancies Direct infiltration of marrow- neutropenia and increase risk of bacterial and fungal infections Atypical infection risks increased Myeloma-cause neutropenia and failure to produce normal IG causing hypogabagloblinaemia Multiple myeloma-herpes zoster Pneumococcal sepsis- bone marrow failure Varicella zoster-chronic lymphocytic leukaemia
59
what is the cause of bone pain in myeloma?
osteolytic lesions due to increased bone turnover, inhibition of osteoblast
60
describe the relationship between gout and haematological malignancy?
Increased cell turnover Hyperuricaemia Myelofibrosis associated
61
describe the relationship between neurological problems and haeatological malignancy?
Focal neurology Spinal cord compression Present with spinal cord compression due to malignancy Peripheral neuropathy-myeloma, amyloidosis
62
describe the common presentation of haematological malignancies?
``` Incidental blood count Symptomatic anaemia Bleeding-minor/major Infection Lymphadenopathy-unresolved for 4-6 weeks Pain-bone, abdominal Medical/surgeical emergency Unexplained weight loss, sweating, dyspnea Non-specific symptoms of tiredness and lethargy Medical co-morbidity-VTE, TIA, CVA ```
63
what information is it important to give to patients with haematological malignancies?
``` Diagnostic information Explanation of diagnosis Confirming malignancy Explain results of investigations Discuss management options Discuss prognosis Explain chemotherapy Look for special needs Written information about diagnosis and treatment National/local self help groups Offer internet sites Discuss fertility Wig Work Attending for chemptherapy Role of GP and other services Family and financial support Care in community ```
64
what tests would be of use in patient with acute leakemia?
``` bloods PB immunophenotyping bone marrow BM karotyp X-rays ```
65
what tests would be of use in a patient with chronic leakemia?
``` bloods PB immunophenotyping bone marrow BM karotyp X-rays ```
66
what tests would be of use in a patient with MPD?
``` bloods PB immunophenotyping bone marrow BM karotyp X-rays ```
67
what tests would be of use in a patient with MDS?
``` bloods PB immunophenotyping bone marrow BM karotyp X-rays ```
68
what tests would be of use in a patient with lymphoma?
``` bloods LN biopsy bone marrow X-rays CT scan PET ```
69
what tests would be of use in a patient with myeloma?
``` bloods bone marrow X-rays MRI PET ```
70
describe myeloid maturation?
``` myeloblast promyelocyte myelocyte metamyelocyte band neutrophil ```
71
what are lymphomas?
Neoplasms of lymphoid origin, typically causing lymphadenopathy Leukaemia vs lymphoma Lymphomas as clonal expansions of cells at certain developmental stages
72
describe biologically rational classification for lymphoma?
Diseases that have distinct morphology, immunophenotype, genetic features, clinical features
73
describe clinically useful classification for lymphoma?
Diseases that have distinct clinical features, natural history, prognosis and treatment
74
what are the types of B cell neoplasms?
Precursor B cell neoplasms Mature B cell neoplasms B cell proliferation of uncertain malignant potential
75
give examples of T cell and NK cell neoplasms?
Precursor T cell neoplasms Mature T cell and NK cell neoplasms T cell proliferation of uncertain malignant potential
76
what are the types of hodgkin lymphoma?
Classical Hodgkin lymphomas | Nodular lymphocyte predominant hodgkin lymphoma
77
what are the mechanisms of lymphomagnesis?
Genetic alterations Infections Antigen stimulation Immunosuppression
78
describe the epidemiology of lymphomas?
5th most frequently diagnosed cancer overall for men and women Hodgkin lymphoma bimodal age groups rise in 20s and 70s Males>female Incidence -NHL increasing over time -Hodgkin lymphoma stable -9750 cases of NHL diagnosed in UK each year and 4450 deaths -1350 diagnosed with HL in UK each year and 300 deaths
79
describe outcomes ofhodgkin lymphoma?
variable survival if untreated mostly curable should be treated
80
describe outcomes of indolent non hodgkin lymphoma?
survivial for years in untreated generally not curable Defer treatment if asymptomatic
81
describe outcomes for aggresive no hodgkin lymphoma?
survival for months if untreated curable in some cases should be treated
82
describe outcomes for very aggresive non hodgkin lymphoma?
survivial for weeks if untreated curable in some should treat
83
what are the risk factors for non hodgkin lymphoma?
``` Immunosuppression or immunodeficiency Connective tissue disease Family history of lymphoma Infectious agents Ionizing radiation ```
84
describe the clinical manifestations of non hodgkin lymphoma?
Variable - Severity – asymptomatic to extremely ill - Time course-evolution over weeks, months or years Systemic manifestations -Fever, night sweats, weight loss, anorexia, pruritis Local manifestations - Lymphadenopathy, splenomegaly most common - Any tissue potentially infiltrated
85
what are the potential complications of lymphoma?
``` Bone marrow failure CNS infiltration Immune hemolysis or thrombocytopenia Compression of structures (spinal cord, ureters) y bulky disease Pleural/pericardial effusions, ascites ```
86
how is a diagnosis of lymphoma made?
Biopsy proven before initiating treatment | Need enough tissue to assess cells
87
what are the types of non hodgkin lymphoma?
Follicular lymphoma Diffuse large B cell lymphoma other NHL
88
what are the stages of lymphoma?
1. neck lymph 2. neck + axilla 3. neck+axilla+groin +abdo lymph 4. all of above +liver +pelvis
89
describe follicular lymphoma?
``` Most common type of ‘indolent’ lymphoma Usually widespread at presentation Often asymptomatic Not curable Associated with BCL-2 gene rearrangement [t(14;18)] Cell or origin-germinal center B cell Watch and wait if asymptomatic Chemotherapy is symptomatic Median survival – years Transformation to aggressive lymphoma can occur ```
90
what is the treatment for follicular lymphoma?
``` Rituximab based chemotherapy Relapse -2nd line chemotherapy followed by ASCT -Maintenance rituximab for 2 years -Zevlin (yattrium labelled anti CD20 antibody Commonly used in uk -RCHOP -RCVP -Trial shows RCHOP is better than RCVP or RMCP ```
91
describe diffuse large B cell lymphoma?
``` Most common type of aggressive lymphoma Usually symptomatic Extranodal involvement is common Cell of origin-germinal center B cell Treatment should be offered Curable 40% ```
92
describe the management of diffuse large B cell lymphoma?
Localised -RCHOP X4 cycles followed by involved field RT (IFRT) Stage IIB-IV -RCHOP X minimum 6 maximum 8 cycles Relapse following chemotherapy -2nd line chemotherapy (various all approximately equally effective) -ASCT
93
describe hodgkin lymphoma?
Cell of origin – germinal centre B cell Reed-Sternberg cell (or RS variants) in the affected tissues Most cells in affected lymph node are not polyclonal reactive lymphoid cells, not neoplastic cells Epideiology – less frequent than non Hodgkin lymphoma / M>F / peak incidence in 3rd decade
94
what are the associated factors with hodgkin lymphoma?
EBV infection Smaller family size Higher socio-economic status Caucasian>non caucasian
95
what is the possible mode of pathogenesisfor hodgkin lymphoma?
Germinal centre B cell - > transforming event such as EBV -> RS cell leading to loss of apoptosis and cytokines leading to inflammatory response
96
what are the histological subtypes of classical hodgkin lymphoma?
Nodular sclerosis (most common) Mixed cellularity Lymphocyte-rich Lymphocyte depleted
97
what are the clinical manifestations of hodgkin lymphoma?
Lymphadenopathy Contagious spread Extranodal sites relatively uncommon except in advanced disease ‘B’ symptoms
98
describe treatment and survival for stage I or II hodgkin lymphoma?
ABVD x4 and radiation 70-80% failure free survival 80-90% overall 5 yr survival
99
describe treatment and outcome for stage III, IV hodgkin lymphoma?
ABVD X6 60-70% failure free survival 70-80% 5 yr survival
100
what are the long term complications of treatment for hodgkin lymphoma?
Infertility MOPP >ABVD / males>females Sperm banking should be discussed Premature menopause Secondary malignancy Skin, AML, lung, MDS, NHL, thyroid, breast Cardiac disease
101
describe myeloproliferative disease?
Neoplastic disorder of hemopoietic stem cells Over production of all cell lines, with usually one line in particular Fibrosis is a secondary event Acute myeloid leukemia may occur
102
what are the types of myeloproliferative disease?
Polycythemia (rubra) vera (PRV, PV) Essential (primary) thromocythemia Myelofibrosis (with myeloid metaplasia), agnognic myeloid metaplasia (MF, MMM, AMM)
103
describe normal platelet reguation?
thrombopoietin Constitutive production of thrombopoietin by liver Bound by platelets Excess stimulates megakaryopoiesis
104
describe issues with platelet regulation in primary/essential thrombocytosis?
Neoplastic stem cell disorder causing dysregulated production of large numbers of abnormal platelets Some cases non-clonal (esp young women) Abnormal platelets aggregate in vivo causing thrombosis Abnormal platelets also cause bleeding
105
what are the clinical features of essential thrombocytosis?
``` None Erythromelagia Peripheral vascular occlusion Transient ischaemic attack Stroke bleeding ```
106
describe making a diagnosis of essential thrombocytosis?
Distinguish from reactive thrombocytosis and chronic myeloid leukemia Secondary causes to be excluded-haemorrhage, infection, trauma, recent surgery, recent chemotherapy, drug induced Clinical setting, blood film, bone marrow and cytogenetics help
107
describe the management of essential thrombocytosis?
Low risk – (age <40 ,platelet count upto 600/aspirin 75mg/d Intermediate risk (age 40-60, platelets 600-1000) hydroxycarbamide / anagrallide / aspirin 75mg/d) High risk –(age >60, platelets>1000, other risks) hydroxycarbamide/ aspirin 75mg/d)
108
what is polycythaemia rubra vera?
A neoplastic (clonal JAK-2 mutation) stem cell disorder, which leads to excessive production of all myeloid cell lines, but predominantly red cells. The increase in whole blood viscosity causes vascular occlusion and ischemia, compounded by increase in platelets
109
what are the secondary causes of polycythemia?
Smoking, COPD, coal miners, high altitude, haepatoma, renal diseases, uterine fibroids
110
what are the clinical features of polycythaemia rubra vera?
``` Headaches Aqua pruritus Vascular occlusion Thrombosis TIA, stroke Splenomegaly ```
111
how is a diagnosis of polycythaemia rubra vera made?
Exclude secondary polycythemia | Look for features of primary polycythemia
112
what is the management for polycythaemia rubra vera?
Phlebotomy treatment of choice reduce haematocrit Low dose aspirin 75mg/day Hydroxycarbamide –if v/s unsuccessful or associated leukocytosis or thrombocytosis Do not treat with iron
113
what is myelofibrosis?
Hemopoietic stem cell disorder Distinguish from secondary marrow fibrosis Bone marrow failure Myeloid metaplasia (neoplastic (clonal) extra-medullary hemopoiesis)
114
what is the management for myelofibrosis?
Supportive care Regular blood transfusion Treat iron overload due to blood transfusion Thalidomide may be useful to reduce splenomegaly Splenectomy in selected patients Allo BMT for younger patients
115
what is the presentation of myelofibrosis?
Normocytic anaemia Anaemia transfusion dependent Abnormal blood film-lecoerythroblastic with tear drop RBCs Splenomegaly (one of the causes of massive splenomegaly Splenic infarts
116
how do you make a diagnosis of myelofibrosis?
``` Typical blood picture Splenomegaly Bone marrow aspirate-dry tap Marrow fibrosis on trephine biopsy Absence of other cause of splenomegaly and marrow fibrosis ```
117
how do lymphomas usually present?
``` Asymptomatic lump Incidental finding ‘B’ symptoms -Lumps -Sweats -Weight loss ```
118
describe the presentation of lymphomas due to complications?
Infection – bacterial / atypical / viral Immune – AIHA / ITP / vasculitis Chemistry – hypercalcaemia / renal failure Coagulopathy Marrow failure Neurology – neuropathy / cerebral / spinal deposits Obstruction – SVC / biliary / bowel
119
describe how a diagnosis of lymphoma is made?
``` Tissue sample Cytochemistry with makers Cytology + immunophenotyping Conventional cytogenetics Fluorescent In-Situ Hybridisation (FISH) Molecular studies ```
120
describe the use of PET scans in diagnosing lymphomas?
``` Injection of 18-Fluorodeoxyglucose (FDG) Glucose analogue labelled with Fluorine 18 Metabolically active areas highlighted Baseline assessment Response assessment ```
121
what is diffuse large B cell lymphoma?
The histologic features of all three components (large immunoblasts and centroblasts, small lymphocytes and histiocytes) of this NHL are most evident in this view. In addition scattered eosinophils can also be seen. A diagnosis of diffuse large B-cell lymphoma, T-cell/histiocyte rich variant was confirmed on flow cytometric analysis and immunohistochemistry.
122
what is the revised international prognostic index (R-IPI)?
``` used for large B cell lymphoma Score 1 point for Age >60 Stage III/IV >1 extranodal site Performance status >1 Raised LDH ``` Three groups:- Very good PFS 94% Good PFS 80% Poor PFS 53%
123
describe the treatment for diffuse large B cell lymphoma?
``` Depends on clinical stage. Patient specific (Fertility, Side effects, Age / co-morbidities / fitness) Clinical trials when available Patient education and support Chemotherapy ```
124
describe the use of chemotherapy in diffuse large B cell lymphoma treatment?
Localised disease, stage I/II -Rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone (RCHOP) x 3, followed by radiotherapy to the involved sites. Bulky (>10cm) stage I/II disease, stage III/IV disease -RCHOP x 6
125
describe follicular lymphoma?
``` Variable presentation and course. Asymptomatic in many. Treatment only for symptomatic / progressive disease. Risk of high grade transformation. Incurable ```
126
what is used to assess prognosis of follicular lymphoma?
FLIPI to assess prognosis: | Based on age <>60, number of nodal sites <>3, LDH normal/elevated, haemoglobin <>120g/L, Stage I/II vs III/IV
127
describe treatment of follicular lymphoma?
Watch and wait. Radiotherapy for localised stage I/II disease. Rituximab-based chemotherapy for symptomatic generalised disease. Rituximab monotherapy Rituximab chlorambucil. Rituximab cyclophosphamide vincristine prednisolone. Rituximab fludarabine cyclophosphamide. BCR inhibitors idelalisib or ibrutinib. Stem cell transplantation for relapsed disease.
128
describe staging designations for lymphoma?
Ann Arbor staging I/II/III/IV, extranodal (E) A - no symptoms B – Temp > 38oC, night sweats, 10% wt loss over <6 months Pruritis not B symptom International prognostic score for advanced stage
129
describe chemotherapy used to treat hodgkin lymphoma?
Anthracycline based adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) – Gold standard. Alkylator based chlorambucil, vinblastine, procarbazine, prednisolone (ChlVPP). Dose intensified alkylator Bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine, prednislone BEACOPP
130
describe the role of radiotherapy post chemotherapy in treating hodgkin lymphoma?
No evidence of benefit if in CR. Patients with PR post chemotherapy receiving DXT to residual mass similar outcome to those in CR. Late toxicity, especially breast Ca. Mantle DXT < 15 years, 136x increase in risk of breast Ca. Baseline risk if irradiated > 30 years.
131
describe the presentation of myeloma?
``` Pain from osteolytic bone lesions Renal issues Anaemia Bone problems Infections – immunepariesis ```
132
what are the laboratory features of myeloma?
``` Routine biochemistry (Raised calcium, Raised urea & creatinine, Raised total protein) Beta 2 microglobulin - prognostic ESR / PV is usually markedly elevated Bone marrow increased plasma cells M band in serum M band in urine (BJP) Serum free light chains Blood film (Anaemia, Rouleaux, Background staining) ```
133
describe the course and prognosis of myeloma?
``` Death -aggressive tumour growth -bone marrow failure -Infection -skeletal complications -renal failure. Median survival was 3 years Modern therapy >6 years or more ```
134
what are the predisposing factors for acute myeloblastic leukaemia?
Radiation, benzene, previous chemo clonal haematological states Inherited bone marrow failure conditions, downs
135
what are the clinical features of acute myeloblastic leukaemia?
Bone marrow failure Extramedullary involvement, usually monocytic subtypes. Granulocytic sarcomas. Hyperleukostasis, WCC > 100 x 109/l
136
describe the WHO classification of acute myeloblastic leukaemia?
AML with recurring cytogenetic abnormalities (15:17, inv16, 8:21, 11q MLL rearrangements). Therapy related AML AML with multilineage dysplasia AML not otherwise classified
137
what subgroups have a good prognosis from acute myeloblastic leukaemia?
Defined by cytogenetics 8:21. 15:17, PML - RAR, responds to ATRA, associated with hyperfibrinolysis. Inv 16
138
describe acute myelocytic leukaemia?
Associated with 15:17 PML:RARa. Good prognosis, 70% 5 year overall survival. Coagulopathy can be fatal. Sensitive to ATRA and arsenic trioxide.
139
describe the treatment of non-APL AML?
Remission induction using anthracycline / nucleoside + cytosine. 2-3 subsequent courses of consolidation chemotherapy. Allo SCT for high risk patients (adverse cytogenetics, relapsed patients). Good risk genetics– 65-70% 5year survival. Standard risk genetics– 55 % 5 year survival Poor risk genetics– 20-30% 5 year survival. Elderly >65years 10% 5 year survival
140
describe the treatment of acute lymphoblastic leukaemia?
Combination chemotherapy with intrathecal methotrexate as induction. Consolidation therapy using high dose methotrexate for CNS prophylaxis. Allo SCT for high risk cases (poor risk genetics, relapse). Maintenance chemotherapy for up to 2 years, not required for B cell ALL.
141
what is the prognosis for acute lymphoblastic leaukaemia?
50-60% response rate in adults 20-40% 5 year survival. Better results in children
142
describe the features of chronic lymphocytic leukaemia?
``` Indolent B lymphoproliferative disorder Commonest adult leukaemia in West. Males>females. Increases with age (Median age 65) Lymphocytosis, clonal mature B cells Lymphadenopathy Hepatosplenomegaly ```
143
how is a diagnosis of chronic lymphocytic leukaemia made?
Peripheral blood B cell lymphocytosis, 5×109/L (NCI) Bone marrow infiltration (>30%) Characteristic immunophenotype: sIg (weak), CD5+, CD23+, FMC7­, CD79b+ (weak), CD19+/CD5+
144
describe the treatment of chronic lymphocytic leukaemia?
``` Only for symptoms or progressive disease No benefit for early treatment Chlorambucil Bendamustine +/- rituximab Fludarabine, Cyclophosphamide, Rituximab Campath (anti CD52) Novel targeted therapies. Solitary plasmacytomas radiotherapy MGUS and asymptomatic Myeloma do not require therapy Patients less than 70 years Thalidomide/lenalidomide/bortezomib containing combination therapy autologous stem cell transplant with high dose Melphalan Older patients attenuated regimens Bisphosphonate for myeloma-bone disease. ```
145
what are the indications of therapy for chronic lymphocytic leukaemia?
``` Constitutional symptoms referable to CLL Progressive marrow failure Anaemia and/or thrombocytopenia Massive or progressive splenomegaly Massive or progressive lymphadenopathy Progressive lymphocytosis ```
146
describe the features of CML?
Rare Diagnosed incidentally or following development of systemic symptoms, splenomegaly or gout. Characterised by Philladelphia chromosome (t9:22), producing constitutive activation of Abl kinase. Risk of transformation to acute leukaemia.
147
what is the treatment for CML?
``` Tyrosine kinase inhibitors:- Imatinib Nilotinib Dasatanib Posnatinib Bosutinib Allogeneic transplantation for refractory/resistant/transformed cases. ```
148
what is myeloma?
``` Malignant plasma cells (terminally differentiated b cells that produce IgG, iGA (IgD)- identifiable ammonut of monoclonal immunoglobulin 9m band) Monoclonal immunoglobulin (m band) ```
149
how is myeloma usually diagnosed?
``` Incidentally or symptomatically Patients with renal failure should be screened for myeloma Average age presentation in 70s At least one of -Renal dysfunction, hypercalcaemia, bone damage, anaemia ->1 bone lesion on whole body MRI/CT/PET -Free light chain ratio >100 ->60% plasma cells in bone marrow ```
150
describe the presentation of myeloma?
Pain from osteolytic bone lesions Renal issues Anaemia Bone problems Amyloidsis –displation of amyloid protein Infections –immuneparesis eg due to neutropenia
151
what are the laboratory features of myeloma?
Blood film–anaeia or rouleaux (sticky chain of red cells on blood film this isn’t specific for myeloma also in acute phase response or waldenstrome macroglobinemia) Raised calcium, urea, creatinine, protein Beta 2 macroglobulin-prognostic ESR/PV elevated Bone marrow increased plasma cells M (monoclonal) band in urine or serum Serum free light chaing Electrophoresis-identify type and level of M protein, may show marked immune paresis 60% IgG, 20% IgA, 20% light chain only, rarely IgD, E,M or non secretory
152
describe the course and prognosis of myeloma?
Determined by international staging system and cytogenetics Stage1 beta 2 macroglobulin <3.5mg/l, albumin >35g/l – 62 months Stage 2 beta 2 macroglobulin 3.5mg/l and/or albumin <35g/l – 44 months Stage 3 beta 3 macroglobulin >5.5mg/l -29 months
153
what are the other investigation findings found in a patient with myeloma?
Bone marrow aspirate – if more than 10% WC are plasma cells this is dianostic of myeloma Enlarged plasma cell with enlarged golgi Poor prognosis – immunoglobulin G rearrangements on chromosome 14 (2-3 yr survival), 17p chromosome (p53 protein) Pathological fractures / spinal cord compression (steroid and radiotherapy) Punched out lesions in skull (pepperpot skull)
154
what is the therapy given for treatment of myeloma?
Asymptomatic – observe 10% risk of progression to symptomatic per year Solitary plasmacytoas radiotheraoy MGUS and asymptomatic myeloma don’t require therapy Patients less tha 70 Thalidomide/lenalidomide / bortezomib containing combination therapy Autologous stem cell transplant with high dose melphalan Older patients attenuated regimens Bisphosphonate for myeloma bone disease
155
what is sickle cell anaemia?
Haemaglobinopathy Heamaglobin –iron haem complex, 2 beta and 2 alpha chaing Occur when there is mutation to alpha or beta change
156
what does thalassemia mean?
reduction in haemaglobin
157
what does haemaglobinopathy mean?
structural change in Hb
158
describe the structure of habmoglobin in sickle cell anaemia?
Mutation in beta globin change Glutamine for valine at position 6 Production of haemoglobin S (2 alpha and 2 abnormal beta) Genetics-Autosomal recessive Hb S has a tendency to polymerise when deoxygenated and produces long insoluble chains, abnormal shape, cant pass through capillary vessels
159
how is a diagnosis of sickle cell anaemia made?
family history, anaemic, blood film analysis (some sickle shape, some normal), detect abnormal Hb using electrophoresis, HBAC, mass spec
160
what are the clincial features of sickle cell anaemia in children?
Children – delayed growth, dactylitis, splenic infarct, aplastic crisis, cardiac, respiratory, renal problem
161
what are the clinical features of sickle cell anaemia in adults?
Adults-acute resp failure, cardiac failure, liver failure, renal problem, vascular necrosis of hip, chronic ulcer, increase stroke risk
162
where is there a high rate of inheritance of sickle cell anaemia?
Inheritence associated with areas where malaria is prevalent due to protection. Middle east, sub sahara Confers survival advantage
163
describe the risks associated with sickle cell anaemia?
Sepsis leading cause of mortality particulary in developing countries Underlying immune dysfunction related to hyposplenism Mainly encapsulated bacteria Highest risk under age of 5 Pneumococcal vaccination and prophylactic penicillin needed
164
what are the clinical issues with sickle cell anaemia and how are they resolved?
Painful vaso-occlusive crisis – bone bain, in children-phalanges. Management with rest and rehydration, analgesia Acute chest syndrome - increasing pain in ribs with associated increasing SOB, hypoxaemic. Manage pain, red cell exchange to suppress Hb S <30%. Significant mortality in developed countries Leg ulcers-vaso-occlusion over medial and lateral malleolus, supportive management, persist for months or years Stroke – thrombtic stroke, stenosis of internal carotid artery due to intimal hyperplasia. Hypertransfusion (regular), screen children for carotid stenosis Anaemic crisis – aplastic criss, parovirus, splenic sequestration Hydroxycarbomide (chemotherapy) for patients with recurrent problems, OD
165
what are the causes of microcytic anaemia?
``` SIT Sideroblastic Iron deficiency Thalassemia Anaemia of chronic disease ```
166
what are the causes of normocytic anaemia?
Acute blood loss Haemolytic anaemia Sickle cell Anaemia of chronic disease
167
what are the causes of megaloblastic anaemia?
Megaloblastic: -b12/folate deficiency Non megaloblastic - alcohol - reticulocytosis - liver disease - pregnancy Hypothyroidism Bone marrow failure (aplastic anaemia, myelodysplasia, leukaemia, myelofibrosis)
168
what does high neutrophil count suggest?
``` bacterial infection inflammation necrosis corticosteroids malignancy stress ```
169
what does low neutrophil level suggest?
``` post chemotherapy agranulocytosis causing drugs (4C's-carbamazepine, clozapine, colchicine, carbimazole) viral infection hypersplenism bone marrow failure felty's syndrome ```
170
what does a high lymphocyte count suggest?
viral infection chronic infection CLL/lymphoma
171
what does a low lymphocyte count suggest?
``` viral infection HIV post chemo bone marrow failure whole body radiation ```
172
what does a high monocyte count suggest?
bacterial infection autoimmune disease leukaemias/hodgkins
173
what does a low monocyte count suggest?
acute infections corticosteroids leukaemias
174
what does a high eosinophil count suggest?
``` allergy parasite infection drug raactions hypereosinophilic syndrome skin diseases malignancy (hodgkins) ```
175
what does a high basophil count suggest?
``` some leukaemias IgE mediated hypersensitivity inflammatory disorders myeloproliferative disorders viral infection ```
176
what factors can cause physiological variations in the total WBC count?
``` Age Sex Individual variation Diurnal variation Exercise Smoking Emotion Pregnancy Racial variation Drugs Elderly people receiving the flu vaccination ```
177
describe the causes of neutropenia?
``` Impaired production Excessive consumption Ethnic Stable vs progressive Main risk is infections Risk of sepsis increases with neuts < 1.0 x109/L. Neuts > 1 x109/L no increase in infections. ```
178
what should you considerin a patient with lymphopenia?
``` HIV Steroids/immunosuppression Exotic infections SLE/autoimmunity Malignancy/Hodgkins/Aplastic anaemia Rare immunodeficiency states ```
179
what are the primary causes of lymphocytosis?
Monoclonal B lymphocytosis / LPD
180
what are the reactive causes of lymphocytosis?
``` Chronic inflammation Viral infections Autoimmunity Smoking Hyposplenism Physiological stress – sepsis, cardiac, surgery Drug induced ```
181
what is bone marrow aspiration?
Examination of bone marrow to further investigate abnormalities in peripheral blood Aspiration – provides film which can be examined for morphology of development of haemopoietic cells
182
what is trephine?
obtaining bone marrow Trephine provides core of bone which is processed as histological specimen and allows view of bone marrow architecture, cellularity and presence/absence of abnormal infiltrates
183
descrbe the process of bone marrow aspiration?
``` iliac crest local anaesthetic bone marrow needle aspirate marrow make smear with glass slide stain with romanowsky technique or perls' reaction for iron ```
184
what are the indications for trephine to obtain bone marrow?
dry tap obtained with aspiration better assessment of cellularity eg aplastic anaemia better assessment of presence of infiltration or fibrosis
185
what is the technique for trephine?
posterior iliac crest local anaesthetic special needle (longer and wider than aspiration) obtain core of bone fix informalin-decalcify stain with haematoxylin and eosin or reticulin stain
186
how is a diagnosis of anaemia made?
``` Blood film Ferritin Iron Studies B12 -may be low in 20% of normal pregnancies – and will return to normal rapidly post delivery Folate Reticulocyte count Direct antigen test Haemoglobinopathy screen ```
187
what blood result will be seen if a patient is responding appropriately to their anaemai?
high reticulocyte count
188
describe a patient driven diagnosis of anaemia/
Red cell production Iron, b12, folate Control – anaemia of chronic disease / renal problems Structural – sickle, thalassaemia, enzymes Bone marrow – haematological malignancies Infiltration toxicity Red cell loss Red cell loss Bleeding Haemolysis
189
what is the use of measuring ferritin level in diagnosing anaemia?
High MW protein ~ 20% iron Low level → iron deficiency Acute phase protein, normal level does NOT rule out IDA Check alongside a CRP
190
in iron deficiency anemia what will the following levels be like 1. ferritin 2. iron 3. transferrin 4. transferrin saturation
1. low 2. low 3. high 4. low
191
in ihaemochromatosis what will the following levels be like 1. ferritin 2. iron 3. transferrin 4. transferrin saturation
1. high 2. high 3. low 4. high
192
in anaemia of chronic disease what will the following levels be like 1. ferritin 2. iron 3. transferrin 4. transferrin saturation
1. normal/high 2. low 3. low 4. low
193
in haemolytic anemia what will the following levels be like 1. ferritin 2. iron 3. transferrin 4. transferrin saturation
1. high 2. high 3. normal/low 4. low
194
describe the features of anaemia of chronic disease?
20% of anaemias over 65 years of age. Hb 7-10g/L. MCV normal or low. Rest of count normal. Non-progressive anaemia. Often associated with chronic disease. B12/Folate/Ferritin normal. Iron/transferrin/transferrin saturation low. Diagnosis of exclusion. Main differential MDS. Defect of iron incorporation into erythron. No role for oral iron. Erythropoietin +/- IV iron effective at elevating Hb, but unlicensed, risk of thrombosis and cost £500-£1000. Refer if progressive anaemia or other abnormalities in blood count or other evidence of haematological disease
195
describe the features of megaloblastic anaemia?
``` B12 and folate deficiency. Macrocytic anaemia, thrombocytopenia. Characteristic morphological features. Raised bilirubin and lactate dehydrogenase (LDH) due to ineffective erythropoiesis. Lab assays for B12 and folate imperfect ```
196
what is pernicious anaemia?
autoimmune disorder in which there is atrophic gastritis with loss of parietal cells in gastric mucosa with failure of intrinsic factor production and b12 malabsorption
197
what is pernicious anaemia associated with?
Common in elderly Blood group A More common in women Associated with other autoimmune diseases Parietal cell antibodies in 90% of ptients Insidious onset, progressively increasing symptoms Neurological changes can become irreversible if untreated – poynueropathy progressively involveing peripheral neres and posterior and lateral columns of the spinal cord
198
what are the investigations for pernicious anaemia?
Haematological findings – features of megaloblastic anaemia Bone marrow – show megaloblastic erythropoiesis Serum bilirubin –may be raised due to ineffective EPO LDH Serum methylmalonic acid and homocysteine –raised in b12 deficiency Serum vitamin B12 – usually below 160ng/l Serum folate level – normal or high and red cell folate is normal or reduced
199
describe the investigation findings in megaloblastic anaemia
``` Hb - low MCV - raised erythrocyte - low reticulocyte - low leukocyte - low/normal platelet - low/normal serum ferritin - raised plasma lactate dehydrogenalse- high ```
200
what is seen on blood film in megaloblastic anaemia?
oval macrocytosis poikilocytosis red cell fragmentation neutrophil hypersegmentation
201
what factors can impact the likelihood of deveoping anaemia?
IDA causes – think about patient age, wealth and geography. Ethnic effect – diet may differ and chapatti flour has poor iron bioavailability IDA number one worldwide is hookworm – parasitic infection. SLIDE UK elderly - malignancies Young women – high risk of IDA - menorrhagia Western diet contains 15mg iron / day – 10 % can be absorbed – approx 1.5 mg day Daily baseline loss 1mg Menstrual loss 20 mg / month Pregnancy takes 1g iron mother to fetus usage not spread evenly across the pregnancy Iron replacement Vit C promotes iron absorption so can co-administer with iron replacement, tea and coffee impair (polyphenols)

Metabolic and Endocrine (12 decks)

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