Pernicious anemia

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 one of many types of the larger family of megaloblastic anemias. It is caused by loss of gastric parietal cells, and subsequent inability to absorb vitamin B₁₂.

Usually seated in an atrophic gastritis, the autoimmune destruction of gastric parietal cells leads to a lack of intrinsic factor.^[1] Since the absorption from the gut of normal dietary amounts of vitamin B₁₂^[2] is dependent on intrinsic factor, the loss of intrinsic factor leads to vitamin B₁₂ deficiency. 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, parietal cell loss, and lack of intrinsic factor only.

The loss of ability to absorb vitamin B₁₂ is the most common cause of adult vitamin B₁₂ deficiency.^[3] Such a loss may be due to pernicious anemia (with loss of intrinsic factor) or to a number of other conditions that decrease production of gastric acid, which also plays a part in absorption of vitamin B₁₂ from foods.

Historically, pernicious anemia (PA) was detected only after it became "clinical" (caused an overt disease state) and the anemia was well established, i.e., liver stores of B₁₂ had been depleted. The "pernicious" aspect of the disease - prior to the discovery of treatment - was its invariably fatal prognosis, similar to leukemia at that time. However, in the time since elucidation of the cause of the disease, modern tests that specifically target B₁₂ absorption can be used to diagnose the disease before it becomes clinically apparent. In such cases, the disease may be diagnosed and treated without the patient ever becoming ill.

Replacement of vitamin stores does not correct the defect in absorption from loss of intrinsic factor. Since the defect defines the disease, a person without the ability to absorb vitamin B₁₂ in this way will have pernicious anemia for the remainder of his or her life. However, unless the patient has sustained permanent peripheral nerve damage before treatment, regular B₁₂ replacement will keep pernicious anemia in check, with no anemia and no further symptoms.

Although initial treatment of the disease usually involves injections of B₁₂ to rapidly replace body stores, a number of studies have shown that long-term vitamin replacement treatment may be maintained with high-dose oral B₁₂ supplements, since sufficient B₁₂ is absorbed from these by a normal intestine, even without any intrinsic factor. In this regard, nasal and sublingual forms of B₁₂ have not been found to have any special value over simple swallowed tablets.^[4]

Signs and symptoms

Pernicious anemia presents insidiously, and many of the signs and symptoms are due to anemia itself, where anemia is present. While it may consist of the triad of paraesthesias, sore tongue and weakness, this is not the chief symptom complex. The patient may complain of fatigue, depression, forgetfulness, difficulty concentrating, low-grade fevers, nausea and gastrointestinal symptoms (heartburn), weight loss. Because PA may affect the spinal cord, the patient may also complain of impaired urination, loss of sensation in the feet, unsteady gait, weakness, and clumsiness. Anemia may cause tachycardia (rapid heartbeat) and cardiac murmurs, along with a waxy pallor. In severe cases, the anemia may cause evidence of congestive heart failure.

Long-term complications may include gastric cancer and carcinoids.^[5]

Many signs and symptoms are attributed to pernicious anemia:

• Fatigue, low blood pressure, rapid heart rate, high blood pressure, pallor, depression, muscle weakness, and shortness of breath (known as 'the sighs')
• Difficulty in proprioception
• Mild cognitive impairment, including difficulty concentrating and sluggish responses, 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 B₁₂ deficiency
• May present with hyperthyroidism or hypothyroidism
• Personality or memory changes^[6]

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.

Causes

Most commonly (in temperate climates), the cause for impaired binding of vitamin B₁₂ by intrinsic factor is autoimmune atrophic gastritis,^[7] 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 B₁₂).

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

Forms of vitamin B₁₂ deficiency other than pernicious anemia must be considered in the differential diagnosis of megaloblastic anemia. For example, a B₁₂ 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 B₁₂.^[8]

A similar disorder involving impaired B₁₂ 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 becomes nonfunctional. Therefore, the mucosal cells are no longer available; nor is the required intrinsic factor. This results in inadequate GI absorption of B₁₂, and may result in a syndrome indistinguishable from pernicious anemia. Gastric bypass or gastrectomy patients must take B₁₂ as in treatment of pernicious anemia: either oral megadoses, or B₁₂ by injection.

Pathophysiology

Vitamin B₁₂ cannot be produced by the human body, and must be obtained from the diet. Normally, dietary vitamin B₁₂ is absorbed by the body in the small bowel only when it is bound by the intrinsic factor (IF) produced by parietal cells of the gastric mucosa. Pernicious anemia is thought to occur when the body's immune system mistakenly targets the intrinsic factor, with a loss of parietal cells. Insufficient IF results in insufficient absorption of the vitamin. Although the normal body stores three to five years' worth of vitamin B₁₂ in the liver, the usually undetected autoimmune activity in one's gut over a prolonged period of time leads to vitamin B₁₂ depletion and the resulting anemia. Inhibition of DNA synthesis in red blood cells results in the formation of large, fragile megaloblastic erythrocytes.

Diagnosis

The insidious nature of the disease, and the fact that there is no single definitive test for pernicious anemia, may mean that a diagnosis is delayed. Pernicious anemia is suspected when the patient's blood smear shows large, fragile, immature erythrocytes (megaloblasts). 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.^[9] 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.^[10]

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).^[11] 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 B₁₂ deficiency, by measuring B₁₂ levels in serum. A Schilling test can then be used to distinguish pernicious anemia from other causes of vitamin B₁₂ deficiency (notably malabsorption).^[12]

The diagnosis of atrophic gastritis Type A should be confirmed by gastroscopy and stepwise biopsy.^[13] Approximately 90% of individuals with PA have antibodies for parietal cells; however, only 50% of all individuals in the general population with these antibodies have pernicious anemia.^[14]

Treatment

Main article: Vitamin B12

The treatment of pernicious anemia varies from country to country and from area to area. There is no permanent cure for pernicious anemia, although repletion of vitamin B₁₂ should be expected to result in a cessation of anemia-related symptoms, a halt in neurological deterioration, and (in cases where neurological problems not advanced) neurological recovery and a complete and permanent remission of all symptoms, so long as B₁₂ is supplemented. 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.

A 2003 study^[15] found that oral and sublingual B₁₂ were absorbed equally well in a group of patients with very low B₁₂. In this study, 22% of the subjects that agreed to undergo the test (5 of 23), had abnormal Schilling tests, but showed no difference in treatment levels from the other subjects. When oral tablets are used to treat PA,^[16] higher-than-normal doses may be needed.^[17] The efficacy of using high dose B₁₂ tablets to treat ordinary PA (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^[14] 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,^[18] 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 IM) 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.^[19] Some medical professionals^[who?] 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,^[20] found that intranasal delivery of B₁₂^[21] led to increases in plasma cobalamin 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.^[22] A control group were fed untreated 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 George Whipple suggested raw liver as a treatment. The first workable treatment for pernicious anemia began when Whipple made a 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 in 1926 that it was contained in raw liver juice (in the process also showing that 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.^[23]

After Minot and Murphy's verification of Whipple's results in 1926, pernicious anemia victims ate or drank at least one-half pound of raw liver, or drank raw liver juice, every day. This continued for several years, until a concentrate of liver juice became available. 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 also reduced the cost of treatment considerably.

The active ingredient in liver remained 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 B₁₂. 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 B₁₂ injections, or else large oral doses of vitamin B₁₂, typically between 1 and 4 mg (1000 to 4000 mcg) daily.

Notable cases

• Alexander Graham Bell - Scottish-Canadian scientist and inventor^[24]
• Annie Oakley^[25]
• Gunnar Nordström Notable Finnish theoretical physicist. Possibly caused by handling of radioactive material and baths in a Finnish sauna where water containing radioactive material was used in the belief that it was healthy.^[26][27]
• Norman Warne - editor/publisher and fiancé of Beatrix Potter.^[28]
• Yoon Eun Hye - a South Korean actress^[29]
• Inez Milholland - American suffragist

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. doi:10.1157/13112591. PMID 18028852. http://www.elsevier.es/revistas/0210-5705/30/580. 
4. ^ "Typically, vitamin B12 deficiency is treated with vitamin B12 injections, since this method bypasses potential barriers to absorption. However, high doses of oral vitamin B12 may also be effective. The authors of a review of randomized controlled trials comparing oral with intramuscular vitamin B12 concluded that 2,000 mcg of oral vitamin B12 daily, followed by a decreased daily dose of 1,000 mcg and then 1,000 mcg weekly and finally, monthly might be as effective as intramuscular administration [24,25]. Overall, an individual patient's ability to absorb vitamin B12 is the most important factor in determining whether vitamin B12 should be administered orally or via injection [8]. In most countries, the practice of using intramuscular vitamin B12 to treat vitamin B12 deficiency has remained unchanged [24]." - [1] Office of Dietary Supplements - Dietary Supplement Fact Sheet: Vitamin B12
5. ^ Lahner E, Annibale B (November 2009). "Pernicious anemia: New insights from a gastroenterological point of view". World J. Gastroenterol. 15 (41): 5121–8. doi:10.3748/wjg.15.5121. PMC 2773890. PMID 19891010. http://www.wjgnet.com/1007-9327/15/5121.asp. 
6. ^ "Pernicious anemia: MedlinePlus Medical Encyclopedia". Nlm.nih.gov. http://www.nlm.nih.gov/medlineplus/ency/article/000569.htm. Retrieved 2010-03-18. 
7. ^ Gastritis, Atrophic at eMedicine
8. ^ Diphyllobothrium latum Infection at eMedicine
9. ^ 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. PMC 1550477. PMID 16916826. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1550477. 
10. ^ 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.
11. ^ Pagana, Timothy James; Pagana, Kathleen Deska (2006). Mosby's manual of diagnostic and laboratory tests. Mosby Elsevier. ISBN 0-323-03903-0. ^{[page needed]}
12. ^ Pernicious Anemia at eMedicine
13. ^ Miederer, S.E. (1977). The Histotopography of the Gastric Mucosa. Thieme, ISBN 3135086011
14. ^ ^{a b} 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. 
15. ^ 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. PMC 1884303. PMID 14616423. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1884303. 
16. ^ 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. 
17. ^ "Pernicious Anemia and B12 Injections". http://healthlink.mcw.edu/article/880000064.html. Retrieved 2008-01-27. 
18. ^ 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. 
19. ^ "Index". Pernicious Anaemia Society. http://www.pernicious-anaemia-society.org/phpbb/index.php. Retrieved 2010-03-18. 
20. ^ 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. 
21. ^ http://www.ncbi.nlm.nih.gov/pubmed/9247460?dopt=Abstract website for the study Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients
22. ^ William B. Castle 1897—1990 A Biographical Memoir by James H. Jandl Copyright 1995 National Academies Press washington d.c.
23. ^ [2]^{[dead link]}
24. ^ Gray, Charlotte. Reluctant Genius: Alexander Graham Bell and the Passion for Invention. New York: Arcade Publishing, 2006. ISBN 1-55970-809-3, page 418.
25. ^ <Please add first missing authors to populate metadata.>. "Annie Oakley - MSN Encarta". Annie Oakley - MSN Encarta. http://encarta.msn.com/encyclopedia_761563729/Annie_Oakley.html. Retrieved 2008-01-27. 
26. ^ eva isaksson - suomalainen Einstein: painovoiman teoriaa 1910-luvulla http://www.helsinki.fi/~eisaksso/nordstrom/gunnar.html
27. ^ Totuuden nimessä: Kaksitoista merkittävää Suomen Tiedeseuran jäsentä (In the name of truth: twelve important members of the Finnish society of science), page 173
28. ^ "Noman Warne - The World of Beatrix Potter". Peter Rabbit. http://www.peterrabbit.com/potters-world-norman-warne.asp. Retrieved 2010-03-18. 
29. ^ "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

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