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

Pernicious anemia (or pernicious anemia - also known as Biermer's anemia, Addison's anemia, or Addison–Biermer anemia) is a form of megaloblastic anemia.

Usually seated in an atrophic gastritis, the autoimmune destruction of gastric parietal cells leads to a lack of intrinsic factor,[1] and since the absorption from the gut of vitamin B-12,[2] is dependent on intrinsic factor this leads to vitamin B-12 deficiency, one of the many causes of megaloblastic anemia.

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

Mechanisms and manifestations

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Pathophysiology

Vitamin B-12 cannot be produced by the human body, and must therefore be obtained from diet. Normally, dietary vitamin B-12 can be absorbed by the terminal ileum only 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 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.

Symptoms


A complication of severe chronic pernicious anaemia 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.

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] Blood and urine tests for methylmalonic acid may indicate a B12 deficiency, even though serum B12 is within the normally-acceptable range. Serum B12 is not necessarily an indicator of efficient use by the body, in the muscles, for example.[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.[12]

Treatment

The treatment of pernicious anemia varies from country to country and from area to area. There is currently no cure for pernicious anemia, although repletion of vitamin B12 may result in a cessation of anemia-related symptoms. Repletion of B12 can be accomplished in a variety of ways.

The most accessible and inexpensive method of repletion is through dietary supplementation, in the form of oral or sublingual B12 tablets. B12 supplements are widely available at supermarkets, health food stores, and drug stores, though quality and cost may vary. In some countries the cobalamin preparation may be available only via prescription. Doctors can prescribe cobalamin tablets that contain doses higher than what is commercially available.

It is reported that many patients die within 7 days of no treatment while in a severe symptomatic state.

A 2003 study[13] found that oral and sublingual B12 were absorbed equally well, but the study's subjects were not noted to be suffering from pernicious anemia. Some patients may need treatment with sublingual (under the tongue) cyanocobalamin or methylcobalamin tablets, which allows B12 to be absorbed via the mucous membranes in the mouth. This may be the preferred method of B12 repletion due to the fact that it bypasses the gastrointestinal tract. When oral tablets are used to treat pernicious anemia,[14] higher-than-normal doses may be needed.[15] The efficacy of using high dose B12 tablets to treat ordinary pernicious anemia (i.e. anemia due to atrophic gastritis) is well established. Oral supplementation allows B12 to be absorbed in places other than the terminal ileum (where B12 absorption usually takes place). A 2006 study[16] found that oral B12 repletion has the potential to be as effective as injections.

However, if oral and sublingual repletion of B12 is inadequate, the patient may require B12 injections,[17] which are usually given once a month, bypassing the need for gastrointestinal absorption altogether. Eventually the patient may be able to do this at home. Cobalamin (one of the forms of B12) 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 typically need to be given for the remainder of the patient's life. The frequency of injections varies by country and health care practitioner, and may be as infrequent as once every three months in some countries. The most common complaint by members of the Pernicious Anaemia Society is that patients have different needs, with some patients needing more frequent injections than others.[18] Some medical professionals believe that subcutaneous injections are more effective than intramuscular injections,[citation needed] but the evidence for this is currently unclear.

There are other methods of administering B12, including nasal sprays and behind-the-ear patches. One small study from 1997, with six participants,[19] found that intranasal delivery of B12 led to increases in plasma cobalimin as high as eight times a given patient's baseline measurement. Further investigation of these delivery methods is needed.

History

The British physician Thomas Addison first described the disease in 1849, 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.[20]

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.

See also

Vitamin B-12 deficiency

Notable sufferers

References

  1. ^ "University of Chicago Med Ctr: Megaloblastic (Pernicious) Anemia". http://www.uchospitals.edu/online-library/content=P00080. Retrieved 2008-01-27. 
  2. ^ Kumar V (February 2007). "Pernicious anemia". MLO 39 (2): 28, 30–1. PMID 17375844. 
  3. ^ Masnou H, Domènech E, Navarro-Llavat M, et al. (December 2007). "Pernicious anaemia in triplets. A case report and literature review". Gastroenterología y Hepatología 30 (10): 580–2. PMID 18028852. http://www.elsevier.es/revistas/0210-5705/30/580. 
  4. ^ Gastritis, Atrophic at eMedicine
  5. ^ Diphyllobothrium latum Infection at eMedicine
  6. ^ "Pernicious anemia: MedlinePlus Medical Encyclopedia". Nlm.nih.gov. http://www.nlm.nih.gov/medlineplus/ency/article/000569.htm. Retrieved 2010-03-18. 
  7. ^ Devalia V (August 2006). "Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay". BMJ 333 (7564): 385–6. doi:10.1136/bmj.333.7564.385. PMID 16916826. 
  8. ^ Ortigues-Marty, I., Micol, D., Dozias, D., Girard, C. L., Lack of correlation between vitamin B12 content in bovine muscles and indicators of the body stores in vitamin B12, CAB Abstracts.
  9. ^ Pagana, Timothy James; Pagana, Kathleen Deska (2006). Mosby's manual of diagnostic and laboratory tests. Mosby Elsevier. ISBN 0-323-03903-0. 
  10. ^ Pernicious Anemia at eMedicine
  11. ^ Miederer,S.E. (1977). The Histotopography of the Gastric Mucosa. Thieme, ISBN 3135086011
  12. ^ Butler CC, Vidal-Alaball J, Cannings-John R, et al. (June 2006). "Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials". Family Practice 23 (3): 279–85. doi:10.1093/fampra/cml008. PMID 16585128. 
  13. ^ Sharabi A, Cohen E, Sulkes J, Garty M (December 2003). "Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route". British Journal of Clinical Pharmacology 56 (6): 635–8. doi:10.1046/j.1365-2125.2003.01907.x. PMID 14616423. 
  14. ^ Lederle FA (September 1998). "Oral cobalamin for pernicious anemia: back from the verge of extinction". Journal of the American Geriatrics Society 46 (9): 1125–7. PMID 9736106. 
  15. ^ "Pernicious Anemia and B12 Injections". http://healthlink.mcw.edu/article/880000064.html. Retrieved 2008-01-27. 
  16. ^ Butler CC, Vidal-Alaball J, Cannings-John R, et al. (June 2006). "Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials". Family Practice 23 (3): 279–85. doi:10.1093/fampra/cml008. PMID 16585128. 
  17. ^ De Paz R, Hernández-Navarro F (2005). "[Management, prevention and control of pernicious anemia]" (in Spanish). Nutrición Hospitalaria : Organo Oficial De La Sociedad Española De Nutrición Parenteral Y Enteral 20 (6): 433–5. PMID 16335029. 
  18. ^ "Index". Pernicious Anaemia Society. http://www.pernicious-anaemia-society.org/phpbb/index.php. Retrieved 2010-03-18. 
  19. ^ Slot WB, Merkus FW, Van Deventer SJ, Tytgat GN (August 1997). "Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients". Gastroenterology 113 (2): 430–3. doi:10.1053/gast.1997.v113.pm9247460. PMID 9247460. 
  20. ^ [1]
  21. ^ Gray, Charlotte. Reluctant Genius: Alexander Graham Bell and the Passion for Invention. New York: Arcade Publishing, 2006. ISBN 1-55970-809-3, page 418.
  22. ^ "Annie Oakley - MSN Encarta". Annie Oakley - MSN Encarta. http://encarta.msn.com/encyclopedia_761563729/Annie_Oakley.html. Retrieved 2008-01-27. 
  23. ^ "Noman Warne - The World of Beatrix Potter". Peter Rabbit. http://www.peterrabbit.com/potters-world-norman-warne.asp. Retrieved 2010-03-18. 
  24. ^ "Kbs Global". English.kbs.co.kr. 2009-10-28. http://english.kbs.co.kr/entertainment/news/1392936_11858.html. Retrieved 2010-03-18. 

External links


Wiktionary

Up to date as of January 15, 2010
(Redirected to pernicious anaemia article)

Definition from Wiktionary, a free dictionary

English

Noun

Singular
pernicious anaemia

Plural
pernicious anaemias

pernicious anaemia (plural pernicious anaemias)

  1. Alternative spelling of pernicious anemia.

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