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|Classification and external resources|
|Classification and external resources|
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. One way pernicious anemia can develop is 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 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. Impaired absorption of vitamin B12 may be due to a loss of intrinsic factor or to a number of other conditions that decrease production of gastric acid, which also plays a part in the 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, people without the ability to absorb B12 in this way will have pernicious anemia for the remainder of their lives. 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.
PA presents insidiously, and many of the signs and symptoms are due to anemia itself, where anemia is present. Untreated pernicious anemia can lead to neurological complications, and in serious cases, death. However, in 20% of cases of cobalamin deficiency, anemia is not observed. While it may consist of the triad of paresthesias, 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 and smooth appearance of the tongue), angular cheilitis (sores at the corner of the mouth), 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 also 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.
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 cubilin receptors on the ileum epithelial cells. PA is characterised by 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, evidence indicates 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 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.
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 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, a genetic factor likely is involved in the disease. Pernicious anemia is often found in conjunction with other autoimmune disorders, suggesting common autoimmune susceptibility genes may be a causative factor.
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 required for purine and thymidylate synthesis, which are required for the synthesis of DNA. Inhibition of DNA replication 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.
The insidious nature of PA may mean that diagnosis is delayed. The Schilling test, the classic test for PA, is no longer widely used, as safer and more efficient methods are available. Part one of the Schilling test consists of taking an oral dose of radiolabelled B12 and having the radioactivity of the urine measured over a 24-hour period. The second part of the test is a repeat of the first, with the addition of oral intrinsic factor. With lower than normal amounts of intrinsic factor produced in PA, the addition of intrinsic factor in the second test allows the body to absorb more B12, producing a higher urine radioactivity. This test can distinguish PA from other forms of B12 deficiency.
PA may be suspected when a patient's blood smear shows large, fragile, immature erythrocytes, known as megaloblasts. A diagnosis of PA first requires demonstration of megaloblastic anemia by conducting a full blood count and blood smear, which evaluates the mean corpuscular volume (MCV), as well the mean corpuscular hemoglobin concentration (MCHC). PA is identified with a high MCV (macrocytic anemia) and a normal MCHC (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.
Serum B12 levels are used to detect B12 deficiency, but they do not distinguish its causes. B12 levels can be falsely high or low and data for sensitivity and specificity vary widely. Normal serum levels may be found in cases of deficiency where myeloproliferative disorders, liver disease, transcobalamin II deficiency, or intestinal bacterial overgrowth are present. Low levels of serum B12 may be caused by other factors than B12 deficiency, such as folate deficiency, pregnancy, oral contraceptive use, haptocorrin deficiency, and myeloma.
The presence of antibodies to gastric parietal cells and intrinsic factor is common in PA. Parietal cell antibodies are found in other autoimmune disorders and also in up to 10% of healthy individuals, making the test nonspecific. However, around 85% of PA patients have parietal cell antibodies, which means they are a sensitive marker for the disease. Intrinsic factor antibodies are much less sensitive than parietal cell antibodies, but they are much more specific. They are found in about half of PA patients and are very rarely found in other disorders. These antibody tests can distinguish between PA and food-B12 malabsorption.
A buildup of certain metabolites occurs in B12 deficiency due to its role in cellular physiology. Methylmalonic acid can be measured in both the blood and urine, whereas homocysteine is only measured in the blood. An increase in both MMA and homocysteine can distinguish between B12 deficiency and folate deficiency because only homocysteine increases in the latter.
Elevated gastrin levels can be found in around 80-90% of PA cases, but they may also be found in other forms of gastritis. Decreased pepsinogen I levels or a decreased pepsinogen I to pepsinogen II ratio may also be found, although these findings are less specific to PA and can be found in food-B12 malabsorption and other forms of gastritis.
The diagnosis of atrophic gastritis type A should be confirmed by gastroscopy and stepwise biopsy. About 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.
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 standard treatment for PA has been parenteral (intramuscular) administration of cobalamin in the form of cyanocobalamin (CN-Cbl) and hydroxocobalamin (OH-Cbl). Andrès et al. recommend a general method to administer CN-Cbl in three stages; 1000 μg/day for 1 week, then 1000 μg/week for 1 month, followed by 1000 μg/month for life. This system allows the frequency of injections to be easily tailored to the patient's serum cobalamin levels and prevent clinical relapse. However, debate concerning the ideal dose and scheduling exists, which may be due to the patient's unique prognosis and/or a collective disagreement between researchers on which derivative of cobalamin to administer. When HeLa cells were separately incubated with equivalent amounts of CN-Cbl and OH-Cbl, OH-Cbl was better retained in the body, converted into twice as much active coenzyme AdoCbl, and increased both the half-life and concentration of free cobalamin in blood.
The oral treatment of PA with CN-Cbl and OH-Cbl provide cells with a source of cobalamin that can be internalized to form active coenzyme forms. A daily intake of 2.4 μg of Vitamin B12 has been proven to be sufficient in replenishing the normal amount of B12 lost through metabolism. However, due to the lack of IF in patients with PA, the intrinsic-factor-mediated absorption is disrupted and the efficiency by which Cbl is absorbed by the ileum is reduced to 1-5% via passive diffusion. The results of an open study of 10 patients with pernicious anemia demonstrated that an oral megadose of 1000 μg/day of CN-Cbl for 3 months increased the serum cobalamin levels by an average 117.4 pg/mL as well improve the clinical abnormalties in 30% of the patients. The recommendation of a daily oral megadose of CN-Cbl for life has not been made a definitive treatment for PA; however, relative to current parenteral treatments, oral treatments are less time consuming, lower in cost, and more convenient for the patient.
Although oral megadoses and intramuscular injections are the most common methods of treatment currently available, several novel methods are being tested, with high promise for future incorporation into mainstream treatment methods. As injections are unfavourable vehicles for drug delivery, current research involves improving the passive diffusion across the ileum upon oral ingestion of cobalamin derivatives. Researchers have recently taken advantage of the novel compound sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), which greatly enhances both bioavailability and metabolic stability. SNAC is able to form a noncovalent complex with cobalamin while preserving its chemical integrity. This complex is much more lipophilic than the water-soluble B12, so is able to pass through cellular membranes with greater ease.
Another method for increasing absorption through the ileum is to ingest a Cbl complex to which IF is already bound. The lack of intrinsic factor produced by the patient's body can be supplemented by using synthetic human IF produced from pea plant recombinants. However, in cases where IF-antibodies are the reason for malabsorption across the ileum, this treatment would be ineffective.
Sublingual treatments have also been postulated to be more effective than oral treatments alone. A 2003 study found, while this method is effective, a dose of 500 μg of cyanocobalamin given either orally or sublingually, is equally efficacious in restoring normal physiological concentrations of cobalamin. Intranasal methods have also been studied as a vehicle for the delivery of cobalamin. A 1997 study monitored the plasma cobalamin concentration of six patients with pernicious anemia over a period of 35 days while being treated with 1500 μg of intranasal hydroxocobalamin. One hour after administration, all patients showed on average an immediate eight-fold increase in plasma cobalamin concentration and a two-fold increase after 35 days with three 1500 μg treatments. However, further studies are needed to investigate the long-term effectiveness of this delivery method.
An alternative method for the treatment of pernicious anemia includes the use of transdermal patches. These patches are composed of CN-Cbl complexed with B12 stabilizers, and epidermal penetration enhancers. Vitamin-loaded electrospun nanofibers are able to deliver the vitamin effectively through the stratum corneum. The transdermal route allows CN-Cbl to passively diffuse through the stratum corneum, viable epidermis, and dermis layer, and ultimately entering the bloodstream. A 20-mg 5% drug-loaded polycaprolactone fiber can release 340 μg of cobabalmin per day. Since the drug is absorbed directly from the epidermis to the bloodstream, it avoids the hepatic first pass effect, improving bioavailability and therapeutic efficacy of the drug. The slow release of the drug from the patch to the bloodstream also increases its half-life, maintaining a constant cyanocobalamin level in blood for longer periods of time. This decreases the dosage required in comparison to oral delivery methods.
A patient with well-treated PA can live a healthy life. Failure to diagnosis and treat in time, however, may result in permanent neurological damage, excessive fatigue, depression, memory loss, and other complications. In severe cases, the neurological complications of pernicious anemia can lead to death - hence the name, "pernicious", meaning deadly.
An association has been observed between pernicious anemia and certain types of gastric cancer, but a causal link has not been established.
PA is estimated to affect 0.1% of the general population and 1.9% of those over 60, accounting for 20-50% of B12 deficiency in adults.
British physician Thomas Addison first described the disease in 1849, from which it acquired the common name of Addison's anemia. In 1871, German physician Michael Anton Biermer (1827–1892) noticed the particular characteristic of the anemia in one of his patients; he later coined the term "progressive pernicious 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). Frieda Robscheit-Robbins worked closely with Whipple, co-authoring 21 papers from 1925-30. For the discovery of the cure of a previously fatal disease of unknown etiology, Whipple, Minot, and Murphy 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 daily.