Pernicious anemia

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Pernicious anemia
Classification and external resources
ICD-10	D51.0
ICD-9	281.0
DiseasesDB	9870
MedlinePlus	000569
eMedicine	med/1799
MeSH	D000752

Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison–Biermer anemia) is a form of megaloblastic anemia due to vitamin B-12 deficiency, caused by impaired absorption of vitamin B-12^[1] due to the immune destruction of intrinsic factor^[2] 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 B12 deficiency, its proper usage refers to that caused by atrophic gastritis and parietal cell loss only. The loss of ability to absorb vitamin B-12 is the most common cause of adult vitamin B-12 deficiency.^[3]

The name of the disease comes from the historical fact that early sufferers were always detected after they were anemic (i.e., had low blood hemoglobin levels). However, with more modern tests which specifically target B-12 absorption, the disease may properly be diagnosed before patients actually become anemic. Thus, it may be proper to refer to patients as continuing to have the disease of "pernicious anemia," even after their anemia and B-12 deficiency has been corrected by means of B-12 injections or oral B-12 megadosing. The reason for the continuing diagnosis of disease presence, is that replacement of vitamin stores does not correct the defect in vitamin absorption which technically defines the disease. Typically, a person who has pernicious anemia (inability to absorb vitamin B-12 normally) will have it for the remainder of their lives, although with vitamin B-12 replacement, the disease-state may cause no other medical problems.

Contents 1 Mechanisms and manifestations 1.1 Pathophysiology 1.2 Presentation 2 Causes 3 Symptoms 4 Diagnosis 5 Treatment 6 History 7 See also 8 Notable sufferers 9 References 10 External links

[edit] Mechanisms and manifestations

[edit] 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.

[edit] 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.

[edit] Causes

Most commonly (in temperate climates), the cause for impaired binding of vitamin B-12 by intrinsic factor is autoimmune atrophic gastritis,^[4] 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,^[5].

A similar disorder involving impaired B-12 absorption can also occur following gastric removal (gastrectomy) or gastric bypass surgery, especially the Roux-en-Y bypass. In this procedure the stomach is separated into two sections, one a very small pouch for holding small amounts of food, and the other, the remainder of the stomach, which is resultingly non-functional. Therefore, the mucosa cells are no longer available, nor is the required intrinsic factor. This results in inadequate GI absorption of B-12, and may result in a syndrome indistinguishable from pernicious anemia. Gastric bypass or gastrectomy patients must take B-12 as in treatment of pernicious anemia: either oral megadoses, or B-12 by injection.

[edit] Symptoms

• Many signs and symptoms are attributed to anemia: Fatigue, low blood pressure, rapid heart rate, pallor, and shortness of breath (known as 'the sighs')
• Difficulty in proprioception
• Mild cognitive impairment, colloquially referred to as brain fog
• Neuropathic pain
• Frequent diarrhea
• Paresthesias, such as pins and needles sensations or numbness in fingers or toes, due to B12 deficiency affecting nerve function
• Jaundice due to impaired formation of blood cells
• Glossitis (swollen red tongue) due to B-12 deficiency
• May present with hyperthyroidism or hypothyroidism
• Personality or memory changes^[6]

[edit] Diagnosis

The insidious nature of the disease, and the fact that there is no single definitive test for pernicious, anemia can often mean that a diagnosis is delayed. The Schilling test is no longer widely available, and the other main diagnostic signpost of low levels of serum B12 cannot be relied upon as sufferers can have high levels of serum B12 and still have pernicious anemia.^[7][8] 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).^[9]. 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).^[10]

The diagnosis of atrophic gastritis Type A should be confirmed by gastroscopy and stepwise biopsy.^[11] 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.

[edit] Treatment

The treatment of pernicious anemia varies from country to country and from area to area. There is, as yet, no cure for pernicious anemia, and consequently treatment centres on replacing vitamin B-12. This is done in a variety of ways. Cobalamin (one of the forms of B-12) is usually injected into the patient's muscle (IntraMuscular or I.M.) using cyanocobalamin (the United States, Canada and most European countries) or hydroxocobalamin (Australia and the U.K.). The injections will be for life and will be given every month in some countries and every three months in other countries. The single most common cause of complaint by members of the Pernicious Anaemia Society is that patients needs vary and some patients need more frequent injections than others ^[12].

In some countries the cobalamin preparation is available over the counter from chemists (pharmacists), while in other countries it is only available via a doctor's prescription.

Patients who are needle-phobic, or patients who are unable to receive injections for another reason can be prescribed cyanocobalmin tablets in very high doses, which means that some of the B-12 is absorbed in other places in the bowel other than the terminal ileum where B-12 absorption usually takes place. The efficacy of using high dose B-12 tablets to treat ordinary pernicious anemia (by definition due to atrophic gastritis) is well established (see below); however the oral route may not be sufficient for other metabolic B-12 derangements, which may require by B-12 injection.

Some patients are treated by cyanocobalamin or methylcobalamin sub-lingual tablets that are placed under the tongue, where some B-12 is absorbed via the membranes in the mouth. However, the efficacy of the mouth membranes versus other membranes in the gastrointestinal tract has not been established, and thus the efficacy of sublingual B-12 vs. simply swallowing high dose B-12 tablets, has not been proven.

Some doctors and medical professionals believe that subcutaneous injections are more effective than intramuscular injections,^{[citation needed]} but this also has not been proven. There are other methods of administering B-12 including behind the ear patches and nasal sprays but the efficacy of these methods of treatment has not been subjected to any serious scientific investigation.

Oral tablets are sometimes used to treat pernicious anemia^[13] though if this approach is used, much higher doses are given than normally required for oral vitamin supplementation, in order to overcome the impaired absorption that characterizes pernicious anemia.^[14]

If oral tablets are not desired, vitamin B-12 can also be administered via injection,^[15] which is usually given once a month, thus bypassing any intrinsic factor problems and the need for gastrointestinal absorption altogether. Often the patient can learn to do this at home with the same type syringes and needles used for insulin treatment of diabetes.

[edit] 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.^{[citation needed]} 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.^[16]

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.

[edit] See also

Vitamin B-12 deficiency

[edit] Notable sufferers

• Inez Milholland, American Suffragette^{[citation needed]}
• Alexander Graham Bell, Scottish scientist and inventor who immigrated to Canada^[17]
• Sir Laurence Gomme public servant and folklorist^{[citation needed]}
• Annie Oakley.^[18]
• Norman Warne, editor/publisher and fiancé of Beatrix Potter.^{[citation needed]}
• Yoon Eun Hye, a South Korean actress^[19]
• Betsie ten Boom, sister to Corrie ten Boom, victim of the Holocaust, and in the book, The Hiding Place^{[citation needed]}
• David Hilbert, German mathematician^{[citation needed]}
• Sam Hughes, Canadian Minister of Militia and Defence^{[citation needed]}
• Henry Sweet, English linguist and phoneticist^{[citation needed]}
• Sir Stafford Cripps - British Politician and Chancellor of the Exchequer in the post-World War II Labour government.^{[citation needed]}
• Suzanne Lenglen - French tennis player^{[citation needed]}
• Sophus Lie - Norwegian mathematician

[edit] References

[edit] External links

• The Pernicious Anaemia Society, a UK-based charitable organisation
• Parietal cell antibody
• Antibody to GPC
• [3]

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