Pernicious anemia is a disease where not enough red blood cells are produced due to a deficiency of vitamin B12.

[4] Other symptoms may include shortness of breath, feeling faint, a smooth red tongue, pale skin, chest pain, nausea and vomiting, loss of appetite, heartburn, numbness in the hands and feet, difficulty walking, memory loss, muscle weakness, poor reflexes, blurred vision, clumsiness, depression, and confusion.

[20] Pernicious anemia may be present without a person experiencing symptoms at first, over time, feeling tired and weak, lightheadedness, dizziness, headaches, rapid or irregular heartbeat, breathlessness, glossitis (a sore red tongue), poor ability to exercise, low blood pressure, cold hands and feet, pale or yellow skin, easy bruising and bleeding, low-grade fevers, tremor, cold sensitivity, chest pain, upset stomach, nausea, loss of appetite, heartburn, weight loss, diarrhea, constipation, severe joint pain, feeling abnormal sensations including tingling or numbness to the fingers and toes (pins and needles), and tinnitus, may occur.

[21][22][23][24][25] Anemia may present with a number of further common symptoms,[21][26] including hair thinning and loss, early greying of the hair, mouth ulcers, bleeding gums,[22] angular cheilitis, a look of exhaustion with pale and dehydrated or cracked lips and dark circles around the eyes, as well as brittle nails.

This is may result in sense loss, difficulty in proprioception, neuropathic pain, difficulty walking, poor balance, loss of sensation in the feet, muscle weakness, blurred vision (either due to retinopathy[27] or optic neuropathy[28]), impaired urination, fertility problems, decreased sense of taste and smell, decreased level of consciousness, changes in reflexes, memory loss, mood swings, depression, irritability, cognitive impairment, confusion, anxiety, clumsiness, psychosis, and, in more severe cases, dementia.

[26] A complication of severe chronic PA is subacute combined degeneration of spinal cord, which leads to distal sensory loss (posterior column), absent ankle reflex, increased knee reflex response, and extensor plantar response.

[1] Vitamin B12 deficiency, which is reversible, is occasionally confused with acute myeloid leukemia, which is an irreversible condition presenting with some of the same hematological symptoms, including hypercellular bone marrow with blastic differentiation and hypersegmented neutrophils.

[37] PA may be considered as an end stage of autoimmune atrophic gastritis, a disease characterised by stomach atrophy and the presence of antibodies to parietal cells and intrinsic factor.

Antibodies produced by the immune system can be cross-reactive and may bind to both H. pylori antigens and those found in the gastric mucosa.

[42] Less commonly, H. pylori and Zollinger-Ellison syndrome may cause a form of nonautoimmune gastritis that can lead to pernicious anemia.

This is probably because the body stores many years' worth of B12 in the liver and gastric surgery patients are adequately supplemented with the vitamin.

[46][47][48] Moreover, it was further indicated that the formation of antibodies to gastric cells was autosomal dominant gene determined, and the presence of antibodies to the gastric cells might not be necessarily related to the occurrence of atrophic gastritis related to PA.[46][48] Although the healthy body stores three to five years' worth of B12 in the liver, the usually undetected autoimmune activity in one's gut over a prolonged period of time leads to B12 depletion and the resulting anemia; pernicious anemia refers to one of the hematologic manifestations of chronic auto-immune gastritis, in which the immune system targets the parietal cells of the stomach or intrinsic factor itself, leading to decreased absorption of vitamin B12.

Inhibition of DNA replication in maturing red blood cells results in the formation of large, fragile megaloblastic erythrocytes.

The neurological aspects of the disease are thought to arise from the accumulation of methylmalonyl- CoA due to the requirement of B12 as a cofactor to the enzyme methylmalonyl-CoA mutase.

[10] PA may be suspected when a patient's blood smear shows large, fragile, immature erythrocytes, known as megaloblasts.

[54] Ovalocytes are also typically seen on the blood smear, and a pathognomonic feature of megaloblastic anemias (which include PA and others) is hypersegmented neutrophils.

Normal serum levels may be found in cases of deficiency where myeloproliferative disorders, liver disease, transcobalamin II, or small intestinal bacterial overgrowth are present.

[57] High serum levels may caused by supplementing with vitamin B12, present of antibodies to intrinsic factor, or due to underlying condition.

The Schilling test distinguished PA from other forms of B12 deficiency,[50] specifically, from Imerslund–Gräsbeck syndrome, a B12-deficiency caused by mutations in CUBN that codes for cubilin the cobalamin receptor.

More comprehensive studies are still needed in order to validate the feasibility of a particular therapeutic method for PA in clinical practices.

Failure to diagnose and treat in time, however, may result in permanent neurological damage, excessive fatigue, depression, memory loss, and other complications.

[citation needed] There is an increased risk of gastric cancer in those with pernicious anemia linked to the common feature of atrophic gastritis.

In 1871, the first accurate description of the disease in continental Europe was made by Michael Anton Biermer, a German physician who noted the insidious course of the condition.

Whipple, Huber, and Robchett studied the effects on hemoglobin and blood regeneration of a variety of treatments, among which only raw liver showed real promise.

[71] Around 1926, George Minot and William P. Murphy, who learned of Whipple's discovery, sought raw liver as a treatment for pernicious anemia.

[74] Fruit and iron were also part of the diet, and it appears that at this point, Minot and Murphy were not quite sure that the liver was a very important factor.

Dorothy Hodgkin and co-workers went on to use X-ray crystallography to elucidate the structure of cobalamin for which she, too, was awarded a Nobel Prize.

It had long been known that the disease was associated with defects in the gastrointestinal tract: patients had chronic gastritis and lack of acid secretion (achlorhydria).

It is known that transport of physiological amounts of vitamin B12 depends on the combined actions of gastric, ileal and pancreatic components.

[79][80] SNAC is able to form a noncovalent complex with cobalamin while preserving its chemical integrity and protect vitamin B12 from gastric acidity.