PATHOPHYSIOLOGY OF ANEMIA IRON DEFICIENCYpptx

anemia physiology

1. Pathophysiology of Anemia DR.PRIYANKA VERMA MBBS MD

2. ESR

3. Hematocrit Value Volume of red blood cells expressed in percentage is called the hematocrit value or packed cell volume (PCV). Anticoagulant mixed blood centrifuged for 30 minutes at a speed of 3000 revolutions per minute (rpm ),

4. Hematocrit Value The red blood cells settle down at the bottom having a clear plasma at the top . Plasma - 55 % and red blood cells - 45%. between plasma and RBCs - white buffy coat  by the aggregation of white blood cells and platelets .

5. Red cell indices The red cell indices defined below are calculated taking normal values of the RBC count 5 million/ μL , PCV 45% and Hb level of 15 g/ dL .

6. 1 . Mean corpuscular volume Average volume of a single RBC . It is calculated by dividing the PCV by the red cell count . MCV = PCV / RBC Count Normal MCV is 90 μm3 ( range 78–94 μm3) Normal MCV = normocytosis . ↓ MCV = microcytosis . ↑ MCV = macrocytosis .

7. 2. Mean cell haemoglobin concentration (MCHC) Amount of Hb expressed as a percentage of the volume of a RBC. It is calculated by dividing the amount of Hb in g/ dL by the volume of packed cells in 100 mL of blood and then multiplying by 100 . MCHC = Hb g% PCV/100 mL 100  

8. 2. Mean cell haemoglobin concentration (MCHC) Normal value of MCHC is 33.3% (range 30–38%). RBCs with normal values of MCHC are called normochromic. MCHC are less than the normal = hypochromic RBCs high levels of MCHC (> 38%) --- Hyperchromia is very rare, cannot occur , since the RBCs cannot hold Hb beyond the saturation point.

9. IRON METABOLISM The total iron content of an adult body is 3-5 g. About 70% - RBC as hemoglobin. 5 % - in myoglobin. About 23% - as ferritin (stored form). Small amounts - cellular enzymes. Plasma small quantity - transferrin . Rest of the body iron - as ferritin or haemosiderin in liver, bone marrow and other tissues.

10. Transport in the Blood The iron that enters the blood stream in ferrous[ Fe²⁺] form gets oxidized again to ferric [ Fe³ ⁺] form by ceruloplasmin present in the plasma . Fe³⁺ then binds to a plasma protein called apotransferrin to form transferrin .

11. Transport in the Blood Thus iron is transported as transferrin in the plasma and can bind 400 mg of iron/100 mL of plasma. This is known as total iron binding capacity of plasma .

12. Iron metabolism ferrous[ Fe²⁺] - ferric [ Fe³⁺]

13. Definition Anaemia is a clinical condition in which the oxygen carrying capacity of blood is reduced . It is characterized by reduction in the number of RBCs less than 4 million/ μL or their content of haemoglobin less than 12 gm/ dL or both . Grading Mild Anaemia : Haemoglobin 8-12 gm/ dL Moderate Anaemia: Haemoglobin 5-8 gm/dl Severe Anaemia : Haemoglobin less than 5 gm/ dL ANAEMIAS

14. Types of anaemia depending upon the causative mechanism are: A. Deficiency anaemias B. Blood loss anaemias or haemorrhagic anaemias C. Haemolytic anaemias D. Aplastic anaemia E. Anaemia due to chronic diseases . CLASSIFICATION: Aetiological (Whitby’s) classification

15. A. Deficiency anaemias Iron deficiency anaemia Megaloblastic anaemia (pernicious anaemia) due to deficiency of vitamin B12 Megaloblastic anaemia due to deficiency of folic acid. Protein and vitamin C deficiency can also cause anaemia.

16. B . Blood loss anaemias or haemorrhagic anaemias Acute post-haemorrhagic anaemia as in accidents Chronic post-haemorrhagic anaemia.

17. C. Haemolytic anaemias . Due to- increased destruction of RBCs. These can be: 1. Hereditary haemolytic anaemias : Thalassaemia, Sickle cell anaemia, Hereditary spherocytosis and Glucose 6-phosphate dehydrogenase (G6PD) deficiency.

18. 2. Acquired haemolytic anaemias such as Immunohaemolytic anaemia ( due to antibodies against RBCs ) Due to direct toxic effects (e.g. in malaria, snake venom, toxic effects of drugs and chemicals , etc.) In splenomegaly Presence of isoagglutinins like antiRh Autoimmune diseases such as rheumatoid arthritis and ulcerative colitis.

19. Aplastic anaemia . It occurs due to the failure of bone marrow to produce RBCs. Anaemia due to chronic diseases . It is seen in tuberculosis, chronic infections, malignancies, chronic lung diseases , etc.

20. Based on the Mean Cell Volume (MCV), i.e . cell size and the Mean Corpuscular Haemoglobin Concentration (MCHC) , i.e. haemoglobin saturation of RBCs, the anaemias can be classified as : 1 . Normocytic normochromic anaemias . 2. Microcytic hypochromic anaemias . 3. Macrocytic normochromic anaemia. Morphological (Wintrobe’s) classification

21. Normocytic normochromic anaemias. By normal MCV (78–94 μm3 or 78–94 μL ) and normal MCHC (30–38%). seen in: Acute post-haemorrhagic anaemia, Haemolytic anaemias and Aplastic anaemias.

22. 2. Microcytic hypochromic anaemias. By reduced MCV (< 78 μm3) and reduced MCHC (< 30%). Iron deficiency anaemia, Chronic post-haemorrhagic anaemia and Thalassaemia.

23. 3. Macrocytic normochromic anaemia. Increased MCV ( > 94 μ m3) and normal MCHC (30–38%). Megaloblastic anaemia (pernicious anaemia) due to deficiency of vitamin B 12 Megaloblastic anaemia due to deficiency of folic acid.

24. Hypochromic microcytic anemia Hemoglobin Prophyrin Iron Globin chain Thalassemia Iron def. anemia Sidroblastic anemia DNA DNA synthesis Megaloblastic anemia: -B12 def. -Folate def . MDS Macrocytic anemia RBC count Hemolysis RBC production Acute bleeding Autoimmune Enzymopathy Membranopathy Mechanical Sickle cell anemia BM failure: -Chemotherapy -Aplastic anemia -Malignancy Anemia of chronic disease Blood loss Normocytic normochromic anemia

25. GENERAL CLINICAL FEATURES OF ANAEMIA Anaemic hypoxia  several cardiorespiratory compensatory responses  So , general clinical features are due to : Tissue hypoxia and Compensatory mechanisms . Muscle hypoxia  Generalized muscular weakness, tiredness and easy fatigability

26. Deficiency of Hb  Pallorness of skin and mucous membranes Compensatory stimulation of respiratory centre  breathlessness with increased rate and force of respiration.

27. Compensatory mechanisms increasing the cardiac output  palpitation, tachycardia and cardiac murmurs In very severe cases of anaemia, features of cardiac failure Cerebral hypoxia  lethargy, headache, faintness, especially on exertion, tinnitus, restlessness, confusion and drowsiness.

28. Ocular manifestations  visual disturbances and retinal hemorrhages and cotton wool spots . GI – symptoms  anorexia, flatulence , nausea, constipation. In pernicious anaemia, there occurs atrophy of papillae on tongue.

29. Reproductive system  amenorrhoea and menorrhagia. Renal system in severe anaemia  disturbances of renal function and albumin urea. Basal metabolic rate  is increased in severe anaemia.

30. Common Anemias

31. IRON DEFICIENCY ANAEMIA Most common anaemia in India . More common: In women between 20–45 years than in men, At periods of active growth in infancy, childhood and adolescence.

32. IRON DEFICIENCY ANAEMIA Daily requirement Only 10% of the dietary intake of iron is absorbed . Adult males is 5–10 mg/day Females is 20 mg/day (to compensate the menstrual loss). Pregnant and lactating women - 40 mg /day.

33. Dietary sources - Meat, liver, egg, leafy vegetables,whole wheat and jaggery. The iron in foods of animal origin is better absorbed than iron in foods of vegetable origin.

34. Causes of Iron Deficiency Anaemia Physiological Increased demand (adolescent girls, menstruation, pregnancy, lactation) Reduced absorption (phytates and oxalates in diet) Tea, coffee consumption Rapidly occurring pregnancies

35. Causes of Iron Deficiency Anaemia Physiological Teenage pregnancy Repeated abortions Reduced iron intake Poverty Exclusively milk fed infants

36. Pathological Menorrhagia Piles Hookworm infestation Malabsorption Gastrectomy Hypochlorhydria Achlorhydria

37. Signs and symptoms General features of anaemia. Characteristic features of iron deficiency anaemia Nails become dry, soft and spoon-shaped ( koilonychia ). Tongue becomes angry red (atrophic glossitis ). Mouth may show angular stomatitis. Oesophagus may develop their membranous webs at the post cricoid area leading to dysphagia ( Plummer– Vinson syndrome).

38. Investigations Findings Peripheral smear - Hypochromic microcytic RBC count— ↓se Haemoglobin content — ↓se Red cell indices MCH, MCV, MCHC — ↓se Marrow cellularity - ↓se TIBC - ↑se Serum ferritin and serum iron - ↓se Stool and urine examination- Presence of ova, cysts and pus cells

39. Treatment Oral administration of Fe2+ salts Parenteral iron: Iron dextran, iron sorbitol, iron sucrose Correction of causative factor if possible. Diet supplementation: Consumption of leafy greens , jaggery, meat, liver. Treatment of infection. Blood transfusion: For severe anaemia. 1 unit of blood increases haemoglobin by 1 g%.

40. MEGALOBLASTIC ANAEMIA Abnormally large cells of erythrocyte series due to defective DNA synthesis because of deficiency of vitamin B12 and folic acid . I. Megaloblastic anaemia due to vitamin B12 deficiency Causes of vitamin B12 deficiency are: 1. Inadequate dietary intake may occur in: Strict vegetarians and Breast-fed infants.

41. 2. Malabsorption of vitamin B12 - may be due to: Gastric causes -autoimmune cause of failure of secretion of intrinsic factor, gastrectomy and congenital lack of intrinsic factor. Intestinal causes – decreased vitamin B12 absorption are tropical sprue, ileal resection, Crohn’s disease, fish tapeworm infestation

42. Addisonian pernicious anaemia Megaloblastic macrocytic anaemia resulting from failure of secretion of intrinsic factor by the stomach not related to total gastrectomy . In the absence of intrinsic factor, dietary vitamin B 12 is not absorbed and this results in vitamin B 12 deficiency .

43. Features of pernicious anaemia include: Features of megaloblastic anaemia Specific features of pernicious anaemia are: Anti-intrinsic factor antibodies in serum (present in 50% cases) Abnormal vitamin B12 absorption test corrected by the addition of intrinsic factor (Schilling test).

44. II. Megaloblastic anaemia due to folate deficiency Salient features of folic acid and its role in erythropoiesis . Causes of folate deficiency are: Inadequate dietary intake due to poor intake of vegetables as seen in poor people, infants and alcoholics. Malabsorption , e.g. in coeliac disease, tropical sprue and Cohn's disease.

45. CLINICAL FEATURES General symptoms and signs of anaemia Neurological Paresthesia of fingers and toes from peripheral neuropathy Signs of sub acute combined degeneration of the spinal cord Dementia, depression, irritability

46. Neurological Involvement in Vitamin B12 Deficiency Deficiency of methylcobalamin B-12 produces impairment in the conversion of homocysteine to methionine. Methionine is needed for the production of choline and choline-containing phospholipids. These are required by the neuronal cells .

47. Neurological Involvement in Vitamin B12 Deficiency Adenosylcobalamin , ( B12 containing cofactor) is required for the conversion of methylmalonyl CoA to succinyl CoA. Lack of this cofactor leads to increase in the levels of methylmalonyl CoA .  As a result, non-physiologic fatty acids are synthesised and incorporated into neuronal lipids .

48. DIAGNOSIS 1. Blood picture : Macrocytic normochromic anaemia Oval macrocytes poikilocytosis , anisocytosis , hypersegmented neutrophils, giant platelets MCV : > 100fL Severe anaemia: Cabot ring, Howell Jolly bodies , basophilic stippling

49. DIAGNOSIS 2 . Bone marrow findings Megaloblastic picture: Megaloblasts ( cell gigantism) Increased pronormoblasts and early normoblasts (70%) Reduced intermediate and late normoblasts (30 %) 3 . S. Vitamin B12: Reduced

50. HAEMOLYTIC ANAEMIAS Haemolytic anaemias result from an increased rate of red cell destruction. The life span of red cells (normal 90---120 days) shortened. Marrow can compensate for increased red cell destruction by increased production of red cells (up to eight folds).

51. HAEMOLYTIC ANAEMIAS Sickle cell anaemia and thalassemia SICKLE CELL ANAEMIA Haemolytic anaemia occurring due to sickling of the red blood cells because of substitution of glutamic acid by valine at 6 th position of β chain of haemoglobin (sickle cell haemoglobin— HbS ).

52. Pathophysiology Low oxygen tension/low pH at tissue level ↓ Hb become less soluble and precipitates as crystals ↓ Crystals elongate and become sickle shaped ↓ Sickle shaped RBC block the microcirculation (as less flexible)

53. Clinical features Growth impairment, splenomegaly (due to reticuloendothelial cell hyperplasia), later auto splenectomy (Fibrotic, small and infracted spleen), vaso occlusive crisis, haematological crisis, Stroke, pleuritic chest pain, chronic leg ulcers, avascular necrosis of femoral head, Vitreous haemorrhage , retinal damage.

54. Diagnosis Peripheral blood smear— Normocytic normochromic anaemia , sickle shaped cells , target cells, increased reticulocytes, leucocytosis, increased platelets Hb electrophoresis— HbS

55. Thalassemia A genetically determined disorder in which the rate of synthesis of one or more types of hemoglobin polypeptide chain is decreased . Thus , there are 2 major classes of thalassemia: α thalassemia and β thalassemia ,

56. Thalassemia β thalassemia - failure to synthesize β chain ,there is excess α chain production that damages red cell precursor and red cells . α- thalassemia Anemia of α-thalassemia (failure to synthesize α chain) is more hemolytic.

57. HEREDITARY SPHEROCYTOSIS ( CONGENITAL HAEMOLYTIC ICTERUS) Biconcave shape of mature RBC is maintained by proteins— spectrin , transmembrane protein band 3 and linker ankyrin . Mutations in these proteins lead to loss of biconcave disc shape of RBC and it becomes sphere shaped ( spherocytes ), Which hemolyse more quickly than normal red cells. Most leading causes of hemolytic anaemia because cells are not able to squeeze through the capillaries and get sequestered in spleen.

58. GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G-6-PD ) DEFICIENCY ANAEMIA It is an inborn error of metabolism predisposing a person to hemolysis when exposed to oxidative stresses such as oxidative drugs , infectious agents . The condition is associated with a low level of G-6-PD enzyme , which is involved in HMP shunt .

59. The HMP shunt  plays a significant role in NADPH 2  formation and in pentose sugars that are biosynthetic precursors of nucleic acids and amino acids . Cells can be protected from highly reactive oxygen species by NADPH  2   So, in case of G-6-PD deficiency , NADPH is low resulting in low levels of reduced glutathione and exposes the person to the risk of haemolytic anaemia during oxidative stress.

60. Hypoplastic /aplastic Anaemia This is due to hypo activity of bone marrow secondary to drug toxicity or irradiation or due to an unknown cause. All the cell counts except agranulocytes are reduced. Normochromic normocytic anaemia develops .

61. Chronic Renal Disease and Chronic Inflammatory Disease In renal disease EP production is less , so RBC production decreases . In chronic diseases, bone marrow activity is less due to some chemical produced at the inflammatory site. Normochromic normocytic anaemia is seen.

62. ANAEMIA IN CHRONIC LIVER DISEASE Chronic liver disease is associated with iron deficiency anaemia , mostly due to chronic haemorrhage in GIT. This occurs because liver is the main organ involved in the production of iron regulatory protein , that is hepcidin.

63. PBL A 25-year-old , Indian 4 month pregnant female come to the OPD with complaints of fatigue, weakness, and shortness of breath with minimal activity. On examination she has pallor, spoon shaped nails, Tongue becomes angry red (atrophic glossitis ). with Hb values - 7 g/ dL MCV 60μm3) (normal range 78–94 μm3) and reduced MCHC 26 %. (normal range 30–38%). Find the probable diagnosis and suggest further investigation.

64. Thank you.