Macrocytic Anemia: Megaloblastic Anemia, Pernicious Anemia, Causes ,Diagnosis

Bone marrow produces abnormally large red blood cells, which results in the blood disorder known as macrocytic anemia. These abnormal blood cells lack the nutrients that red blood cells require to function normally. There are two types of macrocytic anemia. They expand when your body lacks certain nutrients. Despite the fact that macrocytic anemia is not a dangerous illness, ignoring it might have serious negative effects on your health.

Associated with

• Liver disorders
• Hypothyroidism 
• Megaloblastic anemia 
• Chemotherapy drugs
• Mnemonic: LHMC

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Megaloblastic Anemia 

Occurs due to Deficiency of Vitamin B12 and folic acid. Vitamin B12 is Absorbed at terminal ileum. B12 is Absorbed only if B12 is combined with intrinsic factor (IF). Intrinsic factor also called castle's factor is Released by Parietal cells of the stomach. Vegetarian food is deficient in vitamin B12, Food with B12 when ingested,B12 is separated from food by peptic enzymes Enters the stomach then it Binds with haptocorrin - released by Salivary gland. The complex enters the duodenum. Haptocorrin is separated from B12 by Pancreatic enzymes. B12 binds with intrinsic factor (IF) and Moves to the terminal ileum. Terminal ileum has cubilin receptors, B12-IF binds to the receptors and get absorbed. Absorbed B12 is transported by transcobalamin 2. Vitamin B12 is used for Thymidine production which is important for nuclear maturation. In Patients with vitamin B12 deficiency the Nuclear membrane is not matured, Cytoplasm is matured and there is asynchrony between nucleus and cytoplasm ratio.

Vit. B12 Helps in conversion of Methylmalonyl CoA to succinyl CoA and Homocysteine to methionine. Vitamin B12 deficiency doesn't convert the methylmalonyl CoA to succinyl CoA. Methylmalonyl CoA levels increase whereas succinyl CoA levels decrease. Succinyl CoA is important for myelin production. Due to deficiency of myelin production, Leads to Neurological symptoms. Vitamin B12 deficiency doesn't convert homocysteine to methionine. Homocysteine levels increase and methionine levels decrease. Increase in homocysteine levels leads to atherosclerosis. 

Causes of Vitamin B12 Deficiency 

• Vegetarian diet
• Increased demand - may be pregnancy, lactation, growing child etc
• Infections - Diphyllobothrium latum

Pernicious Anemia 

It is an autoimmune disorder. 3 types of antibodies which causes prenicious anemia are:

• Type 1: Inhibits binding of B12 to intrinsic factor. 
• Type 2: Inhibits binding of B12-IF to iliac cubilin receptors. 
• Type 3: Ab against Parietal cells.

Clinical Features 

• Fatigue and pallor.
• Hyperpigmentation - mainly seen in knuckles and interphalangeal areas.

• Atrophic glossitis - Called beefy red tongue (smooth tongue).
• Atrophic gastritis - Due to Pernicious anemia (Ab against Parietal cells). It is a Risk factor for gastric adenocarcinoma.

Clinical Feature seen only in B12 deficiency and not seen in folic acid deficiency. Neurological manifestations are: 

• Subacute combined degeneration.
• Mnemonic: SACD.
• Degeneration of spinal tract.
• Both sensory and motor loss - so called combined.

RBC Indices

• Hemoglobin - low.
• MCV - high (> 100fl).
  • Normal - 80 to 100 fl.
• MCH - high.
• MCHC - normal.

Blood Picture

Shows problems associated with:

• RBC
• WBC
• Nuclear cytoplasmic asynchrony affects all the cells along with RBCs.

RBC Findings

The RBCs shows the presence of:

• Macrocytes - Large RBCs.
• Macroovalocytes - Large oval shaped RBCs.
• Howell jolly bodies - dot like structures on RBCs,Composed of DNA or nuclear remnants. Seen in Megaloblastic anemia and post splenectomy. 
• Cabot rings are also seen- They are Composed of arginine mitotic spindle. Can be molded in any shape and are Seen as 8 shaped structures. 

Finding in WBC

Hypersegmentation of neutrophil is observed.

Normal lobes of Neutrophils is  2 to 5 lobes. A neutrophil is said be hypersegmented when 5% of the Neutrophils have 5 lobes. Any 1 neutrophil has more than or equal to 6 lobes. The megaloblastic anemia present with pancytopenia ultimately. In this RBC, WBC and platelets count is low.

Bone Marrow Findings

Bone marrow hypercellular (hyperplasia)- It is erythroid hyperplasia as RBCs are mostly affected. In normal bone marrow-Myeloid / erythroid ratio is 3:1. In erythroid hyperplasia there will be a reversal of the M / E ratio. More erythrocytes are present. It Shows sieve like chromatin.

Biochemical Findings

Ineffective erythropoiesis causes lysis there is Increases serum bilirubin and LDH.

Serum bilirubin	Increases
Serum LDH	Increases
Vitamin B12	Decreases
Folic acid	Decreases
Homocysteine	Increases
Methylmalonyl CoA	Increases
Anti IF antibody	Present (Pernicious anemia)

Schilling Test

It is used to find the cause of megaloblastic anemia. It is not for the diagnosis of megaloblastic anemia. 

Folate Metabolism and Deficiency 

Site of folate absorption - Jejunum. Chromosome controlling the folate metabolism - chromosome 21. Deficiency of folate seen in Alcoholic patients and in Pregnancy, In some cases may cause neural tube defects.

Clinical Features are Same as vitamin B12 deficiency. Neurological symptoms are not seen. Serum folate and RBC folate is less. The FIGLU test is positive. It is Urine test for folic acid deficiency. 

FIGLU Test

Histidine converts to FIGLU (Formimino glutamic acid) and it uses folic acid converts to glutamate In folate deficiency as there is no folate available to convert to glutamate. Therefore, FIGLU is excreted through urine treatment includes vitamin B12 and folic acid supplements. 

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