Vitamin B12 deficiency anemia
|Vitamin B12 deficiency anemia|
|Other names||Pernicious anemia, Biermer's anemia, Addison's anemia, Addison–Biermer anemia|
|Micrograph showing nodular enterochromaffin-like cell hyperplasia, as demonstrated with chromogranin A immunostaining, in the body of the stomach. Parietal cells are not readily apparent. These changes are in keeping with autoimmune metaplastic atrophic gastritis, a histologic correlate of vitamin B12 deficiency anemia.|
|Symptoms||Feeling tired, feeling like passing out, breathlessness, headache, dizziness, decreased ability to think, pale skin, low blood pressure, pins and needles sensations, depression, confusion, changes in reflexes|
|Usual onset||> 60 years old|
|Causes||Not enough vitamin B12|
|Diagnostic method||Blood tests, bone marrow tests|
|Treatment||Vitamin B12 pills or injections|
|Prognosis||With treatment a normal life|
|Frequency||1 per 1000 people|
Vitamin B12 deficiency anemia, of which pernicious anemia (PA) is a type, is a disease in which not enough red blood cells are produced due to a deficiency of vitamin B12. Anemia is defined as a condition in which the blood has a lower than normal number of red blood cells. The most common initial symptom is feeling tired, among others, a range of symptoms, such as breathlessness, feeling like one is going to pass out, a sore red tongue (glossitis), headaches, pale skin, chest pain, rapid heartbeat, a frequent fall of blood pressure, numbness in the hands and feet, loss of appetite, and upset stomach (dyspepsia), may be experienced. In prolonged or untreated cases of anemia, it often has more severe symptoms, such as memory problems, changes in mobility, muscle weakness, poor reflexes, clumsiness, depression, confusion, guilt and psychosis. Without treatment some of these problems may become permanent.
Pernicious anemia refers to anemia that results from lack of intrinsic factor. Lack of intrinsic factor is most commonly due to an autoimmune attack on the cells that create it in the stomach. It can also occur following the surgical removal of part of the stomach or from an inherited disorder. Other causes of low vitamin B12 include not enough dietary intake (which can be a risk in a vegan diet), celiac disease, or tapeworm infection. When suspected, diagnosis is made by blood and, occasionally, bone marrow tests. Blood tests may show fewer but larger red blood cells, low numbers of young red blood cells, low levels of vitamin B12, and antibodies to intrinsic factor.
Pernicious anemia can be treated with injections of vitamin B12. If the symptoms are severe, injections are typically recommended initially. For those who have trouble swallowing pills, a nasal spray is available. Often, treatment is lifelong.
Pernicious anemia due to autoimmune problems occurs in about one per 1000 people. Among those over the age of 60, about 2% have the condition. It more commonly affects people of northern European descent. Women are more commonly affected than men. With proper treatment, most people live normal lives. Due to a higher risk of stomach cancer, those with pernicious anemia should be checked regularly for this. The first clear description was by Thomas Addison in 1849. The term "pernicious" means "deadly", and this term came into use because before the availability of treatment the disease was often fatal.
Signs and symptoms
Pernicious anemia often presents slowly, meaning that it insidiously and unnoticeably can cause harm. Untreated, it can lead to neurological complications, and in serious cases, death. The disease often goes unrecognized, as the body becomes used to feeling unwell.
The onset may be often vague and slow; the symptoms are often present with anemia, of which including symptoms of B12 deficiency. If anemia is present, a range of signs and symptoms may be experienced, such as feeling constant tiredness and weakness, feeling like one is going to pass out, dizziness, headaches, rapid heartbeat (fluttering, or Irregular heartbeat), breathlessness “the sighs”, a sore red tongue (glossitis), a frequent fall of blood pressure (hypotension), cold hands and feet, pale skin, easy bruising and bleeding, low-grade fevers, shakiness and constantly feeling cold, chest pain, upset stomach, nausea, angular cheilitis, loss of appetite, heartburn, weight loss, diarrhea, constipation, severe joint pain, feeling abnormal sensations including tingling or numbness to the fingers and toes (pins and needles), and tinnitus. Anemia may presents with a number of further common symptoms, including hair thinning and loss, early greying of the hair, mouth ulcers, bleeding gums, a yellowish skin (jaundice), a look of exhaustion with pale and dehydrated or cracked lips and dark circles around the eyes, as well as brittle nails.
In more severe or prolonged cases of pernicious anemia, nerve cells damage may occur, of which can lead to a more severe symptoms, including sense loss, difficulty in proprioception, neuropathic pain, unsteady walking (ataxia), poor balance, loss of sensation in the feet, muscle weakness, blurred vision (either due to retinopathy or optic neuropathy), impaired urination, fertility problems, decreased level of consciousness, changes in reflexes, memory loss, mood swings, depression, irritability, cognitive impairment, confusion, anxiety, clumsiness, psychosis, and, in more severe cases, dementia. Decreased taste or smell also may occur. Anemia may also lead to cardiac murmurs, and/or altered blood pressure (low or high). The deficiency also may present with thyroid disorders. In severe cases, the anemia may cause 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 deficiency, which is reversible, is occasionally confused with acute myeloid leukemia, which is an irreversible autoimmune condition presenting with some of the same hematological symptoms, including hypercellular bone marrow with blastic differentiation and hypersegmented neutrophils. Pernicious anemia can contribute to a delay in physical growth in children, and may also be a cause for delay in puberty for adolescents.
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 proteases released by the pancreas in the small bowel. 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. In a study, B12 deficiency caused by Helicobacter pylori was positively correlated with CagA positivity and gastric inflammatory activity, rather than gastric atrophy.
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. In spite of that, previous family studies and case reports focusing on PA have suggested that there is a tendency of genetic heritance of PA in particular, and close relatives of the PA patients seem to have higher incidence of PA and associated PA conditions. Moreover, it was further indicated that the formation of antibodies to gastric cells was autosomal dominant gene determined, and the presence of antibodies to the gastric cells might not be necessarily related to the occurrence of atrophic gastritis related to PA.
Although the healthy 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; pernicious anemia refers to one of the hematologic manifestations of chronic auto-immune gastritis, in which the immune system targets the parietal cells of the stomach or intrinsic factor itself, leading to decreased absorption of vitamin B12. Asymptomatic autoimmune gastritis likely precedes gastric atrophy by 10 to 20 years, followed by the onset of Iron deficiency anemia that occurs as early as 20 years before vitamin B12 deficiency “pernicious 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 catalyzed 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 maturing 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.
Pernicious anemia is thought mainly to be an autoimmune disorder that damages the parietal cells of the stomach – as it leads to decreased production of the intrinsic factor and impaired absorption of B12. However, pernicious anemia may also have a genetic component to it as well, potentially running in families. Pernicious anemia may be suspected when a patient's blood smear shows large, brittle, immature, erythrocytes, known as megaloblasts. a diagnosis of pernicious anemia It requires a blood count test and a blood smear and these tests include:
- Complete blood count and peripheral blood smear – 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 vitamin B12 – serum levels are used to detect its deficiency, but they do not distinguish its causes. vitamin 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.
- Intrinsic factor and parietal cell antibodies – the blood is checked for antibodies against IF and parietal cells in the stomach. The presence of antibodies to gastric parietal cells and IF is common in PA. Parietal cell antibodies are found in other autoimmune disorders and also in up to 10% of healthy individuals. 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.
- Methylmalonic acid and/or homocysteine – vitamin B12 plays an important role in metabolic processes and cellular functions. Therefore, its deficiency leads to the accumulation of some metabolic products. Methylmalonic acid and/or homocysteine is one of the metabolic products that can be measured in the blood. as the increase in the levels of both helps differentiate between vitamin B12 deficiency and folic acid deficiency, because homocysteine alone 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 vitamin 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 with host for vitamin B12.
The classic test for PA, the Schilling test, is no longer widely used, as more efficient methods are available. This historic test consisted, in its first step, of taking an oral dose of radiolabelled vitamin B12, followed by quantitation of the vitamin in the patient's urine over a 24-hour period via measurement of the radioactivity. A second step of the test repeats the regimen and procedure of the first step, with the addition of oral intrinsic factor. A patient with PA presents lower than normal amounts of intrinsic factor; hence, addition of intrinsic factor in the second step results in an increase in vitamin B12 absorption (over the baseline established in the first). The Schilling test distinguished PA from other forms of B12 deficiency, specifically, from Imerslund-Grasbeck Syndrome (IGS), a B12-deficiency caused by mutations in cubilin the cobalamin receptor.
The treatment of PA varies by country and area. Opinions vary over the efficacy of administration (parenteral/oral), the amount and time interval of the doses, or the forms of vitamin B12 (e.g. cyanocobalamin/hydroxocobalamin). More comprehensive studies are still needed in order to validate the feasibility of a particular therapeutic method for PA in clinical practices. A permanent cure for PA is lacking, although repletion of B12 should be expected to result in 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.
A person with well-treated PA can live a healthy life. Failure to diagnose 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. A review of literature shows that the prevalence of PA is higher in Northern Europe, especially in Scandinavian countries, and among people of African descent, and that increased awareness of the disease and better diagnostic tools might play a role in apparently higher rates of incidence.
However, this was not investigated in more depth until 1849, by British physician Thomas Addison, from which it acquired the common name of Addison's anemia. In 1871, the first accurate description of the disease in Europe was by Michael Anton Biermer, a German physician who referred to the insidious course of the condition, and because it was untreatable and fatal at the time, he first referred to it as “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.
Pernicious anemia was a fatal disease before about the year 1920, until the importance of the liver in hematopoiesis was recognized, the treatment of pernicious anemia was unsuccessful and arbitrary. It may have motivated George Whipple, who had a keen interest in liver diseases, to investigate the liver's role in hematopoiesis. Whipple began evaluating the effects of treatments for anemia caused by chronic blood loss. Whipple, Huber, and Robchett have studied the effects on hemoglobin and blood regeneration of a variety of treatments – among which only raw liver has shown real promise. Serendipity is said to have played a role in this discovery. Whipple observed that blood regeneration was poor in dogs fed cooked liver after chronic blood loss, had it not been that a lazy laboratory technician had given the dogs raw liver, the much more dramatic response might not have been discovered at that point in history.
Around 1926, George Minot and William P. Murphy, who learned of Whipple's discovery, sought raw liver as a treatment for pernicious anemia. They later suggested a high-protein diet with high amounts of raw liver. This caused a rapid improvement in symptoms and a simultaneous rise in red blood cell counts. Fruit and iron were also part of the diet, and it appears that at this point, Minot and Murphy weren't quite sure that the liver was a very important factor. It was thought that iron in liver tissue, not liver juice-soluble factor, cured hemorrhagic anemia in dogs; Thus, the discovery of liver juice as a treatment for pernicious anemia had been by coincidence. However, Minot, Murphy, and Whipple received the joint Nobel Prize for discovering a cure for a previously fatal disease of unknown cause in 1934, becoming the first Americans to be awarded the Nobel Prize in Physiology and Medicine.
Since it is not easy to eat a diet of raw liver, extracts of liver were developed for intramuscular injection, so as to provide a concentration of liver juicer. In 1928, chemist Edwin Cohn prepared a liver extract that was 50 to 100 times stronger than the natural food "liver". The extract can even be injected into a muscle, which means patients no longer need to ingest large amounts of liver or juice. This became part of the standard management of pernicious anemia until the 1950s. The active ingredient in the liver remained unknown until 1948. The anti-pernicious anemia factor was only isolated from the liver by Smith, Rex and others. The substance was cobalamin, which the discoverers called “vitamin B12”. They showed that giving a few micrograms could prevent relapse in the disease. Dorothy Hodgkin and co-workers went on to use X ray crystallography to elucidate the structure of cobalamin (which called vitamin B12); work for which she, too, was awarded a Nobel Prize.
Understanding of the pathogenesis of pernicious anaemia increased over subsequent decades. It had long been known that the disease was associated with defects in the gastrointestinal tract: patients suffered from chronic gastritis and lack of acid secretion (achlorhydria). It is known that transport of physiological amounts of vitamin B12 depends on the combined actions of gastric, ileal and pancreatic components. The gastric moiety was discovered and named ‘intrinsic factor’ by William Castle in 1930. A further important advance was made in the early 1960s by Doniach with the recognition that pernicious anemia is an autoimmune disease. Pernicious anemia is eventually treated with either injections or large oral doses of B12, typically between 1 and 4mg daily.
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 vitamin B12, so is able to pass through cellular membranes with greater ease.
Recombinant intrinsic factor
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.
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