Haematology

Question 1

What is the definition an epidemiology of aplastic anaemia?

Answer 1

Aplastic anaemia is defined by pancytopenia (deficiency of all blood cell elements) with diminished haematopoietic precursors in the bone marrow. It is quite rare (2-4 in 1,000,000), can occur at any age and is slightly more common in males.

Question 2

What is the aetiology of aplastic anaemia?

Answer 2

Aetiology:
• Idiopathic (>40%): May be due to the destruction or suppression of the stem cell by autoimmune mechanisms.

• Acquired: Drugs (chloramphenicol, gold, alkylating agents, antiepileptics, sulphonamides, methotrexate, nifedipine), chemicals (DDT [insecticide], benzene), radiation, viral infections (B19 parvovirus, HIV, EBV), paroxysmal nocturnal haemoglobinuria.
• Inherited: Fanconi’s anaemia, dyskeratosis congenita.

Question 3

What are the clinical features of aplastic anaemia?

Answer 3

Slow (months), or rapid (days) onset. History and examination findings can be divided by causes due to anaemia, thrombocytopaenia and leukopaenia:

• Anaemia: Patient may complain of tiredness, lethargy and dyspnoea. On examination, may notice patient to be pale (pallor).
• Thrombocytopaenia: Patient may complain of easy bruising, bleeding gums and epistaxis (nose bleeds). On examination, may notice bruising and petechiae.
• Leukopaenia: Patient may present with multiple bacterial or fungal infections. No hepatomegaly, splenomegaly (as points to myeloproliferative disorders) nor lymphadenopathy. Frequency and severity of infections increased.

Question 4

How can aplastic anaemia be investigated?

Answer 4

Bloods:
• ↓Hb, ↓Platelets, ↓WCC, normal MCV, low or absent reticulocytes. This is to establish pancytopenia.
• Blood film to exclude leukaemia (absence of abnormal circulating white blood cells)

A bone marrow biopsy to show a hypocellular marrow is the definitive test for AA. Moreover, there should be an absence of abnormal cells (exclude malignancy) and no fibrosis (exclude myelodisplastic syndromes), as pancytopenia is common, but AA is not.

Question 5

Define the types of DIC

Answer 5

DIC is a disorder of the clotting cascade that can complicate a serious illness. DIC may occur in two forms.
1. Acute overt form where there is bleeding and depletion of the platelets and clotting factors.

2. Chronic non-overt form where thromboembolism is accompanied by generalised activation of the coagulation system.

Question 6

What is the aetiology of DIC?

Answer 6

Aetiology:
• Infection: Particularly gram-negative sepsis (due to endotoxin).
• Obstetric complications: Missed miscarriage, severe pre-eclampsia, placental abruption and amniotic emboli.
• Malignancy: Acute promyelocytic leukaemia (acute DIC); lung, breast, GI malignancy (chronic DIC).
• Severe trauma or surgery
• Others: Haemolytic transfusion reaction, burns, severe liver disease, aortic aneurysms, haemangiomas.

Question 7

What are the clinical features of DIC?

Answer 7

Patient already severely unwell with symptoms of underlying disease. Symptoms and signs associated with DIC include:
• Petechiae, purpura, epistaxis, ecchymoses, mucosal bleeding and overt haemorrhage. Generalised bleeding in at least 3 different locations is highly suggestive of DIC.
• Delirium, confusion or coma.
• Oliguria, hypotension, or tachycardia (circulatory collapse)
• Purpura fulminans, gangrene or acrocyanosis.

Question 8

How can DIC be investigated?

Answer 8

Bloods: 
	• FBC (↓platelets, ↓Hb)
	• Clotting (↑APTT/PT/TT)
	• ↓fibrinogen
	• ↑fibrin degredation products and d-dimers.

Blood film may show schistocytes (RBC fragments).

Question 9

What is the definition and epidemiology of Haemochromatosis?

Answer 9

Haemochromatosis is a multisystem disorder resulting from excessive intestinal iron absorption which may lead to organ damage (particularly liver, joints, pancreas, pituitary and heart).

The most common form occurs mainly in people of northern European descent. Carrier frequency is ~1 in 10, but not all express disease. Prevalence of those affected 1 in 400. Typical age of presentation is 40-60 years. Females have a later onset and a less severe presentation as a result of iron loss through menstruation.

Question 10

What is the aetiology of Haemochromatosis?

Answer 10

Primary haemochromatosis is caused by a mutation in HFE gene, decreased levels of hepcidin, and thus increased duodenal iron absorption. Secondary haemochromatosis is a result from blood transfusions, as after the erythrocytes are broken down, the iron is recycled.

Question 11

How can Haemochromatosis be investigated?

Answer 11

• ↑Iron, ↓TIBC (Total Iron Binding Capacity measures ferritin), ↑ferritin and transferrin saturation.
• HFE mutation analysis
• Test various organs for complications e.g. liver biopsy, LFTs, fasting blood sugar, echocardiogram, ECG, testosterone, FSH and LH assays.

Question 12

What is the definition and epidemiology of haemolytic anaemia?

Answer 12

Haemolytic anaemia encompasses a number of conditions that result in premature erythrocyte breakdown. Relatively common haematological disease.

Question 13

What are the risk factors for haemolytic anaemia?

Answer 13

Strong risk factors include:
• Hx of autoimmune disorders
• Lymphoproliferative disorders (particularly those with CLL and NHL)
• Prosthetic heart valve
• Family origin in Mediterranean, Middle East, Sub-Saharan Africa, or Southeast Asia (haemoglobinopathies more common)
• Family history of haemoglobinopathy or RBC membrane defects
• Recent exposure to cephalosporins, penicillins, quinine derivatives, or NSAID

Question 14

What is the aetiology of haemolytic anaemia?

Answer 14

Hereditary causes include:
• Membrane defects: hereditary spherocytosis, eliptocytosis
• Metabolic defects: Glucose-6 Phosphate Dehydrogenase deficiency.
• Abnormal haemoglobin production: Sickle-cell disease, thalassaemias.

Acquired causes include:
• Autoimmune: Warm or cold antibodies attach to erythrocyte causing intravascular haemolysis and extravascular haemolysis.
• Isoimmune: transfusion reaction, haemolytic disease of the newborn.
• Drugs: Penicillin, quinine (through formation of drug-antibody-erythrocyte complex)
• Trauma: Microangiopathic haemolytic anaemia caused by red cell fragmentation in abnormal circulation (e.g. haemolytic uraemic syndrome, DIC, malignant hypertension, pre-eclampsia) and artificial heart valves.
• Infection: malaria and sepsis.
• Paroxysmal nocturnal haemoglobinuria.

Question 15

What are the clinical features of haemolytic anaemia?

Answer 15

Commonly presents with jaundice (due to increased bilirubin in blood), haematuria, and symptoms of anaemia (fatigue, dyspnoea, dizziness).

On examination, many patients have pallor (due to anaemia), are jaundiced and have hepatosplenomegaly.

Question 16

How can haemolytic anaemia be investigated?

Answer 16

Bloods:
• FBC: ↓Hb, ↑reticulocytes, ↑MCV, also ↑unconjugated bilirubin, ↓haptoglobin

Blood film:
Leucoerythroblastic picture, macrocytosis, nucleated erythrocytes or reticulocytes, polychromasia. Identifies specific abnormal cells, such as spherocytes, elliptocytes, sickle cells, fragmented erythrocytes, malarial parasites, erythrocyte Heinz bodies (denatured Hb, stained with methyl violet seen in G6PD deficiency).

Urine: ↑urobilinogen. If haemolysis is intravascular (extravascular is where macrophages in spleen an liver break down RBCs), there is haemoglobinuria and haemosiderinuria.

Direct Coomb’s test can identify erythrocytes coated with antibodies (agglutinins) using antihuman globulin. Warm agglutinins and cold agglutinins.

Ham’s test for paroxysmal nocturnal haemoglobunuria; Hb electrophoresis or enzyme assay for sickle-cell or thalassemia.

Question 17

What is the definition and epidemiology of haemolytic uraemic syndrome and TTP?

Answer 17

Haemolytic Uraemic Syndrome (HUS) is characterised by a triad of haemolytic anaemia, thrombocytopenia and acute renal failure. 90% of cases occur in the paediatric population, related to outbreaks of gastroenteritis caused by verotoxin-producing E.Coli.

In adults, a sporadic form is seen, which is often impossible to distinguish from thrombotic thrombocytopenic purpura (TTP). TTP has additional features of fever and fluctuating CNS signs.

Question 18

What is the [pathophysiology] and aetiology of haemolytic uraemic syndrome and TTP?

Answer 18

[ Factors that cause endothelial injury particularly in renal glomerulus. This results in exposure of basement membrane with resultant microvascular thrombosis, fragmentation of erythrocytes, and destruction of platelets, and ultimately causing renal insufficiency. ]

Causes include:
• Infectious causes: Verotoxin producing E. Coli, Shigella, neuraminidase-producing infections, HIV.
• Drugs: Oral contraceptive pill, cyclosporine, mitomycin, 5-fluorouracil.
• Others: Malignant hypertension, malignancy, pregnancy, SLE, scleroderma.

Question 19

What are the clinical features of haemolytic uraemic syndrome and TTP?

Answer 19

GI symptoms: Severe abdominal pain, nausea and vomiting. Diarrhoea, especially bloody diarrhoea. On examination, patients show abdominal tenderness.

General: Malaise, fatigue, nausea, fever <38. On examination, pallor, slight jaundice, bruising (severe thrombocytopenia), generalised oedema, hypertension and retinopathy.

Renal: Oliguria or anuria, haematuria.

In TTP, note CNS signs, which may be weakness, problems in vision, fits, and decreased consciousness.

Question 20

How can haemolytic uraemic syndrome and TTP be investigated?

Answer 20

Blood:
• FBC: normocytic anaemia, ↑neutrophils, ↓↓platelets
• U&Es: ↑Urea, createnine, urate, K+ and ↓Na+
• Clotting (Normal PT, APTT) to exclude other causes of thrombocytopenia.
• LFTs: ↑unconjugated bilirubin, ↑LDH (from haemoloysis)
• Blood cultures, ABG, Blood film (shows schistocytes)

Urine: >1g protein/24h, haematuria, fractional excretion Na+ >1%.

Stool sample: stool culture to detect E. Coli O157:H7

Question 21

What are the types of haemophilia?

Answer 21

Haemophilia results from the inherited deficiency of clotting products. There are three subtypes:

1. Haemophilia A: (most common) caused by deficiency in factor VIII.
2. Haemophilia B: Caused by deficiency in factor IX (Christmas disease).
3. Haemophilia C: (rare) caused by deficiency in factor XI.

Question 22

What is the aetiology and epidemiology of haemophilia?

Answer 22

Haemophilia A and B exhibit X-linked recessive inheritance. A variety of genetic mutations in the factor VIII and XI genes have been described. 30% of cases are new mutations. X-linked pattern means it affects males (1-5/10,000 for Haemophilia A and 1/30,000 for Haemophilia B).

[Rare cases of women
with severe haemophilia are described because of extreme lyonization, homozygosity, mosaicism, or Turner syndrome.]

Question 23

What are the symptoms of haemophilia?

Answer 23

Symptoms usually begin in early childhood (sometimes noticed after prolonged bleeding after heel-prick or circumcision) .
• History of recurrent or severe bleeding. Spontaneous or trauma-induced (onset may be delayed after several days after bleeding - as primary haemostasis [platelet plug formation] still works).
• Painful bleeding into muscles is a hallmark of haemophilia. Patients will complain of pain and swelling in the area, decreased motility, erythema and increased local warmth.
• Haemarthrosis is another hallmark of haemophilia. Painful bleeding into joints, causing swelling.
• Mucocutaneous bleeding after dental work, and easy bruising is common.

Female carriers are often asymptomatic, but may have low enough levels to cause excess bleeding after trauma.

Question 24

What are the examination features of haemophilia?

Answer 24

On Examination: Patients usually have multiple bruises, muscle haematomas, haemarthroses, and joint deformities. May also have signs of iron-deficiency anaemia.

Question 25

How is haemophilia investigated?

Answer 25

Clotting screen: ↑APTT (reflects the activity of the intrinsic and common pathway), coagulation factor assay shows ↓Factor VIII or IX or XI (depending on type of haemophilia). Other investigations according to complications e.g. arthroscopy, head/neck CT/MRI, pelvic US.

Question 26

What is the definition, epidemiology and aetiology of ITP?

Answer 26

ITP is a syndrome characterised by immune destruction of platelets resulting in bruising or bleeding tendency. Presents in children between 2-7 years. Chronic ITP is seen in adults and is four times more common in women. It is often idiopathic. Acute ITP is usually seen after a viral infection in children, while the chronic form is more common in adults. The aetiology responsible for breaking tolerance and for initiating autoimmune attack is unknown.

Question 27

What are the clinical features of ITP?

Answer 27

Patients present with easy bruising, mucosal bleeding, menorrhagia and epistaxis. On examination, find visible petechiae, bruises (purpura or eccymyoses). Typically, signs of other illness (e.g. infections, wasting, splenomegaly) would suggest other causes.

Question 28

How is ITP investigated?

Answer 28

ITP is diagnosed by exclusion. Exclude myelodysplasia, acute leukaemia, marrow infiltration. Blood: • FBC (decreased platelets, normal clotting screen) • May detect autoantibodies Blood film used to diagnose psuedothrombocytopaenia where platelet clumping gives falsely low platelet counts. Bone marrow biopsy to exclude other pathology. May notice an increase in megakaryocytes.

Question 29

What is the definition and epidemiology of ALL?

Answer 29

ALL is a malignancy of the bone marrow and blood characterised by the proliferation of lymphoblasts (primitive lymphoid cells). It is the most common malignancy of childhood, with peak incidence occurring between 2 and 5 years of age. The second peak is in the elderly.

Question 30

What is the pathophysiology of ALL?

Answer 30

In ALL, the lymphoblast is arrested in development due to cytogenetic abnormalities, gene mutations and chromosomal translocations. They also undergo malignant transformation and proliferation, with subsequent replacement of normal marrow elements. This leads to bone marrow failure and infiltration into tissues.

Question 31

What are risk factors for ALL?

Answer 31

Risk Factors include: • Environmental - irradiation and viruses • Genetic - down's syndrome, neurofibromitosis type 1, Fanconi's anaemia, achrondraplasia, ataxia telangiectasia, xeroderma pigmentosum, and X-linked agammaglobuminaemia.

Question 32

What are the clinical features of ALL?

Answer 32

These arise due to bone marrow failure, and tissue infiltration. Bone Marrow Failure: • Symptoms include: anaemia (fatigue, dyspnoea), bleeding (spontaneous bruising, bleeding gums, menorrhoagia), and opportunistic infections (bacterial, viral, protozoal). Anaemia and thrombocytopaenia occur due to bone marrow replacement. • On examination, can cause pallor, bruising, bleeding, and infection. Organ Infiltration: • Symptoms of tender bones/bone pain, lymph node enlargement, mediastinal compression (in T-cell ALL as thymic involvement). Symptoms of meningeal involvement such as headache, visual disturbances and nausea. • On examination, lymphadenopathy, hepatosplenomegaly, cranial nerve palsies, retinal haemorrhage, or papilloedema on fundoscopy, leukaemic infiltration of the anterior chamber of the eye, testicular swelling.

Question 33

How is ALL investigated?

Answer 33

Bloods: • FBC: normocytic normochromic anaemia with low reticulocyte count is present in 80% of patients. Thrombocytopaenia is present in 75% of patients, while leukocytosis is present in only 50% patients (and presence has poor prognosis). • Serum electrolytes increased such as calcium and uric acid. • ↑LDH (many cancers increase LDH as it is important when switching to anaerobic respiration). Peripheral blood smear shows leukaemic lymphoblasts. However, this is not sufficient for the diagnosis of ALL, and thus a bone marrow biopsy/aspiration is needed. From this, many studies can be performed including: • Immunophenotyping using cell-surface antigens e.g. CD20. • Cytogenetics karyotyping chromosomal abnormalities. • FISH (Flourescent In-Situ Hybridisation) • PCR CXR may show mediastinal involvement, thymic enlargement, lytic bone lesions.

Question 34

What is the definition and epidemiology of AML?

Answer 34

AML is a malignancy of primitive myeloid lineage white blood cells with proliferation in the bone marrow and blood. It is the most common acute leukaemia in adults, with incidence increasing with age.

Question 35

What are the clinical features of AML?

Answer 35

Like other acute leukaemias, symptoms are due to bone marrow failure and tissue infiltration. Bone marrow failure: • Patients present with anaemia (lethargy, dyspnoea), bleeding (thrombocytopaenia or DIC), and opportunistic/recurrent infections. • Signs include pallor, cardiac flow murmur, ecchymosis, bleeding and signs of infection. Tissue infiltration: • Patients present with gum swelling or bleeding, CNS involvement (headaches, nausea, diplopia) especially with M4 and M5 variants. • Signs include skin rashes, gum hypertrophy, deposit of leukaemic blasts may rarely be seen in the eye, tongue and bone (and cause fractures).

Question 36

How can AML be investigated?

Answer 36

Blood: • FBC (↓Hb, ↓platelets, ↓variable WCC) • ↑Uric acid, ↑LDH, ↑Clotting studies, fibrinogen, and D-dimers Blood film shows blast cells with cytoplasmic granules or Auer rods. Bone marrow aspirate or biopsy shows hypercellular marrow with >30% blast cells. Immunophenotyping used to classify the lineage of abnormal cells, for categorisation. Cytogenetics for diagnostic and prognostic information. Immunocytochemistry: Myeloblast granules are positive for Sudan black, chloroacetate esterase and myeloperoxidase, monoblasts are positive for non-specific and butyrate esterase.

Question 37

Define CLL

Answer 37

CLL is characterised by the progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin. There is an overlap between CLL and non-Hodgkin's lymphoma. It is also called B-CLL, because it is a malignant disease of B-cells.

Question 38

What is the epidemiology of CLL?

Answer 38

CLL commonly affects the elderly (90% >50), and males more than females. CLL is rare in Asians.

Question 39

What are the clinical features of CLL?

Answer 39

Up to 40-50% are asymptomatic and only diagnosed on routine blood count. Systemic symptoms include lethargy, malaise, and night sweats. Patients also present with symptoms of bone marrow failure: recurrent infections, herpes zoster. On Examination: Non-tender lymphadenopathy (usually cervical and symmetrical) is the most frequent clinical sign. Splenomegaly is also common, and less commonly, hepatomegaly. Symptoms of bone marrow failure in later stages of the disease: pallor, cardiac flow murmur, and purpura. CLL can also be associated with autoimmune conditions towards haematopoietic stem cells. Most commonly this is haemolytic anaemia, but can also be immune thrombocytopaenia, neutropenia and red cell aplasia.

Question 40

How can CLL be investigated?

Answer 40

Bloods: • A FBC shows gross lymphocytosis (B-cells >5 x109/L). Anaemia (normocytic and normochromic) is a feature in later stages as a result of marrow infiltration, or hypersplenism, or haemolytic anaemia. ↓platelets may be seen for the same reason, or because of autoimmune thrombocytopaenia. • ↓Serum immunoglobulins. Blood film may show smudge/smear cells. If there is active haemolysis, may also show spherocytes. A bone marrow biopsy or aspirate can show lymphocytic replacement of normal marrow elements. FISH cytogenetics, can be used to determine prognostic information. CT scans such as from Chest, Abdomen and Pelvis from the basis of patient's symptoms.

Question 41

What is the definition and epidemiology of CML?

Answer 41

CML is a malignant clonal disease characterised by proliferation of granulocyte precursors in the bone marrow and blood. It is distinguished by AML by its slower progression. Incidence increases with age, mean 40-60 years, and is 4x more common in males.

Question 42

What is the aetiology of CML?

Answer 42

95% of cases are caused by the Philadelphia chromosome t(9;22), which results in fusion gene BRC-ABL. The disease can exist in three stages: Relatively stable chronic phase of variable duration (average of 4–6 years), which transforms into an accelerated phase (3–9 months) and then an acute leukaemia phase (blast transformation).

Question 43

What are the clinical features of CML?

Answer 43

Asymptomatic (40-50% diagnosed on routine FBC). Symptoms caused by hypermetabolism include: weight loss, anorexia, malaise, and sweating. Bone marrow failure symptoms include: leathrgy, dyspnoea, easy bruising, epistaxis (infection is rare). Splenomegaly can cause abdominal discomfort and early satiety. Occasionally presents with gout or hyperviscosity symptoms (visual disturbance, headaches, priapism). On examination: Splenomegaly is a common finding (90%). May also be signs of bone marrow failure such as pallor, and purpura/ecchymoses.

Question 44

How can CML be investigated?

Answer 44

Bloods: • A FBC shows gross elevated WCC (with increased basophils/neutrophils/eosinophils). Anaemia (normocytic and normochromic) is usual feature. ↓ or normal platelets. • Metabolic profile shows elevated K+, LDH or uric acid due to extensive cell turnover. Blood film shows immature granulocytes in peripheral blood. A bone marrow biopsy or aspirate can show granulocytic hyperplasia. Biopsy required for diagnosis, and karyotyping of disease. FISH cytogenetics show Philadelphia chromosome in 95% of cases.

Question 45

Define Macrocytic anaemia

Answer 45

Macrocytic anaemia is anaemia associated with a high MCV of erythrocytes (>100 fl in adults).

Question 46

What is the aetiology of Macrocytic anaemia?

Answer 46

Causes can be split into megaloblastic or non-megaloblastic anaemia. Megaloblastic anaemia occurs when there is a disruption in DNA synthesis, which delays nuclear maturation and cell division. Causes of megaloblastic anaemia include: • Vitamin B12 deficiency secondary to: ○ Decreased absorption due to post-gastrectomy, pernicious anaemia (most common cause of B12 deficiency in the west) , terminal ileal resection, Crohn's disease, bacterial overgrowth, pancreatic insufficiency, fish tape-worm, metformin, omeprazole. ○ Decreased intake due to diet particularly veganism. ○ Abnormal metabolism. • Folate deficiency secondary to: ○ Decreased intake, likely due to alcoholism, elderly age, anorexia. ○ Increased demand, due to pregnancy, lactation, malignancy, chronic inflammation, chronic haemolysis, exfoliative dermatitis. ○ Decreased absorption due to jejunal disease e.g. coeliac disease, or drugs such as phenytoin, trimethoprim, methotrexate. • Drugs: methotrexate (inhibits dihydrofolate reductase), hydroxyurea (inhibition of ribonucleotide reductase), azathioprine, zidovudine. Causes of non-megaloblastic anaemia include: alcohol excess, liver disease, myelodysplasia, multiple myeloma, hypothyroidism, haemolysis (shift to immature cells - reticulocytosis), and drugs.

Question 47

What are the clinical features of Macrocytic anaemia? | As well as signs of Pernicious anaemia and vitamin B12 deficiency.

Answer 47

Patients present with non-specific signs of anaemia. These include tiredness, lethargy, dyspnoea. They may also have symptoms of the cause e.g. weight loss, diarrhoea, and steatorrhea in coeliac disease. They may also have a family history of autoimmune diseases, or a past medical history of GI surgery. On examination may notice signs of: • Anaemia - e.g. pallor, tachycardia. There may be signs of the cause e.g. malnutrition, jaundice, hypothyroid appearance. • Signs of pernicious anaemia - mild jaundice, glossitis, angular stomatis, and weight loss. • Sigs of vitamin B12 deficiency - peripheral neuropathy, atxia, subacute combined degeneration of the spinal chord, optic atrophy, and dementia.

Question 48

How can Macrocytic anaemia be investigated?

Answer 48

Bloods: • FBC (↑MCV, pancytopania in megaloblastic anaemia, varying degrees of cytopaenia in myelodysplasia, exclude reticulocytes) • LFTs (↑bilirubin as a result of ineffective erythropoiesis or haemolysis), ESR, TFT • Serum vitamin B12, red cell folate • Antibodies against parietal cells of intrinsic factor (pernicious anaemia). Blood film to look for macrocytes (large erythrocytes). In megaloblastic anaemia, find macroovalocytes, and neutrophils with hypersengented nuclei. Schilling test to investigate pernicious anaemia. Bone marrow biopsy (rarely necessary).

Question 49

How is pernicious anaemia treated?

Answer 49

IM hydroxycobalamin (intra-muscularly to bypass digestive system) given thrice weekly for 2 weeks, then every 3 months for life.

Question 50

What is the definition and epidemiology of Microcytic anaemia?

Answer 50

Microcytic anaemia is an anaemia associated with low MCV (<80 fl). Relatively common, as iron-deficiency anaemia is the most common cause of anaemia world-wide.

Question 51

What is the aetiology of Microcytic anaemia?

Answer 51

Microcytic anaemia is caused by reduced haemoglobin synthesis, either by reduced haem, or reduced globin chain synthesis. Common causes include: • Iron-deficiency (most common cause). This can be due to: ○ Blood-loss e.g. through gastrointestinal tract, urogenital tract, parasite, trauma. ○ Decreased absorption secondary to small bowel disease, post-gastrectomy. ○ Increased demands secondary to pregnancy, growth. ○ Decreased intake through diet, often affecting vegans. • Anaemia of Chronic Disease (cytokines block iron utilisation) can be normocytic as well as microcytic. • Sideroblastic anaemia (where bone marrow produces ringed sideroblasts which are mutated precursors to RBC with iron accumulation in perinuclear mitochondria). • Lead poisoning interferes with haem and globin synthesis. • Thalassaemias are disorders in globin chain synthesis.

Question 52

What are the symptoms of Microcytic anaemia?

Answer 52

Tend to present with non-specific symptoms of tiredness, lethargy, malaise, dyspnoea. May also have an exacerbation of pre-existing angina or intermittent claudication (muscle cramping, typically calf). May have more specific signs for lead poisoning such as anorexia, nausea, vomiting, abdominal pain, constipation an peripheral nerve lesions. A family history is important to establish risk of congenital disorders such as thalassemia.

Question 53

What are the potential examination features of Microcytic anaemia?

Answer 53

Patient may have general signs of anaemia e.g. pallor of skin and mucous membranes. Brittle nails and hair. If long-standing and severe, koilonychia. Other signs include: • Glossitis - caused by iron-deficiency or vitamin B deficiency (not microcytic anaemia) • Angular chelitis/stomatitis is also caused by iron-deficiency or vitamin B deficiency. Signs of thalassemia (jaundice, hepatosplenomegaly). Signs of lead poisoning (blue gumline, peripheral nerve lesions, encephalopathy, convulsions, decreased consciousness).

Question 54

What are the complications of microcytic anaemia?

Answer 54

high-output cardiac failure and complications of the cause.

Question 55

How can microcytic anaemia be investigated?

Answer 55

Bloods: • FBC: ↓Hb, ↓MCV may also have reticulocytes. • ↓Serum iron, ↑iron-binding capacity in iron-deficiency anaemia, ↓or normal in ACD . ↑ferritin in ACD, ↓ferritin in iron-deficiency anaemia. Blood Film: • In iron-deficiency anaemia: microcytic hypochromic (central pallor >one-third cell size), anisocytosis (variable cell size) and poikilocytosis (variable cell shape). • In sideroblastic anaemia: dimorphic blood film with a population of hypochromatic microcytic cells. • In lead poisoning: Basophilic stippling (coarse dots represent condensed RNA in cytoplasm) Hb electrophoresis for haemoglobin variants or thalassaemias. In iron-deficiency anaemia in >40 years and post-menopausal woman, do an upper GI endoscopy and colonoscopy and investigations for haematuria should be considered if no obvious cause of blood loss.

Question 56

How is microcytic anaemia managed?

Answer 56

Iron deficiency: • Oral iron supplements (e.g. 200 mg ferrous sulphate tablets taken with food) • Monitor Hb and MCV, aiming for Hb rise of 1g/dL/week. Sideroblastic anaemia: Treat the cause (e.g. stop causative drugs). Pyridoxine can be used in inherited forms. If no response, consider blood transfusions and iron chelation. Lead poisoning: Remove the source, dimercaprol, D-penicillamine, Ca2+ EDTA.

Question 57

What is the definition and epidemiology of Multiple Myeloma?

Answer 57

Multiple Myeloma is a haematological malignancy characterised by proliferation of plasma cells resulting in bone lesions and production of monoclonal immunoglobulin (paraprotein, usually IgG or IgA). Second most common haematological malignancy, peak incidence in 70-year olds. Afro-Caribbeans > White people > Asians.

Question 58

What is the aetiology of Multiple Myeloma?

Answer 58

Unknown aetiology. Postulated viral trigger. Certain cytokines (e.g. IL-6) act as potent growth factors for plasma cell proliferation.

Question 59

What are the clinical features of Multiple Myeloma?

Answer 59

Patients usually complain/present with: • Bone pain (especially backache) resulting from vertebral collapse and pathological fractures if severe. This is because of high serum levels of RANKL produced by plasma cells and bone marrow stroma, activating osteoclast activation. • Features of anaemia such as lethargy, weakness, pallor. • Recurrent infections related to deficient antibody production (relative hypogammaglobinaemia - due to high levels of paraprotein inhibiting production of useful antibodies), abnormal cell-mediated immunity and neutropenia. • Features of renal failure and/or hypercalcaemia such as polydipsia, polyuria, anorexia, vomiting, constipation and mental disturbance. Tachycardia and dehydration can be examination findings. • Amyloidosis occurs in 5% • In 2% there are symptoms of hyperviscosity, such as visual disturbance, headaches, bleeding. Can be remembered as CRAB symptoms. (Calcium, Renal, Anaemia, Bone). Other examination findings include purpura, hepatosplenomegaly, macroglossia, carpel tunnel syndrome (due to amyloidosis) and peripheral neuropathies.

Question 60

How can Multiple Myeloma be investigated?

Answer 60

Bloods: • Presence of paraprotein (also in urine) - mainly IgG and IgA. • Elevated serum immunoglobulin-free light chains (light chains synthesised by plasma cells and unpaired with heavy chains). • FBC ↓Hb, normocytic normochromic • ↑ESR and CRP • U&Es (↑creatinine, ↑Ca2+, in 45%). Radiological investigations of skeleton (chest, pelvic and/or vertebral) X-ray or MRI, looking osteolytic lesions without surrounding sclerosis. Bone marrow aspirate and trephine showing ↑plasma cells. Also allows for cytogenetics and FISH analysis.

Question 61

What is the definition and epidemiology of Myelodysplasia?

Answer 61

Myelodysplastic syndromes are a group of disorders of haematopoeitic stem cells characterised by chronic cytopaenia (anaemia, neutropeania, thrombocytopaenia) and abnormal cellular maturation. There is a tendency to progress to AML (acute myeloid leukaemia), although death often occurs before this develops. Mean age of diagnosis is 65-75 years, more common in males. Twice as common as AML.

Question 62

What is the aetiology of Myelodysplasia?

Answer 62

Aetiology is usually primary in patients, but can also be secondary to chemotherapy and/or radiotherapy.

Question 63

What are the clinical features of myelodysplasia?

Answer 63

50% are asymptomatic and diagnosed after a blood count. Symptoms and signs due to bone marrow failure include: • Anaemia - fatigue, dizziness, pallor, cardiact flow murmur. • Neutropaenia - recurrent infections • Thrombocytopaenia - easy bruising, epistaxis, purpura, ecchymoses • Gum hypertrophy and splenomegaly.

Question 64

How can myelodysplasia be investigated?

Answer 64

Bloods: FBC show pancytopaenia. Blood film: Normocytic or macrocytic red cells Bone marrow aspiration: hypercellular marrow.

Question 65

What is the definition and epidemiology of Normocytic anaemia?

Answer 65

Normocytic anaemia is a reduction in Hb concentration, but with the cell size normal. Also tends to be normochromic. A normochormic normocytic anaemia is a very frequent finding, but is important to decide weather the anaemia is significant, and thus weather to investigate.

Question 66

What is the aetiology of Normocytic anaemia?

Answer 66

Causes include: • Acute Bleeding peptic ulcers or oesophageal varices • Trauma • Hypersplenism (causing pooling of erythrocytes) • Aplastic anaemia • Anaemia of Chronic Disease (as well as cause microcytic anaemia) • Renal failure • Endocrine failure (hypothyroidism, hypopituitarism). • Polymyalgia rheumatica

Question 67

What are the clinical features of Normocytic anaemia?

Answer 67

Tend to present with non-specific symptoms of tiredness, lethargy, malaise, dyspnoea. May also have an exacerbation of pre-existing angina or intermittent claudication (muscle cramping, typically calf). As anaemia of chronic disease is an important cause, patient may be generally unwell, or have symptoms of their chronic disease.

Question 68

How can Normocytic anaemia be investigated?

Answer 68

* FBC which shows normocytic anaemia. * Serum iron, ferritin and transferrin to distinguish between iron-deficiency anaemia, and to confirm Anaemia of Chronic Disease. * Abdominal ultrasound to locate bleeding, or endoscopy to investigate GI bleeding.

Question 69

Define Polycytaemia

Answer 69

Polycythaemia is an increase in haemoglobin concentration above the upper limit of normal for a person's age or sex. Classified into relative polycythaemia (normal red cell mass but decreased plasma volume) or absolute (true) polycythaemia (increased red cell mass).

Question 70

What are the causes of the different types of Polycytaemia?

Answer 70

There are three main aetiology of polycythaemia: • Polycythaemia vera - a group of Philadelphia chromosome negative myeloproliferative neoplasms. It is strongly liked with JAK2 tyrosine kinase mutations. Is this a cancer? • Secondary polycythaemia: ○ Appropriate ↑ in erythropeitin due to chronic hypoxia (e.g. in chonic ling disease), leading to upregulation of erythropoiesis. ○ Inappropriate ↑ in erythropeitin due to renal carcinoma, cysts, hydronephrosis, hepatocellular carcinoma, fibroids, cerebellar hemangioblastoma. Also erythropoitin abuse by athletes. • Relative polycythaemia caused by dehydration (e.g. diuretics, burns, enteropathy), Gaisbock's syndrome (seen in young male smokers with increased vasomotor tone and hypertension).

Question 71

What are the symptoms of Polycytaemia?

Answer 71

Patient presents with symptoms caused by hyperviscosity including: • Headaches, dyspnoea, tinnitus, blurred vision. • Pruritus after a hot bath, and night sweat. Also presents with thrombosis (DVT, stroke), pain resulting from peptic ulcer disease, angina, gout, choreiform movements (chorea - repetitive and rapid, jerky, involuntary movement that appears to be well-coordinated).

Question 72

What are the examination features of Polycytaemia?

Answer 72

Note plethoric complexion, scratch marks as a result of itching, conjunct ival suffision, and retinal venous engorgement. Patient probably has hypertension. Splenomegaly seen in 75% of patients with polycythaemia vera. Other signs of underlying causes.

Question 73

How can Polycytaemia be investigated?

Answer 73

* Required for diagnosis: FBC (↑Hb >16.5 for females, and >18.5 g/dl for males), ↑Haematocrit and ↓MCV * Isotope dilution techniques to distinguish between relative and absolute polycythaemia. • Polycythaemia vera can be investigated by: ○ FBC (↑WCC and platelets) ○ Testing for JAK2 gene mutation Bone marrow biopsy (however, usually not needed if patient has polycythaemia and JAK2 mutation).

Question 74

What is the definition and epidemiology of Sickle Cell Disease?

Answer 74

Sickle-cell disease is a group of haemoglobin disorders resulting from the inheritance of the sickle β-globin gene (Hb S). Sickle cell disease includes compound heterozygosity for Hb S and C and for Hb S and β-thalassaemia. Sickle cell trait is only carrying one copy of Hb S. Sickle cell anaemia rarely presents before 4-6 months because of continuous production of foetal haemoglobin. The disease is common in Africa, the Caribbean, Middle East, and areas with high prevalence of malaria. Carrier frequency in Afro-Caribbeans is ~8%.

Question 75

What is the aetiology of Sickle Cell Disease?

Answer 75

It is an autosomal recessive inherited point mutation in the β-globin gene resulting in HbS. [Deoxygenation of Hb S alters the conformation, resulting in sickling of red cells with increased fragility and inflexibility. They are prone to: 1. Sequestration and destruction leading to decreased RBC survival (~20 days). 2. Occluding small vessels causing hypoxia, which in turn, causes further sickling and occlusion. ]

Question 76

What factors precipitate suckling in Sickle Cell Disease?

Answer 76

Factors precipitating sickling are infection, dehydration, hypoxia and acidosis.

Question 77

What are the acute complications of Sickle Cell Disease?

Answer 77

• Infections (major cause of mortality and morbidity in patients with SCD) - common sites of infection include bacteraemia, meningitis, and pneumonia/ACS (Acute Chest Syndrome). • Severe anaemia due to either sequestration (pooling of red cells in various organs such), aplastic crises (due to infection by parviovirus or folate deficiency), or haemolytic crises. ○ Signs/Symptoms of sequestration depend of organ(s) affected: § Spleen: splenomegaly is common in early disease, but later reduces in size because of splenic atrophy. § Liver: exacerbation of anaemia. § Lungs: can cause acute chest syndrome (breathlessness, cough, pain, and fever). § Corpora cavernosa: Priapism and impotence. • Vaso-occlusive crises which can lead to infarction of the affected tissue. Signs and symptoms include: ○ Autosplenectomy (splenic atrophy or infarction) leading to increased risk of infections with encapsulated organisms such as pneumococcus, haemophilus influenzae, meningococcus). ○ Abdominal pain. ○ Bones: Painful crises affecting small bones of hand or feet (dactylitis). It is usually the first presentation for many children, with earlier presentation correlating with worse prognosis. ○ Myalgia and arthralgia. ○ CNS: can cause fits or strokes. ○ Retina: can cause visual loss (proliferative retinopathy) and can be seen as cotton wool spots from areas of ischaemia.

Question 78

What are the chronic complications of Sickle Cell Disease?

Answer 78

Chronic pain, and anaemia. Lots of other chronic complications, depending on vaso-occlusive crises leading to ischaemia of tissue.

Question 79

How can Sickle Cell Disease be investigated?

Answer 79

Bloods: • FBC: anaemia; reticulocytes are ↑ in haemolytic crises, or ↓ in aplastic crises. • U&Es DNA-based assays provide the most accurate diagnosis, but is relatively expensive. Blood film shows sickle cells, anisocytoses and features of hyposplenism (target cells, Howell-Jolly bodies). Sickle solubility test: Dithionate added to blood, causes ↑ turbidity. Haemoglobin electrophoresis shows Hb S, absence of Hb A (In Hb SS) and ↑ levels of Hb F. X-rays of long-bones used to confirm presence of bone infarcts. MRI or CT of head to see if there are neurological complications.

Question 80

How is Sickle Cell Disease managed?

Answer 80

Acute painful crises are managed with oxygen, IV fluids, strong analgesia (IV opiates) (antihistamines if opiate causes pruritus) and antibiotics. Those with chronic disease, treat with: • Infection prophylaxis with penicillin and regular vaccinations. • Folic acid in severe haemolysis or pregnancy. • Hydroxyurea as this increases levels of Hb F and reduces frequency of sickle cell crisis. • Red cell transfusion in severe anaemia. Repeated transfusions with iron chelators may be necessary for those with frequent crises. • Advice to avoid precipitating factors (dehydration, hypoxia, infection). • Surgical: Bone marrow transplant can cure under 16s.

Question 81

What is the prognosis of Sickle Cell Disease?

Answer 81

Most, with good care, survive up to 50 years. Major mortality is usually a result of pulmonary or neurological complications (adults) or infection (children).

Question 82

What is the definition of Hodgkin's Lymphoma?

Answer 82

Lymphomas are a group of diseases caused by malignant lymphocytes that accumulate in lymph nodes and other lymphoid tissue. Hodgkin's lymphoma is a lymphoma that has Reed-Sternberg cells (B-lymphoid lineage) present..

Question 83

What is the epidemiology of Hodgkin's Lymphoma?

Answer 83

The disease has a bimodal age distribution, with peaks around 20-30 years and >50 years. It is more common in males.

Question 84

What are the symptoms of Hodgkin's Lymphoma?

Answer 84

Most patients present with painless, asymmetrical, firm and discrete enlargement of superficial lymph nodes. Most commonly in cervical, occasionally axillary or inguinal nodes. 'B symptoms' (nomenclature based on Ann-Arbor staging rather than lymphocytes). These symptoms include: • Fevers >38 oC • Night sweats • Weight loss > 10% body weight in last 6 months. Other symptoms include pruritus, cough or dyspnoea (intrathoracic disease).

Question 85

What are the examination features of Hodgkin's Lymphoma?

Answer 85

Feel non-tender firm rubbery lymphadenopathy (cervical, axillary or inguinal). Modest splenomegaly occurs in half of patients, hepatomegaly may also be present. Skin excoriations due to cutaneous Hodgkin lymphoma occurs as a late complication. There may be other signs of intrathoracic disease (e.g. pleural effusion, superior vena cava obstruction).

Question 86

How can Hodgkin's Lymphoma be investigated?

Answer 86

Bloods: • FBC: Normochromic normocytic anaemia is most common. ↑ neutrophils, eosinophils. • Lymphopenia in advanced disease • ↑ESR and CRP • LFTs: ↑LDH and ↑transaminases if liver involved Lymph node biopsy is needed for diagnosis. The distinctive multinucleate polypoid RS cell is central to the diagnosis of the four classic types. Immunohistochemical studies are invaluable in differentiating HL from other lymphomas as well as non-haematological processes. A bone marrow biopsy or aspirate can be done, however bone marrow involvement is only seen in very advanced disease. Imaging such as CXR, CT of thorax, abdomen and pelvis are used to investigate masses.

Question 87

What is the definition of Non-Hodgkin's Lymphoma?

Answer 87

Non-Hodgkin lymphomas are a diverse group of clonal lymphoid tumours (e.g MALT lymphoma, Burkitt lymphoma etc. - all lymphomas apart from Hodgkin's lymphoma). 85% are of B-cell origin, and the remainder of T-cell or NK-cell origin. NHLs are classified within a group of mature B-cell or T-cell neoplasms.

Question 88

What is the epidemiology and aetiology of Non-Hodgkin's Lymphoma?

Answer 88

Incidence of NHL increases with age, and is more common in males and the west. In some countries, it is the 5th most common malignancy. The aetiology is unknown for most NHLs, although infectious agents (particularly EBV, HTLV-1) are an important cause in particular subtypes.

Question 89

What are the symptoms of Non-Hodgkin's lymphoma?

Answer 89

Symptoms much more variable than in Hodgkin's lymphoma, as encompasses different diseases with different characteristic cytogenetic features. General symptoms include: • Painless enlarging mass often in the neck, axilla or groin. • Systemic symptoms (less frequently than in Hodgkin's): fever, night sweats, weight loss, symptoms of hypercalcaemia. • Symptoms related to organ involvement - extranodal disease is more common In NHL: skin rashes, headache, sore throat, abdominal discomfort, testicular swelling.

Question 90

What are the examination features of Non-Hodgkin's Lymphoma?

Answer 90

* Painless firm rubbery lymphadenopathy - cervical, axillary or inguinal in origin. * Skin rashes such as mycosis fungoides in cutaneous T-cell lymphoma, and skin rashes in sezary syndrome. * Abdominal mass * Hepatosplenomegaly. * Signs of bone marrow involvement such as pallor, infections and purpura.

Question 91

How can Non-Hodgkin's Lymphoma be investigated?

Answer 91

Blood: • FBC may show bone marrow involvement through anaemia, thrombocytopaenia, neutropenia. • U&Es and LFTs to assess kidney and liver involvement. • ↑ESR due to inflammation or monoclonal paraprotein production. • ↑LDH can be an indicator of the proliferative rate. Blood film can show lymphoma cells or nucleated erythrocytes pointing towards bone marrow involvement. Lymph node biopsy can help confirm diagnosis. Also allows histopathologic evaluation, immunophenotyping and cytogenetic analysis to diagnose the type of lymphoma. Imaging techniques (CXR, CT, PET) are valuable in evaluating extranodal involvement. Bone marrow biopsy or aspirate. Staging is the same as for Hodgkin's lymphoma.

Question 92

What is the definition and epidemiology of Thalassaemia?

Answer 92

Thalassaemias are a heterogeneous group of genetic disorders that result from a reduced rate of globin chain synthesis. Thalassaemias are found worldwide, but ore common in the Mediterranean and areas of the middle east.

Question 93

What is the aetiology of Thalassaemia?

Answer 93

Autosomal recessive genetic defects result in an imbalance of globin chain production, and deposition on erythroblasts and erythrocytes causing ineffective erythropoiesis, haemolysis, anaemia and extramedullary haematosis.

Question 94

What are the types of Thalassaemia?

Answer 94

The clinical conditions arise from either α or β globin gene deletions. α-Thalassaemia conditions include: • Hydrops fetalis - 4 α gene deletions leading to intrauterine death. • Microcytic hypochromic anaemia - 3 gene deletions. • Microcytic hypochromic red cells (no anaemia) - 1 or 2 deletions. β-thalassaemia conditions include: • β-thalassaemia major: homozygous gene mutations causing no or minimal β-chain synthesis. • β-thalassaemia intermedia: Mild defect in β-chain synthesis causing microcytic anaemia • β-thalassaemia trait: heterozygous carrier asymptomatic, mild microcytic anaemia, ↑red cell count.

Question 95

What are the clinical features of β-thalassaemia major?

Answer 95

* Anaemia presenting at 3-6 months (when gamma-chain synthesis switches to beta-chain). Presents with general failure to thrive and prone to infections. * On examination, notice pallor, malaise, dyspnoea and mild jaundice. * Frontal bossing and thalassaemia facies (marrow hyperplasia). * Hepatosplenomegaly (erythrocyte pooling, extramedullary haemopoises)

Question 96

What are the clinical features of α- or β- Thalassaemia trait?

Answer 96

May be asymptomatic. Detected on routine blood tests or from a family history.

Question 97

How can Thalassaemia be investigated?

Answer 97

Bloods: • FBC: ↓Hb, ↓MCV, ↓MCH. (microcytic anaemia) Blood film: Hypochromic, microcytic anaemia, target cells, nucleated red cells and increased reticulocyte count. Hb electrophoresis: Absent or ↓Hb A and ↑Hb F Bone marrow biopsy/aspirate: hypercellular with erythroid hyperplasia. Genetic testing: Rarely necessary. For specific mutations. Skull X-ray