MACROCYTIC ANEMIAS

MACROCYTIC ANEMIAS

These are the anemias in which the RBC have an MCV of greater than 100fl

There are 2 groups of macrocytic anemias

1. Megaloblastic anemia

2. Non megaloblastic macrocytic anemia

Requirements for Red Blood Cell Production

ErythropoeitinProteins, required for globin synthesis Iron Vitamin B12 and folic acidVitamin B6 Vitamin C Thyroid hormones, estrogens and

androgens

MEGALOBLASTIC ANEMIA

These are a group of disorders in which the cause the anemia is due to deficiency of vitamin B12 and folic acid

The macrocytes in this condition is usually “oval” - hence they are also called as MACRO OVALOCYTES

NON MEGALOBLASTIC MACROCYTIC ANEMIAS

These are disorders in which the macrocytosis is not due to vitamin B12 or folic acid deficiency

Here the macrocytes are “ROUND” The conditions in which such round macrocytes are seen

are1. Reticulocytosis2. Hypothyroidism / myxedema3. Myelodysplastic syndrome4. Scurvy (Vit-C dif) 5. Sideroblastic anemia6. Liver disorders

MEGALOBLASTIC ANEMIA

Vitamin B12 and folic acid are important nutrients required in the process of nuclear maturation

They are required during erythropoiesis (during DNA synthesis)

These anemias may be caused because of a nutritional deficiency or impaired absorption mainly.

MEGALOBLASTIC ANEMIA

Impaired DNA synthesis leading to defective cell maturation and cell division

Nuclear maturation delays from the cytoplasmic maturation – NUCLEAR CYTOPLASMIC ASYNCHRONY

Abnormally large erythroid precursors and red cells

Affect all marrow elements. Neurologic symptoms (dorsal

columns)Ineffective erythropoiesis:

High indirect bilirubinVery high LDH

MEGALOPLASTIC ANAEMIA.

Folic Acid:– It a vitamin which yellow in colour, water soluble,

necessary for the production of the RBC, WBC and platelets.

– It is not synthesized in the body.– It is found in large number of green fresh vegetables,

fruits.Daily requirement: The human body needs about 100-150 µg daily.

Absorption: It is absorbed in the Duodenum and Jejunum.Transportation: Weakly bound to albumin.

METABOLIC FUNCTION

1. Purine synthesis

2. Conversion of homocysteine to methionine ( which also requires B12 )

FOLIC ACID DEFICIENCY

1. INCREASED DEMAND

2. DECREASED INTAKE

3. DECREASED ABSORPTION

4. METABOLIC INHIBITION

INCREASED DEMAND

PregnancyLactation Infancy Puberty and growth periodPatients with chronic hemolytic anemiasDisseminated cancer

DECREASED INTAKE

ElderlyLower socio economic statusChronic alcoholics

DECREASED ABSORPTION

Acidic food substances in foods like legumes, beans

Drugs like phenytoin, oral contraceptivesCeliac disease which affect the gut

absorptionHeat sensitive – more loss during cooking

METABOLIC INHIBITION

Vitamin B12:

This vitamin is synthesized in nature by micro-organism in the intestine of man and animals, but we can not obtain it from the bacteria in our bodies, because it is synthesizing in the large colon after the site of absorption and it is wasted in the faeces in about 5µg/day. So we obtain it from animal food such as liver, kidney, meat and dairy products as milk and cheese.

VITAMIN B12

Abundant in animal foodsMicroorganisms are the ultimate origin of

cobalamin It is stored in liver for many years It is efficiently reabsorbed from bile It is resistant to cooking and boiling

Diary requirements:

The human body needs about 1-2 µg daily.Absorption:

B12 is combined with glycoprotein called the intrinsic factor (IF), which is synthesized in the gastric cells. The absorption occurs in the distal ileum.

Transportation:

Transport by a protein synthesized in the liver called Transcobalamine II, which carry vitamin B12 to liver, nerves and bone marrow.

VITAMIN B12 DEFICIENCY

INCREASED REQUIREMENTDECREASED INTAKE IMPAIRED ABSORPTION

INCREASED DEMAND

PregnancyLactationPubertyGrowth periodHyperthyroidismDisseminated cancer

DECREASED INTAKE

Inadequate intakeVegetarian diet

IMPAIRED ABSORPTION INTRINSIC FACTOR DEFICIENCY due to

chronic gastritis or antibodies against stomach cells.

- PERNICIOUS ANEMIA- GASTRECTOMY

Malabsorption statesDiffuse intestinal diseases. Eg., lymphoma,

systemic sclerosisCompetitive parasitic uptake – fish tapewormBacterial overgrowth

CLINICAL FEATURES

Patients develop all general symptoms and signs of the anaemia.

Knuckle pigmentation Angular stomatitisAtrophic glossitis- “beefy” tongueNeurological disorders: sever deficiency of

the folic acid causes neuropathies diseases.Deficiency during pregnancy causes neural

tube defect.

PERIPHERAL BLOOD FINDINGS

1. Hemoglobin – decreased2. Hematocrit – decreased3. RBC count – decreased/normal4. MCV - >100fl ( normal 82-98fl)5. MCH –increased6. MCHC – NORMAL7. Reticulocytopenia.8. Total WBC count – normal / low9. Platelet count – normal/ low10. Pancytopenia, especially if anaemia is sever.

PERIPHERAL SMEAR

RBC:Poikilocytosis - tear drops and schistocytesAnisocytosis - oval macrocytes

-Macro ovalocytes (macrocytic normochromic)

-well hemogloibised, thicker than normal

-inclusions like HOWELL JOLLY BODIES, basophilic stippling, Cabot rings

PERIPHERAL SMEAR

WBC:

Normal count or reduced count

Hypersegmented neutrophils (>5 lobes)

MACRO POLYMORPHO NUCLEAR CELLS (Macropolys)

PLATELETS:

Normal or decreased

BONE MARROW

Markedly hypercellularMyeloid : erythroid ratio decreased or

reversed. (Normally, there are three myeloid precursors for each erythroid precursor resulting in a 3:1 ratio, known as the M:E (myeloid to erythroid) ratio)

Erythropoiesis : MEGALOBLASTIC

MEGALOBLAST

1. Abnormally large precursor

2. Deeply basophilic royal blue cytoplasm

3. Fine chromatin with prominent nucleoli

4. Nuclear cytoplasmic asynchrony

5. Abnormal mitoses

6. Maturation arrest

BIOCHEMICAL FINDINGS

Increase in serum unconjugated bilirubin- because of ineffective erythropoiesis

Increase is LDHNormal serum iron and ferritin

TESTS FOR FOLATE AND B12 DEFICIENCY

Serum folate assay Red cell folate assaySerum B12 assay

PERNICIOUS ANEMIA

Scandinavian countries more prevalentDisease of elderly – 5th to 8th decadesGenetic predispositionTendency to form antibodies against

multiple self antigens

PATHOGENESIS

Immunologically mediated, autoimmune destruction of gastric mucosa

CHRONIC ATROPHIC GASTRITIS – marked loss of parietal cells

Three types of antibodies:a) Type I antibody- 75% - blocks vitamin B12 and IF

bindingb) Type II antibody – prevents binding of IF-B12 complex

with ileal receptorsc) Type III antibody – 85-90% patients – against specific

structures in the parietal cell Associated with other autoimmune diseases like

autoimmune thyroiditis

DIAGNOSTIC FEATURES

1. Moderate to severe megaloblastic anemia2. Leucopenia with hypersegmented neutrophils3. Mild to moderate thrombocytopenia4. Mild jaundice due to ineffective erythropoiesis

and peripheral hemolysis5. Neurologic changes 6. Low levels of serum B12

7. Elevated levels of homocysteine 8. Striking reticulocytosis after parenteral

administration of vitamin B12

9. Serum antibodies to intrinsic factor