PERNICIOUS ANEMIA: VIT B12 ABSORPTION, PATHOGENESIS, CLINICAL FEATURES AND DIAGNOSIS
Author: Sanketh DS, MDS
Pernicious anemia is a type of megaloblastic anemia caused due to the lack of a substance called intrinsic factor, which leads to deficiency of Vitamin B12. Intrinsic factor is a glycoprotein produced by the parietal cells in the fundic region of the stomach that helps Vitamin B12 be absorbed by the body. Vitamin B12 along with folate is necessary for the synthesis of a protein called thymidine. Thymidine forms one of the building blocks of DNA. Deficiency of thymidine causes abnormalities in rapidly dividing cells of the body, especially red blood cells. Impaired DNA formation in the erythrocyte precursors, leads to premature apoptosis of these cells in the marrow, causing a dip in the number of red blood cells, leading to anemia.
VITAMIN B12 ABSORPTION & PATHOGENESIS OF PERNICIOUS ANEMIA
Vitamin B12, known as cobalamin, is present in eggs and animal foods and is not found in vegetables and fruits.
1. Vitamin B12 is attached to binding proteins in food and is released from these proteins during peptic digestion in the stomach.
2. The fundic region of the stomach housing the parietal cells, secrete pepsin, which helps in releasing Vitamin B12 from its binding protein.
3. Once detached, Vitamin B12 attaches to a salivary protein called R-binder or haptocorrin. VitB12-haptocorrin complex passes through the stomach to be separated by pancreatic proteases in the duodenum.
4. Once released, Vit B12 attaches to a glycoprotein called Intrinsic Factor (IF) that is secreted by the parietal cells in the fundic region of the stomach.
5. VitB12-IF complex once in the distal ileum, attaches to IF receptors present on the intestinal enterocytes.
6. Once attached to the receptors, the complex is endocytosed by the ileal enterocytes and VitB12 now associates itself to another carrier protein called transcobalamine II.
7. After being secreted out of the cell into the plasma, transcobalamine II carries Vit B12 to other parts of the body.
This process of Vitamin B12 absorption clearly shows why intrinsic factor is important for VitB12 absorption. Hence a lack of intrinsic factor causes malabsorption of VitB12 leading to deficiency states causing pernicious anemia. Now, an auto-immune attack by T-cells, on the parietal cells of the gastric mucosa, leads to gastric injury and lack of production of IF. Why or how the auto-immune attack happens is not known. The gastric mucosal injury further triggers the formation of auto-antibodies against the gastric mucosal cells. In fact there are three types of auto-antibodies reported – Type I antibodies, prevent binding of VitB12 with IF, Type II antibodies prevent the binding of the VitB12-IF complex with the receptors on the ileal cells and Type III antibodies target the parietal cells. However, it has to be understood that these antibodies though diagnostic for pernicious anemia, are not primarily the cause for the condition. It is the auto-immune attack by T-cells that causes the condition and triggers the formation of auto-antibodies as well.
Pernicious anemia usually occurs in persons greater than 30 years of age and could affect adults of either gender. It presents with general symptoms of anemia like, pallor, weakness, fatigue, shortness of breath and headache. These symptoms reflect the blood’s reduced oxygen carrying capacity. Pernicious anemia also presents with neurological symptoms like tingling and burning sensation in the extremities, paraesthesia and numbness. This is due to the fact that Vitamin B12 also functions to maintain myelin in the nervous system. This condition has also been reported to present with gastrointestinal symptoms like nausea, vomiting and diarrhoea.
As for the oral symptoms glossitis is the main symptom of pernicious anemia. The papillae are atrophied, either throughout the entire surface or in patches. Generally, the inflamed, erythematous tongue in pernicious anemia is described as “beefy red” and is called as “Hunter’s glossitis” or “Moeller’s glossitis”. The inflammation in the tongue has periods of remission and exacerbation. This might alter the taste sensation and may also cause a burning sensation of the mouth.
Pernicious anemia is diagnosed by decreased levels of VitB12 in the serum with normal levels of folate. Serum antibodies to IF are specific for pernicious anemia.
A blood smear may reveal, macrocytic and hyperchromic picture. In Vit B12 deficiency, erythrocytes are large, hence macrocytic, and have more than usual amounts of haemoglobin and stain darker, hence hyperchromic. However, it has to be noted that the increase in haemoglobin in each individual erythrocyte is only proportional to its size and the overall concentration of haemoglobin is reduced (due to the decreased erythrocytes). Another characteristic finding is the presence of hypersegmented granulocytes.
Bone marrow aspirates reveal megaloblasts and gastric analysis shows achlorhydria or absence of hydrochloric acid in gastric secretions.
Intra-muscular injections of VitB12 have shown to improve symptoms, both the systemic and oral symptoms rapidly. High doses of oral cobalamine therapy is an equally effective treatment.
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