Pernicious anemia

Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of megaloblastic anemia due to 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 anemia' is sometimes also incorrectly used to indicate megaloblastic anemia 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 anemia 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 anemia, 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 anemia must be considered in the differential diagnosis of megaloblastic anemia. For example, a B-12 deficient state which causes megaloblastic anemia and which may be mistaken for classical pernicious anemia, may be caused by infection with the tapeworm Diphyllobothrium latum, possibly due to the parasite's competition for vitamin B-12, .

Symptoms and signs

• Due to anemia:
• 'Fog days' - cognitive impairment
• Pallor
• Fatigue
• Shortness of breath - known as 'the sighs'.
• Rapid heartbeat
• Tongue symptoms: red, burning or sore
• Digestive disturbances:
• Upset stomach
• Weight loss
• Loss of appetite
• Diarrhea
• Constipation
• Abdominal pain
• Jaundice due to impaired formation of blood cells
• Fever
• Malaise
• Paresthesias
• Finger paresthesias
• Pins and needles
• Tingling or burning fingers
• Numb fingers
• Due to low muscle tone:
• Muscle spasms
• Unsteadiness
• Movement disorders
• Weakness
• Spasticity
• Personality changes
• Chest pain

Diagnosis

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

Pernicious anemia 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 anemia 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 anemia.

Treatment

Being a manifestation of vitamin B-12 deficiency, pernicious anemia 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 anemia.

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. In 1907 Richard Clarke Cabot reported on a series of 1200 patients with PA. Their average survival was between one and three years. Dr. William Bosworth Castle performed an experiment whereby he ingested raw hamburger meat and regurgitated it after an hour and subsequently fed it to a group of ten patients. A control group were fed un-treated raw hamburger meat. The former group showed a disease response whereas the latter group did not. This was not a sustainable practice but it demonstrated the existence of an 'intrinsic factor' from gastric juice.

Pernicious anemia 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 anemia 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 anemia 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 anemia). Whipple discovered that ingesting large amounts of liver seemed to cure anemia from blood loss, and tried liver ingestion as a treatment for pernicious anemia, 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 anemia, 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 anemia 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.

Notable sufferers

• Inez Milholland, American Suffragette
• Alexander Graham Bell, Scottish scientist and inventor
• Annie Oakley.
• Norman Warne, editor/publisher and fiancé 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

References

External links

• The Pernicious Anaemia Society, a UK-based charitable organisation
• Pernicious anemia symptoms, causes, treatments and background details
• Parietal cell antibody
• Antibody to GPC