Pernicious anaemia

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Pernicious anaemia (also known as Biermer's anaemia or Addison's anaemia or Addison-Biermer anaemia) is a form of megaloblastic anaemia due to vitamin B-12 (vitamin B₁₂) deficiency, caused by impaired absorption of vitamin B-12 due to the absence of intrinsic factor in the setting of atrophic gastritis, and more specifically of loss of gastric parietal cells. While the term "pernicious anaemia" is sometimes also incorrectly used to indicate megaloblastic anaemia due to any cause of vitamin B-12 deficiency, its proper usage refers to that caused by atrophic gastritis and parietal cell loss only.

It is the most common result of adult vitamin B-12 deficiency.

Mechanisms and manifestations

Pathophysiology

Vitamin B-12 cannot be produced by the human body, and must therefore be obtained from diet. Normally, dietary vitamin B-12 can only be absorbed by the ileum when it is bound by the intrinsic factor produced by parietal cells of the gastric mucosa. In pernicious anemia, this process is impaired because of loss of parietal cells, resulting in insufficient absorption of the vitamin, which over a prolonged period of time ultimately leads to vitamin B-12 deficiency and thus megaloblastic anemia. This anaemia is a result of the body's inability to produce DNA in sufficient quantities for blood cell synthesis, due to interruption of a biochemical pathway that is dependent on vitamin B-12 and/or folic acid as cofactors, which synthesizes thymine, a DNA component.

Presentation

The presentation of pernicious anemia resembles that of any other form of anaemia, but is often accompanied by the manifestations of vitamin B₁₂ deficiency (notably neurological abnormalities such as peripheral neuropathy), as well as by other manifestations of autoimmune atrophic gastritis.

Causes

Most commonly (in temperate climates), the cause for impaired binding of vitamin B₁₂ by intrinsic factor is autoimmune atrophic gastritis, in which autoantibodies are directed against parietal cells (resulting in their loss) as well as against the intrinsic factor itself (rendering it unable to bind vitamin B-12).

Less frequently, loss of parietal cells may simply be part of a widespread atrophic gastritis of non-autoimmune origin, such as that frequently occurring in elderly people affected with long-standing chronic gastritis of any cause (including Helicobacter pylori infection).

Note that forms of vitamin B-12 deficiency other than pernicious anaemia must be considered in the differential diagnosis of megaloblastic anaemia. For example, a B-12 deficient state which causes megaloblastic anemia and which may be mistaken for classical pernicious anaemia, may be caused by infection with the tapeworm Diphyllobothrium latum, possibly due to the parasite's competition for vitamin B-12, .

Symptoms and signs

Diagnosis

A diagnosis of pernicious anaemia first requires demonstration of megaloblastic anaemia (through a full blood count) which evaluates the mean corpuscular volume (MCV), as well the mean corpuscular hemoglobin concentration (MCHC). Pernicious anaemia is identified with a high MCV and a normal MCHC (that is, it is a macrocytic, normochromic anaemia). . Ovalocytes are also typically seen on the blood smear, and a pathognomonic feature of megaloblastic anemias (which include pernicious anaemia and others) is hypersegmented neutrophils.

Pernicious anaemia can also be diagnosed by evaluating its direct cause, vitamin B-12 deficiency (by measuring B-12 levels in serum). A Schilling test can then be used to distinguish pernicious anaemia from other causes of vitamin B-12 deficiency (notably malabsorption).

A diagnosis of atrophic gastritis should be confirmed by gastroscopy with biopsies. Approximately 90% of individuals with pernicious anemia have antibodies for parietal cells; however only 50% of all individuals in the general population with these antibodies have pernicious anaemia.

Treatment

Being a manifestation of vitamin B-12 deficiency, pernicious anaemia is treated by administering vitamin B-12 supplements. Oral tablets are sometimes used, though if this approach is used, much higher doses are given than normally required in order to overcome the impaired absorption that characterizes pernicious anaemia.

If oral tablets are not desired, vitamin B-12 can also be administered via injection, which is usually given once a month. Often the patient can learn to do this at home with the same syringes and needles used for insulin treatment of diabetes.

History

Dr. Addison first described the disease, from which it acquired the common name of Addison's Anemia. Dr. Newcastle found that he could regurgitate his own gastric juices and feed it to his patients, also causing disease improvement. However, this was not a sustainable practice. Pernicious anaemia was a fatal disease before about the year 1920, when Whipple suggested raw liver as a treatment. After verification of Whipple's results in 1926, pernicious anaemia victims ate or drank at least 1/2 a pound of raw liver, or drank raw liver juice every day. This continued for several years until a concentrate of liver juice became available after 1928.

The first workable treatment for pernicious anaemia began with the work of George Whipple who made the discovery in the course of experiments in which he bled dogs to make them anemic, then fed them various foods to see which would make them recover most rapidly (Whipple was looking for treatments for anemia from bleeding, not pernicious anaemia). Whipple discovered that ingesting large amounts of liver seemed to cure anemia from blood loss, and tried liver ingestion as a treatment for pernicious anaemia, reporting improvement there also, in a paper in 1920. George Minot and William Murphy then set about to partly isolate the curative property in liver and showed that it was contained in raw liver juice (in the process also showing that ironically it was the iron in liver tissue, not the soluble factor in liver juice, which cured the anemia from bleeding in dogs; thus the discovery of the liver juice factor as a treatment for pernicious anaemia, had been by coincidence). For the discovery of the cure of a previously fatal disease of unknown etiology the three men shared the 1934 Nobel Prize in Medicine.

In 1928 chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural food (liver). The extract could even be injected into muscle, which meant that patients no longer needed to eat large amounts of liver or juice. This reduced the cost of treatment considerably.

The active ingredient in liver was unknown until 1948, when it was isolated by two chemists, Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. The substance was a cobalamin, which the discoverers named vitamin B-12. The new vitamin in liver juice was eventually completely purified and characterized in the 1950s, and other methods of producing it from bacteria were developed. It could be injected into muscle with even less irritation, making it possible to treat pernicious anemia with even more ease. Pernicious anaemia was eventually treated with either vitamin B-12 injections, or else large oral doses of vitamin B-12, typically between 1 and 4 mg (1000 to 4000 mcg) daily.

Famous sufferers

• Inez Milholland, American Suffragette.
• Alexander Graham Bell, Scottish scientist and inventor.
• Annie Oakley.
• Norman Warne, Editor/Publisher & fiance of Beatrix Potter.
• Yoon Eun Hye, A South Korean actress
• Betsie ten Boom, Sister to Corrie ten Boom, victim of the Holocaust, and in the book, The Hiding Place
• David Hilbert, German mathematician.
• Sam Hughes, Canadian Minister of Militia and Defence.