Professor Ahmad Alaysh Msc (UK) MRCP (UK) consultant physician/hematologist

1. Professor Ahmad AlayshMsc (UK) MRCP (UK)consultant physician/hematologist

2. Microcytic anemias

3. Microcytic anemias • Iron deficiency anemia (IDA) • Anemia of chronic diseases • Thalassemia trait • Sideroblastic anemia • Lead poisoning

4. IDA • Iron homeostasis (metabolism and requirements) • Prevalence of IDA: affects almost 500 million people worldwide. • Developing countries: combination of pathological blood loss (e.g. intestinal hookworm)and the limited bioavailability of iron in predominantly vegetarian diets. • Developed countries: less common in adults (0.2% in men, 2.6% in premenopausal women and 1.9% in postmenopausal women), but common in infants and young children.

5. Normal values • Adult males, mean Hb 15.5 g/dl (lower limit of normal 13.5g/dl • Adult females, mean Hb 14 g/dl (lower limit of normal 11.5g/dl

6. IDA • Causes: • Blood loss • Menorrhagia • GI bleeding (hookworm, peptic ulcer, hiatus hernia, inflammatory bowel disease, carcinoma, hemorrhoids –piles) • Hematuria • Increased physiological requirements • Infant and adolescent growth • Premenopausal women • Pregnancy • Malabsorption • Coeliac disease • Post-gastrectomy • Atrophic gastritis • Dietary • Vegetarians especially in combination with increased physiological requirement • Seldom sole cause

7. Management • History and examination: • Laboratory investigation: • Investigation of underlying cause: • Treatment:

8. IDA • Clinical features: rapidly developing anemia is more debilitating • General symptoms and signs: fatigue, weakness, dyspnea, palpitation, headache, tinnitus, lack of concentration and chest pain (due to exacerbation of angina pectoris). Pallor of skin and mucous membranes. • Symptoms and signs specific to IDA: nail fattening and koilonychia (concave or spoon-shaped nails), sore tongue (glossitis) and papillary atrophy, angular stomatitis, dysphagia due to an esophageal web (Plummer-Vinson syndrome). Psychomotor delay and behavioral problems in young children

9. IDA • Symptoms and signs due to the underlying cause of IDA: heavy periods (menorrhagia), indigestion or a change in bowel habit, bleeding per rectum, hematuria.

10. History • Symptoms of anemia • Onset of symptoms • Duration of symptoms • Associated symptoms, angina • Symptoms related to possible causes of anemia

11. History • Dietary history (vegetarian), Abnormal feeding habits (PICA) • Drug history (NSAID, steroids, warfarin) • History of chronic diseases • History of bleeding (GIT, menorrhagia etc) • History of dysphagia (PVS) • History of surgery (gastrectomy)

12. Physical examination • Pallor of skin and mucous membranes • Angular stomatitis • Tongue, colour, smoothness, (atrophic glossitis) • Pulse (tachycardia) • Hands (pallor of palmer creases) • Nails (Koilonychia, platenychia) • Signs of underlying diseases – CTD, CLD, CRF, chronic infections (TB), IBD, SBE malignancy .etc

13. Investigations • Peripheral blood film: • Hypochromicmicrocytic anemia (low MCH & MCV) • Anisocytosis (variation in red cell size) • Poikilocytosis (variation in red cell shape) • Occasional target cells

16. Result Tests to confirm IDA • Test

17. Investigation of underlying disease • Abdominal and pelvic ultrasound • Barium studies of GIT • Faecal occult blood • Urinalysis for hematuria • Upper and lower GI endoscopy • Gynecological referral if appropriate

18. Treatment • Correct cause if possible • Correction of low Hb • Oral iron (ferrous sulphate 200mg TDS → ↑Hb by 2gm/dl every three weeks) – adequate response, continue for at least 6/12 to replace body stores • Parenteral iron • Blood transfusion

19. Treatment • Failure to respond to oral iron • Wrong diagnosis • Non-compliance • Malabsorption • Continued bleeding

20. Treatment • Blood transfusion :- • Avoid if possible • Give packed cells • Diuretics if elderly • Symptomatic anemia, dyspnea (CCF), angina

21. Anemia of chronic diseases • Anemia is proportional to disease activity • MCV → normal or reduced • Serum iron → reduced • Transferrin saturation → normal or reduced • TIBC → normal or reduced • Ferritin → normal or increased • Marrow iron → normal or increased

22. Thalassemia trait • Mild anemia: Hb concentration 10-14g/dl • MCV → very much reduced (out of proportion to the degree of anemia • Serum iron → normal • Transferrin saturation → normal • TIBC → normal • Ferritin → normal • Marrow iron → normal

23. Sideroblastic anemia • Anemia: any severity • MCV → normal, reduced or increased • Serum iron → normal or increased • Transferrin saturation → normal or increased • TIBC → normal or reduced • Ferritin → normal or increased • Marrow iron → normal or increased

24. Lead poisoning • Lead absorption is increased by dietary deficiency of iron • Pre-school children are at most risk • Anemia is normocytic or mildly hypochromic • Lead accumulation in mitochondria of erythroblasts inhibits delivery of iron to protoporphyrin and thus haem synthesis • Ringed sideroblasts may result • Measurement of the increased protoporphyrin which remains in the red cells is used as a screen for lead poisoning

25. Macrocytic anemias

26. Macrocytic anemias • Macrocytosis with normoblastic bone marrow • Macrocytosis with megaloblastic bone marrow

27. Macrocytosis with non-megaloblastic bone marrow • MCV of 100-110fl • Normal serum vitamin B₁₂ and folate • Causes: • Alcohol (direct toxic effect on erythropoiesis) • Liver disease (deranged cholesterol metabolism on the lipid component of red cell membrane) • MDS (impaired DNA synthesis) • Hypothyroidism • Pregnancy • Neonates • Reticulocytosis

28. Megaloblastic anemia • Delayed maturation of nucleus of red cell precursors in BM due to defective synthesis of DNA, red cells either die in BM (ineffective erythropoiesis) or enter blood stream as enlarged misshapen cells with reduced survival time. • Commonly due to vitamin B₁₂ or folate deficiency or both

29. Vitamin B₁₂ deficiency • Causes: • Deficiency of gastric intrinsic factor (PA, gastrectomy) • Intestinal malabsorption (ileal resection/Crohn’s disease, stagnant loop syndrome, tropical sprue, fish tapeworm and congenital malabsorption) • Dietary deficiency (vegans)

30. Pernicious anemia • Autoimmune disorder • IgG autantibodies targeted against gastric parietal cells and the B₁₂ transport protein intrinsic factor (IF) → reduced availability of the B₁₂-IF complex which is absorbed in the terminal ileum • Gastric parietal cell atrophy and achlorhydria, a more generalized epithelial cell atrophy and megaloblastic anemia • Disease is common in Northern Europe in women >40 years of age and is familial

31. Pernicious anemia • Premature greying of hair blue eyes and may develop other autoimmune disorders (vitiligo, thyroid disease and addison’s disease • Slight jaundice caused by the hemolysis of ineffective erythropoiesis. • Patients usually have symptoms of anemia and the generalized epithelial abnormality can manifest as glossitis and angular stomatitis • Demyelination of the dorsal and lateral columns of the spinal cord results in SCDC (sensory ataxia) • Increased incidence of carcinoma of the stomach

32. Diagnosis • Blood count and film: • macrocytic anemia (↑MCV ranging from 100-140fl). MCV may be normal if IDA, thalassemia or anemia of chronic disease coexist • Pancytopenia • Hypersegmented neutrophils • Anisopoikilocytosis

34. Diagnosis • Bone marrow: hyperplastic and megaloblastic erythropoiesis with unbalanced development of the nucleus and cytoplasm →premature cell death and mild hyperbilirubinemia • Estimation of vitamin B₁₂ and folate levels • Low vitamin B₁₂ • Serum folate may be elevated and red cell folate reduced (folate is trapped in it’s extracellular methyl FH₄ form)

35. Diagnosis • Autoantibodies: • PCA are found more commonly in the serum than IFA (90% vs 50%) • IFA→ almost diagnostic of PA • PCA → occur in about 15% of healthy elderly people and in association with other autoimmune diseases • Antibodies may also be detected in gastric juice

36. Diagnosis • Tests for vitamin B₁₂ absorption: Schilling test Patients swallow B₁₂ labelled with radioactive cobalt and absorption is usually measured indirectly by quantifying urinary excretion. If malabsorption is corrected by adding IF to the oral dose, PA is the likely cause.

37. Treatment • IM injections of vitamin B₁₂ 1000µg (1mg) –hydroxycobalamin are given over the first few weeks and then one injection every three months for life • Prediction of response: Reticulocytosis 6-7 days after the start of therapy • Blood transfusion is best avoided as it may lead to circulatory overload • Hypokalemia occasionally requires correction

38. Folate deficiency • Causes: • Dietary deficiency • Malabsorption (coeliac disease, tropical sprue, small bowel disease or resection) • Increased requirement (pregnancy, HA, myeloproliferative/malignant/inflammatory disorders) • Drug induced suppression of DNA synthesis (folate antagonists, metabolic inhibitors and prolonged use of nitrous oxide)

39. Folate deficiency • Clinical picture and investigations: • Symptoms of anemia or of an underlying disease • Initial tests are as for PA with a macrocytic anemia and a megaloblastic BM • Both serum and red cell folate levels are reduced in significant deficiency but red cell folate is a better measure of tissue folate stores • Investigation for malabsorption: Jejeunal biopsy

40. Folate deficiency • Treatment: oral folic acid 5mg once daily for several months (depending on the underlying cause) • Prophylaxis: increased demands (pregnancy and HA) • vitamin B₁₂ deficiency must be excluded before folate is prescribed (SCDC)

41. Aplastic anemia

42. Aplastic anemia Pancytopenia resulting from BM failure or aplasia

43. Aplastic anemia (AA) • Primary • Congenital • Acquired - idiopathic • Secondary

44. Secondary AA • Ionizing radiation – accidental exposure ( RT, Radioactive isotopes, nuclear power stations) • Chemicals – benzene, TNT, insecticides, hair dyes, DDT • Drugs – regularly cause BM suppression (busulphan, cyclophosphamide), occasionally cause BM suppression (chloramphenicol, sulphonamides, gold, phenylbutazone) • Infections – viral hepatitis, EBV, HIV • Pregnancy

47. Hemopoietic growth factors • Interleukin -1 • IL – 4 • IL – 5 • IL – 6 • IL – 7 • IL – 11 • Thrombopoietin – TPO • Erythropoietin – EPO • G-CSF • GM-CSF • M-CSF • Interferon - α • Interleukin – 3

48. Etiology of AA • Autoimmune disease, recovery of patients following use of immunosuppressive agents with antilymphocyte globulin (ALG) or cyclophosphamide • Severe damage to either the pleuripotential stem cell population (the seed) or the microenvironment of BM in which they develop (the soil) or to a combination of both

49. Congenital AA – Fanconi anemia ☺Features • Autosomal recessive • Aplastic anemia • Hypoplastic kidneys • Absent or hypoplastic thumb or radius • Microcephaly • Mental retardation • Age of presentation: 5 –10 years • 10% → AML • Treatment – Androgens +/- BMT • Androgens – remission rarely lasts > two years – virilization

50. AA – Clinical features • Peak age incidence → 30 years • M>F • Insidious or acute onset • Symptoms and signs are because of • Anemia • Leukopenia (increased susceptibility to infection) • Thrombocytopenia (increased bleeding tendency) • Lymphadenopathy and hepatosplenomegaly are not a feature