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Senior Academic Half Day

Senior Academic Half Day

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Senior Academic Half Day

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  1. Senior Academic Half Day Dr S W Bokhari Consultant Haematologist UHCW

  2. Topics to cover • Low blood counts - Anaemia due to haematinic deficiency - Some other causes of anaemia - Thrombocytopenia

  3. Anaemias • MCV B12/folate def Haemolytic anaemia with reticulocytosis Liver disease Hypothyroidism Alcohol Myelodysplasia Drugs • MCV Iron deficiency Thalassemias • Normal MCV Anaemia of chronic disease Aplastic anaemia

  4. Anaemias due to haematinic deficiency Aim • Outline practical overview of B12, folate and Iron deficiency

  5. Megaloblastic anaemia • Group of disorders characterised by presence of distinctive morphological appearances of red cells in the marrow Causes -B12 deficiency -Folate deficiency -Abnormal metabolism of these vitamins -Faults in DNA synthesis not related to B12 and folate

  6. Vitamin B12 deficiency-Causes • Nutritional (vegans) • Malabsorption • Gastric causes 1.pernicious anaemia 2.Total or partial gastrectomy • Intestinal causes 1. Intestinal stagnant loop syndrome (jej diverticulosis, ileocolic fistula, anatomical blind loop, intestinal stricture) 2. Ileal resection and chron’s disease 3. Tropical sprue 4. TCII deficiency 5. Fish tapeworm (Diphyllobothrium latum)

  7. Vitamin B12 • 2 main natural forms (Deoxyadenosyl cobalamin, Methyl cobalamin) • 2 main pharmaceutical forms (Cyanocobalamin, Hydroxycobalamin) • Dietry source: animal products only • Body stores: 2-3 mg 50% in liver Sufficient for 2-4 years

  8. Biochemistry Homocysteine Methionine (Methyl B12) DNA Methyl THF THF dTMP CYTOSOL dUMP

  9. Absorption • B12 in average diet 5 -7 ug/day • Doses >1 mg: 1% absorbed passively • R-binder: high level in saliva/gastric juice ph2 – R:IF ~ 50:1 ph8 – R:IF ~ 3:1 • IF: when present >70% B12 absorbed if absent <1% • Enterohepatic circulation: 5-10 ug/day B12 analogues bind to R binder • Absorption in terminal ileum. • Transportation: 75% TCI 10-20 % TCII

  10. Mrs KC • 55 years • Shortness of breath, sore mouth, tingling and numbness in hands and feet • Good diet, no GI symptoms, No drugs. • Hb: 4.1 Platelets:85 WCC: 3.1 • MCV: 109 • LFT: normal; Reticulocytes: 20 LDH: 1100 • Blood film:----------------------------------

  11. Blood Film----diagnosis?

  12. Diagnosis? • B12 level: 105 • IF antibodies: positive

  13. Pernicious Anaemia • Severe lack of IF due to gastric atrophy • Incidence 25/100,000/year aged over 40years • 10 female: 7 male • 20% have positive family history • Association with autoimmune disease (30% with Crohn’s disease) • 90% parietal cell antibody positive (~20% in normal population) • 60% IF antibody positive

  14. Clinical features • Symptoms: Malaise, SOB, Paraesthesia, sore mouth, weight loss, alopecia/grey hair, irritability, poor memory, depression, personality change, hallucinations, impotence, postural hypotension • Signs: Smooth tongue, angular chellosis, vitiligo, PUO, LVF, sensory disturbance, subacute combined degenration, optic atrophy, altered colour vision

  15. Laboratory Abnormalities • Upto 40% not anaemic • Upto 30% not macrocytic (masked by IDA/thalassaemia) • Pancytopenia • Neutrophil hypersegmentation • Hyposplenism • Howell Jolly bodies

  16. Laboratory Abnormalities - Chemistry • Increased serum Iron • Increased Iron stores • Increased bilirubin and LDH • Decreased immunoglobulins • Decreased cholesterol

  17. Presentation and Management Optic atrophy Urgent referral Subacute comb.deg. Pancytopenia Check B12 Treat blind with B12 & folate

  18. Cont… When to screen: • Unexplained macrocytic anaemia • Unexplained normocytic anaemia (elderly, GI disease, autoimmune disease, family h/o of PA) • Dimentia anaemic or • Unexplained psychiatric illness not

  19. Cont… B12 <170 pg/mlB12 170-200 normal FBC/well Treat Neurology or repeat 3-4 mo 5 1mg injections >65/debilitated 1mg every 3 months <65: Treat Level normal/static IF Abs ?improved Schillings test ?B12 ^ probably spurious

  20. Assessment of megaloblastic anaemia • Confirmed megaloblastic BM: Plasma B12 90-95% B12 <200 5-10% B12 200-300 1% B12 > 300 • But 50% of patients with B12<200 are not Megaloblastic • Therefore B12 <100 usually B12 deficient • Only 50% of patients with a B12 100-200 will be truly deficient; others spurious low B12

  21. Causes of Spurious low B12 • Iron deficiency- 30% IDA have low B12 which corrects with FeSO4 alone • Folate deficiency- 30% folate deficient patients have a low B12 which corrects with folate alone • Myeloma • Megadose Vit C • Vegetarian diet • Pregnancy • TC I deficiency • Pancreatic disease

  22. Schilling Test • Low B12 (<100) + pos IF Ab +>60yrs = PA • If <60yrs/ IF Ab negative Schilling test • Requirements: • Normal renal function • B12 replete

  23. Schilling Test- Part 1 1 ug B12 (0.5 ug CiCo^57) orally 1000ug B12 IM Gut normal IF normal Absorbed ~30% Urine Blocks all binding sites Must collect 24 hr urine (~25% collections inadequate)

  24. Schilling test – Part 2 • If absorption reduced in part 1 1ug B12(0.5 CiCo^57) + IF orally 1000ug B12 IM No change normal excretion= IF deficient Gut disease (B12 excretion controls: 11-32% PA part 1: 0-6% PA part 2: 3-30%) • If problems with incontinence or renal failure; collect plasma sample 8 hours after oral B12 Co^57

  25. Folate deficiency • Nutritional esp. old age, institutions, poverty • Malabsorption eg coeliac disease • Excess utilisation • Physiological (pregnancy, lactation) • Pathological eg hemolytic anaemia • Excess urinary folate loss • Active liver disease • CCF • Drugs (anti-convulsants, sulphasalazine) • Alcoholism • ITU

  26. Serum folate • Not sensitive or specific • Spurious low values – anorexia alcoholism anticonvulsants pregnancy • Falsely raised values – acute food intake Haemolysis

  27. Red cell folate • Levels are 30x greater than serum • Better longer term measure • Raised by – reticulocytosis haemoconcentration • Lowered by – B12 deficiency (methyl THF leaks out of RBC)

  28. Response to B12/folate therapy • BM normal by 48 hours but giant metamyelocytes persist for 14 days • Serum Iron normal by 48 hrs • K drops in first 48 hrs • Uric acid increases and peaks at 96 hrs • Reticulocyte response by D2-D3- peaks by day 7 • Hb increased by 1-1.5 gm per week (If MCV <80 ?IDA) • Hypersegmented neutrophils persist for 14 days • Bil/LDH correct over 7 days

  29. Response to therapy Neurology: • If present for < 3/12, usually reverse but may take upto 6/12 • No improvement after >12/12 • Spinal cord damage usually irreversible • Only 30% of optic atrophy pts improve

  30. Iron deficiency • 3.1% adult men • 5.3% adult women • Children upto 14 (non-menstruating females) 2-3% • Menstruating girls upto 14 yrs age 9% • 30% menstruating females have low ferritin

  31. Symptoms and signs • Anaemia – speed of onset angina/CCF • Glossitis • Angular stomatitis (~10%) • Postural hypotension • Palpitations • Mild alopecia

  32. Iron deficiency- interesting facts • 7mg Fe/1000 kcal diet = Poor iron content • Phytates/phosphates reduce absorption = reduce Fe availability • Iron losses males 0.5-1 mg/day females 1-2 mg/day pregnancy 1.5-3 mg/day children 1 mg/day (2-3 yrs require 5- 7 mg/day) • Breast milk/Toddlers diet often don’t keep up with Iron demand

  33. Iron deficiency- Points to remember • 1 Aspirin /day – average gut loss 2-3ml/d = 2-3 mg Iron • 1 Hookworm – average gut blood loss 0.03 ml/day • Liver disease– get Iron deficiency with a normal MCV; ferritin likely to be normal or increased, therefore difficult to diagnose • 1/3rd of patients with Fe deficiency have low/ borderline B12 • After partial gastrectomy, 50% of patients will be Iron deficient at 5 years

  34. 4% myoglobin (4%) transferrin(0.1%) 29% enzymes(0.2%) Ferritin 66% Haemoglobin Total body Iron 3-4 gms 6 gms of Hb made per day = 20 mg Fe Plasma Fe pool= 4 mg, hence large turnover

  35. Iron deficiency – helpful film comments • Microcytes • Anisocytosis • Poikilocytosis • Pencil cells • Target cells: few, not many • Polychromasia = reticulocytes ?bleeding • Neutropenia ; reverts with Iron therapy • Thrombocytosis

  36. Diagnosis • Serum Ferritin measures Fe stores Sensitive Specific FerritinCauses of low ferritin Fe deficiency CV <4% Hypothyroid Diurnal variation <10% Serum FeCauses of low serum Fe Fe def. CV >20% Inflammation Diurnal variation> 50% Infection malignancy trauma Causes of high TIBC Fe def.

  37. Plasma Ferritin • Low plasma ferritin: Iron deficiency Hypothyroidism Vitamin C deficiency • High plasma ferritin: Iron overload Acute phase response Liver damage Sensitivity 0.23 and specificity 1.0 for diagnosis of IDA

  38. Haemolytic anaemia • Immune • Non-Immune

  39. Evidence of haemolysis • FBC • Reticulocytes • LFT • LDH • Haptoglobin • Blood film – Schistocytes -- Spherocytes

  40. Spherocytes Schistocytes

  41. Immune vs non-Immune • Direct Coomb’s Test

  42. Causes of false positive DCT • Autoimmune conditions • Paraproteinemias e.g myeloma • Post allogeneic transplant

  43. Causes of Immune haemolysis • Autoimmune • Allo-immune (blood transfusion, mismatched bone marrow transplants) • Drug-induced

  44. Autoimmune haemolysis • Cold AIHA • Warm AIHA • Paroxysmal cold haemoglobinurea

  45. Practical problems • Difficulties in blood grouping • Difficulties in cross-matching blood

  46. Management • Blood transfusion • Steroids • IVIG – less effective • Rituximab • Chemotherapeutic agents