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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. The two major reactions involving B12 in the human body are:

• Vitamin B12 in the from of cyanocobalamin is required in the synthesis of methionine. Methionine is produced from homocysteine and is catalysed by the enzyme methionine synthase. This enzyme utilises cyanocobalamin as a cofactor. Deficiency of vitamin B12 causes a decreased production of methionine and buildup of homocysteine. Hyperhomocysteinemia is implicated as a risk factor in cardiovascular disease.
• The Kreb's cycle utilises vitamin B12 in the reaction converting methylmalonyl-CoA to succinyl-CoA. Thus vitamin B12 deficiency causes a buildup of methylmalonic acid, the substrate for the enzyme methylmalonyl coenzyme A mutase. Methylmalonic acid levels are elevated in the urine of people affected with pernicious anemia and other forms of B12 deficiency.

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.
• 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.

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.

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.

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 : Intramedullary hemolysis	Weight loss	Peripheral neuropathy
Shortness of breath	Nausea and vomiting	Ataxia
Dizziness	Smooth, beefy, red tongue - Glossitis	Weakness
Tachycardia	Diarrhea	Hyperreflexia
Fatigue		Confusion
		Depression

Physical examination findings

Most important physical examination findings are the neurological findings of long standing B12 deficiency which leads to subacute combined degeneration of the spinal cord.

• Hematological signs include pallor and icterus.
• Neurological signs: Vitamin B12 deficiency causes nerve demyelination. B12 deficiency also causes a buildup of methylmalonic acid which is toxic to neuronal cells and causes apoptosis..

The main neurological manifestation of pernicious anemia and vitamin B12 deficiency is subacute combined degeneration. The posterior and lateral columns of the spinal cord are affected. Lateral column demyelination manifests as hyperreflexia and spasticity, while posterior column defects are loss of proprioception and vibration sense. Ataxia and loss of tandem gait are also manifestations of posterior column demyelination. Recreational or accidental inhalation of nitrous oxide gas (laughing gas) can precipitate subacute combined degeneration in people with low levels of vitamin B12.

• Gastrointestinal signs: Upto 25% of people affected with pernicious anemia develop glossitis. The tongue appears red, "beefy" and smooth due to atrophy and blunting of the lingual papillae.

Subacute combined degeneration

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Microscopic Pathology

Atrophic gastritis in pernicious anemia is seen due to autoimmune (cytotoxic T cell) mediated destruction of the parietal cells of the gastric mucosa. The following changes can be seen on peripheral smear:

1. The most obvious peripheral smear finding is megaloblasts and macrocytes.

Megaloblastic anemia results due to the lagging behind of nuclear development when compared to cytoplasmic development. This is known as nuclear-cytoplasmic asynchrony. Such defective cells are destroyed in the bone marrow (intramedullary hemolysis).

1. Decreased number of RBCs (erythopenia)
2. Macrocytosis- the RBCs in pernicious anemia are very large. Macrocytosis is defined as cells that have an MCV >100 femtolitres (normal :80-100fL)
3. Hypersegmented neutrophils : Neutrophils containing ≥ 6 lobes.
4. Poikilocytosis and anisocytosis
5. Low reticulocyte count (reticulopenia)
6. Howell-Jolly bodies

Atrophic gastritis in pernicious anemia