Pernicious anemia

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, which are responsible, in part, for the secretion of intrinsic factor, a protein essential for subsequent absorption of vitamin B12 in the ileum.

Usually seated in an atrophic gastritis, the autoimmune destruction of gastric parietal cells (and autoantibody inactivation of intrinsic factor) leads to a lack of intrinsic factor. Since the absorption from the gut of normal dietary amounts of vitamin B12 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 (B12) is the most common cause of adult B12 deficiency. 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 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 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 PA 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 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.

Signs and symptoms
PA presents insidiously, and many of the signs and symptoms are due to anemia itself, where anemia is present. However, in 20% of cases of cobalamin deficiency, anemia is not observed. While it may consist of the triad of paraesthesias, sore tongue and weakness, this is not the chief symptom complex. Common symptoms include anemia, fatigue, depression, low-grade fevers, nausea, gastrointestinal symptoms (heartburn, diarrhoea, dyspepsia ), weight loss, neuropathic pain, jaundice, glossitis (swollen red tongue), atrophy of the tongue papillae, angular chelitis, dehydrated/cracked and pale lips and dark circles around the eyes (look of exhaustion) , brittle nails, and thinning and early greying of the hair. Because PA may affect the nervous system, symptoms may also include difficulty in proprioception, memory changes, mild cognitive impairment (including difficulty concentrating and sluggish responses, colloquially referred to as brain fog), impaired urination, loss of sensation in the feet, unsteady gait, difficulty in walking, muscle weakness and clumsiness. Anemia may cause tachycardia (rapid heartbeat) and cardiac murmurs, along with a yellow waxy pallor, low blood pressure, high blood pressure and shortness of breath (known as 'the sighs'). The deficiency may present with thyroid disorders. In severe cases, the anemia may cause evidence of congestive heart failure. 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. Other than anemia, hematological symptoms may include cytopenias, intramedullary hemolysis and pseudothrombotic microangiopathy.

Causes
Vitamin B12 cannot be produced by the human body, and must be obtained from the diet. When foods containing B12 are eaten, the vitamin is usually bound to protein and is released by stomach acid. Following its release, most B12 is absorbed by the body in the small bowel (ileum) after binding to a protein known as intrinsic factor. Intrinsic factor is produced by parietal cells of the gastric mucosa (stomach lining) and the intrinsic factor-B12 complex is absorbed by receptors on the ileum epithelial cells. PA is characterised by vitamin B12 deficiency caused by the absence of intrinsic factor.

PA may be considered as an end stage of immune gastritis, a disease characterised by stomach atrophy and the presence of antibodies to parietal cells and intrinsic factor. A specific form of chronic gastritis, Type A Gastritis or Atrophic Body Gastritis is highly associated with PA. This autoimmune disorder is localised to the body of the stomach, where parietal cells are located. Antibodies to intrinsic factor and parietal cells cause the destruction of the oxyntic gastric mucosa, in which the parietal cells are located, leading to the subsequent loss of intrinsic factor synthesis. Without intrinsic factor, the ileum can no longer absorb the B12.

Although the exact role of Helicobacter pylori infection in PA remains controversial, there is evidence that H.pylori is involved in the pathogenesis of the disease. A long standing H.pylori infection may cause gastric autoimmunity by a mechanism known as molecular mimicry. Antibodies produced by the immune system can be cross-reactive and may bind to both H.pylori antigens and those found in the gastric mucosa. The antibodies are produced by activated T cells and B cells that recognise both pathogen and self-derived peptides. The autoantigens believed to cause the autoreactivity are the alpha and beta subunits of the H+/K+-ATPase.

Less commonly, H.pylori and Zollinger-Ellison syndrome may also cause a form of non-autoimmune gastritis that can lead to pernicious anemia.

Impaired B12 absorption can also occur following gastric removal (gastrectomy) or gastric bypass surgery. In these surgeries, either the parts of the stomach that produce gastric secretions are removed or they are bypassed. This means that intrinsic factor, as well as other factors required for B12 absorption are not available. However, B12 deficiency after gastric surgery does not usually become a clinical issue. This is probably because the body stores many years' worth of B12 in the liver and gastric surgery patients are adequately supplemented with the vitamin.

Although no specific PA susceptibility genes have been identified, it is likely that there is a genetic factor to the disease. Pernicious anaemia is often found in conjunction with other autoimmune disorders, suggesting common autoimmune susceptibility genes may be a causative factor.

Pathophysiology
Although the normal body stores three to five years' worth of B12 in the liver, the usually undetected autoimmune activity in one's gut over a prolonged period of time leads to B12 depletion and the resulting anemia. B12 is required by enzymes for two reactions; the conversion of methylmalonyl CoA to succinyl CoA and the conversion of homocysteine to methionine. In the latter reaction, the methyl group of 5-methyltetrahydrofolate is transferred to homocysteine to produce tetrahydrofolate and methionine. This reaction is catalysed by the enzyme methionine synthase with B12 as an essential cofactor. During B12 deficiency, this reaction cannot proceed, which leads to the accumulation of 5-methyltetrahydrofolate. This accumulation depletes the other types of folate that are required for purine and thymidylate synthesis, which are required for the synthesis of DNA. Inhibition of DNA synthesis in red blood cells results in the formation of large, fragile megaloblastic erythrocytes. The neurological aspects of the disease are thought to arise from the accumulation of methylmalonyl CoA due to the requirement of B12 as a cofactor to the enzyme methylmalonyl CoA mutase.

Diagnosis
The insidious nature of the disease may mean a diagnosis is delayed. PA is suspected when the patient's blood smear shows large, fragile, immature erythrocytes (megaloblasts).

If antibodies are highly suggestive for a diagnosis of PA, and are found in nearly 100% of patients, with a sensitivity of around 70%. Antiparietal cell antibodies are inferior to intrinsic factor antibodies, as they are less sensitive and less specific. Elevated gastrin levels and decreased pepsinogen I levels may also be found, although these findings are less specific to pernicious anemia.

The Schilling test is the classic test for PA, but it is no longer widely used, as there are other quicker and easier methods (in addition to difficulties with the radiolabelled agent). 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. 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.

A diagnosis of PA 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 PA 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 B12 deficiency (notably malabsorption).

The diagnosis of atrophic gastritis type A should be confirmed by gastroscopy and stepwise biopsy. 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.

Forms of B12 deficiency other than PA 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 PA may be caused by infection with the tapeworm Diphyllobothrium latum, possibly due to the parasite's competition for B12.

Treatment
The treatment of PA varies from country to country and from area to area. A permanent cure for PA is lacking, although repletion of B12 should be expected to result in a cessation of anemia-related symptoms, a halt in neurological deterioration, and (in cases where neurological problems are 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 found oral and sublingual B12 were absorbed equally well in a group of patients with very low B12. In this study, 22% of the subjects who agreed to undergo the test (five 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, higher-than-normal doses may be needed. 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 it usually takes place). A 2006 study found oral B12 repletion has the potential to be as effective as injections.

However, if oral or sublingual repletion is inadequate, the patient may require B12 injections, 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 patients have different needs, with some patients needing more frequent injections than others. Some medical professionals believe subcutaneous injections are more effective than intramuscular injections, but the evidence for this is currently unclear.

The other methods of administering B12 include nasal sprays and behind-the-ear patches. One small study from 1997, with six participants, found intranasal delivery of B12 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.

Gastric bypass or gastrectomy patients must take B12 as in treatment of PA: either oral megadoses, or by injection.

Prognosis
A patient with well-treated pernicious anemia (PA) can live a healthy life, although exhaustion, memory loss and other symptoms may persist depending on the stage in which the individual was diagnosed. Failure to treat can lead to severe consequences for those with severe PA. Giving rise to the name, "pernicious," meaning fatal, patients may experience symptoms such as severe fatigue, depression, irritability, neurological damage, heart and organ failure, and even death. Having PA is not a death sentence, however, so long as it is properly maintained. Patients should regularly see their doctors for checkups and keep up with cyanocobalamin injections.

Long-term complications may include gastric cancer and carcinoids.

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. Untreated raw hamburger meat was fed to the control group. 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 (he was looking for treatments for anemia from bleeding, not pernicious anemia). Whipple discovered 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 in 1926 showed it was contained in raw liver juice (in the process also showing 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.

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 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 PA with even more ease. Pernicious anemia was eventually treated with either injections or large oral doses of B12, typically between 1 and 4 mg (1000 to 4000 mcg) daily.

Notable cases

 * Alexander Graham Bell - Scottish-Canadian scientist and inventor
 * Annie Oakley
 * David Hilbert - German mathematician
 * Sophus Lie - Norwegian mathematician
 * 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)
 * Norman Warne - editor/publisher and fiancé of Beatrix Potter
 * Yoon Eun Hye - a South Korean actress
 * Inez Milholland - American suffragist
 * Suzanne Lenglen - French tennis player and one of the first international female sport stars.