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Senior Academic Half Day Dr S W Bokhari Consultant Haematologist UHCW Topics to cover Low blood counts - Anaemia due to haematinic deficiency - Some other causes of anaemia - Thrombocytopenia 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 Anaemias due to haematinic deficiency Aim Outline practical overview of B12, folate and Iron deficiency 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 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) 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 Biochemistry Homocysteine Methionine (Methyl B12) Methyl THF THF DNA dTMP CYTOSOL dUMP 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 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:---------------------------------- Blood Film----diagnosis? Diagnosis? B12 level: 105 IF antibodies: positive 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 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 Laboratory Abnormalities Upto 40% not anaemic Upto 30% not macrocytic (masked by IDA/thalassaemia) Pancytopenia Neutrophil hypersegmentation Hyposplenism Howell Jolly bodies Laboratory Abnormalities Chemistry Increased serum Iron Increased Iron stores Increased bilirubin and LDH Decreased immunoglobulins Decreased cholesterol Presentation and Management Optic atrophy Subacute comb.deg. Pancytopenia Urgent referral Check B12 Treat blind with B12 & folate 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 Cont… B12 <170 pg/ml B12 170-200 normal FBC/well Treat Neurology or 5 1mg injections >65/debilitated 1mg every 3 months <65: IF Abs Schillings test Treat ?improved ?B12 ^ repeat 3-4 mo Level normal/static probably spurious 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 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 Schilling Test Low B12 (<100) + pos IF Ab +>60yrs = PA If <60yrs/ IF Ab negative Schilling test Requirements: - Normal renal function - B12 replete Schilling Test- Part 1 1 ug B12 (0.5 ug CiCo^57) orally Gut normal 1000ug B12 IM IF normal Absorbed ~30% Urine Must collect 24 hr urine (~25% collections inadequate) Blocks all binding sites Schilling test – Part 2 If absorption reduced in part 1 1ug B12(0.5 CiCo^57) + IF orally No change Gut disease 1000ug B12 IM normal excretion= IF deficient (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 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 Serum folate Not sensitive or specific Spurious low values – anorexia alcoholism anticonvulsants pregnancy Falsely raised values – acute food intake Haemolysis 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) 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 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 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 Symptoms and signs Anaemia – speed of onset angina/CCF Glossitis Angular stomatitis (~10%) Postural hypotension Palpitations Mild alopecia 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 57 mg/day) Breast milk/Toddlers diet often don’t keep up with Iron demand 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 4% 29% myoglobin (4%) transferrin(0.1%) enzymes(0.2%) Ferritin 66% Total body Iron 3-4 gms 6 gms of Hb made per day = 20 mg Fe Plasma Fe pool= 4 mg, hence large turnover Haemoglobin Iron deficiency – helpful film comments Microcytes Anisocytosis Poikilocytosis Pencil cells Target cells: few, not many Polychromasia = reticulocytes ?bleeding Neutropenia ; reverts with Iron therapy Thrombocytosis Diagnosis Serum Ferritin Sensitive Ferritin CV <4% Diurnal variation <10% Serum Fe CV >20% Diurnal variation> 50% measures Fe stores Specific Causes of low ferritin Fe deficiency Hypothyroid Causes of low serum Fe Fe def. Inflammation Infection malignancy trauma Causes of high TIBC Fe def. 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 Haemolytic anaemia Immune Non-Immune Evidence of haemolysis FBC Reticulocytes LFT LDH Haptoglobin Blood film – Schistocytes -- Spherocytes Spherocytes Schistocytes Immune vs non-Immune Direct Coomb’s Test Causes of false positive DCT Autoimmune conditions Paraproteinemias e.g myeloma Post allogeneic transplant Causes of Immune haemolysis Autoimmune Allo-immune (blood transfusion, mismatched bone marrow transplants) Drug-induced Autoimmune haemolysis Cold AIHA Warm AIHA Paroxysmal cold haemoglobinurea Practical problems Difficulties in blood grouping Difficulties in cross-matching blood Management Blood transfusion Steroids IVIG – less effective Rituximab Chemotherapeutic agents