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Revision as of 15:24, 24 June 2020
"sandbox:SN"
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Pernicious anemia (also called Addison's anemia) is a type of red blood cell disorder caused by impaired vitamin B12 metabolism. Vitamin B12 is primarily absorbed by the small intestine, after being bound to intrinsic factor secreted by parietal cells of gastric mucosa. When this process is disrupted by conditions like atrophic gastritis, celiac disease, small bowel resection etc, B12 deficiency ensues. Historically, this type of anemia was called "pernicious" because it was harder to treat and most often resulted in death. Red blood cells in this type of anemia are abnormally large, and are called macrocytic.
Pathophysiology
Vitamin B12 is an essential vitamin for humans and animals because we cannot synthesise it on our own. B12 is a cofactor in DNA synthesis and other important biochemical reactions. Vitamin B12 deficiency manifests as anemia because hematopoetic stem cells in the bone marrow which are rapidly dividing need B12 for division and DNA production. This process is impaired leading to ineffective hematopoeisis. Vitamin B12 is also necessary for production of myelin which is an important component in the covering sheath of nerves. Deficiency results in improper nerve conduction due to nerve destabilisation.
Physiology
Vitamin B12 is also called cobalamin because it contains cobalt at the core of its structure. Dietary sources of vitamin B12 include meat, fish and eggs. When consumed through its dietary source, B12 is bound to protein till it enters the stomach. In the stomach, B12 is uncoupled from its carrier protein due to the presence of gastric acid, which is why vitamin B12 deficiency is so commonly seen among those on chronic antacid medication. Once in the stomach, it is then bound to gastric R binder, a glycoprotein secreted by the salivary glands till it reaches the duodenum. In the duodenum and jejunum, the pancreatic enzymes digest the gastric R binder and cobalamin is bound to intrinsic factor (IF). Intrinsic factor is secreted by the gastric parietal cells. Once bound to IF, vitamin B12 travels up to the ileum where IF is removed and B12 binds with carrier proteins called transcobalamins and this complex is taken up by the liver and bone marrow, among other tissues. Inside the cells, the transcobalamin-B12 complex is dissolved and cobalamin is reduced to methylcobalamin which serves as a cofactor and coenzyme in many important biochemical reactions[1].
Pathogenesis
Pernicious anemia is a type of megaloblastic anemia caused due to improper vitamin B12 absorption by the body. Impaired absorption occurs because of deficiency of intrinsic factor which is produced by the parietal cells of the stomach. The etiology of pernicious anemia can be due to autoimmune causes or genetic disease. In autoimmune disease, the antibodies attack most of the gastric mucosa, but the antrum is spared.
Autoimmune causes of pernicious anemia
This is the most common cause of pernicious anemia. In autoimmune pernicious anemia, the body produces antibodies against parietal cells or intrinsic factor.
- Antibodies against parietal cells of the gastric mucosa work to inhibit the H+/K(+)-ATPase which is the proton pump present in the parietal cells. The proton pump serves as an auto antigen and activates the cytotoxic CD4+ T cells which proceed to destroy gastric mucosal cells.[2][3]
- Intrinsic factor antibodies are present in fewer cases of pernicious anaemia but are highly specific. There are 2 types of IF antibodies. They prevent the binding and absorption of cobalamin in the ileum via its receptor.[4]
Genetics
Some forms of pernicious anemia are congenital and a genetic link has been postulated because of a higher incidence in certain populations. Affected people have a complete or near total absence of intrinsic factor and the presence of antibodies against intrinsic factor. The genetic variant is transmitted through an autosomal recessive pattern.[5]
Associated Conditions
People affected with pernicious anemia might have other coexisting autoimmune conditions such as autoimmune thyroiditis, autoimmune diabetes, vitiligo etc. Autoimmune thyroiditis is most commonly seen in patients with pernicious anemia, particularly females. HLA DR3 has been implicated in the development of autoimmune diseases such as pernicious anemia[6].
Signs and symptoms
The symptoms of pernicious anemia take months, and often years to manifest. Patients most commonly present with symptoms of anemia like lightheadedness, dizziness, shortness of breath etc. The population affected with pernicious anemia is usually the elderly (>60 years) owing to its insidious onset. However, the genetic form presents in children below 15 years of age.
| Hematological symptoms | Gastrointestinal symptoms | Neurological symptoms |
|---|---|---|
| Pallor : due to ineffective hematopoeisis | Loss of appetite | Parasthesias |
| Icterus : ineffective hematopoeisis causes destruction of cells in the bone marrow raising indirect bilirubin levels | Weight loss
|
Peripheral neuropathy |
| Shortness of breath | Nausea and vomiting | Ataxia |
| Dizziness | Smooth, beefy, red tongue - Glossitis | Weakness |
| Tachycardia | Diarrhea | Hyperreflexia |
| Fatigue | Confusion | |
| Depression |
Microscopic Pathology
References
- ↑ Harrington DJ (2017). "Laboratory assessment of vitamin B12 status". J Clin Pathol. 70 (2): 168–173. doi:10.1136/jclinpath-2015-203502. PMID 27169753.
- ↑ Callaghan JM, Khan MA, Alderuccio F, van Driel IR, Gleeson PA, Toh BH (1993). "Alpha and beta subunits of the gastric H+/K(+)-ATPase are concordantly targeted by parietal cell autoantibodies associated with autoimmune gastritis". Autoimmunity. 16 (4): 289–95. doi:10.3109/08916939309014648. PMID 7517707.
- ↑ Toh BH, Sentry JW, Alderuccio F (2000). "The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis". Immunol Today. 21 (7): 348–54. doi:10.1016/s0167-5699(00)01653-4. PMID 10871877.
- ↑ Schade SG, Abels J, Schilling RF (1967). "Studies on antibody to intrinsic factor". J Clin Invest. 46 (4): 615–20. doi:10.1172/JCI105563. PMC 442045. PMID 6021209.
- ↑ Gordon MM, Brada N, Remacha A, Badell I, del Río E, Baiget M; et al. (2004). "A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency". Hum Mutat. 23 (1): 85–91. doi:10.1002/humu.10297. PMID 14695536.
- ↑ Zulfiqar AA, Andres E (2017). "Association pernicious anemia and autoimmune polyendocrinopathy: a retrospective study". J Med Life. 10 (4): 250–253. PMC 5771255. PMID 29362601.