pernicious anemia pernicious anemia pernicious anemia is a disease in which not enough red blood cells are produced due to a deficiency of vitamin b12. those affected often have a gradual onset. the most common initial symptoms are feeling tired and weak. other symptoms of anemia may include shortness of breath, lightheadedness, headaches, sore red tongue, cold hands and feet, pale or yellow skin, chest pain, and an irregular heartbeat. the digestive tract may also be disturbed giving symptoms that can include nausea and vomiting, heartburn, upset stomach and loss of appetite. symptoms of vitamin b12 deficiency may include decreased ability to think, numbness in the hands and feet, memory problems, blurred vision, trouble walking, poor balance, muscle weakness, decreased smell and taste, poor reflexes, clumsiness, depression, and confusion. without treatment, some of these problems may become permanent. "addison's anaemia" redirects here. for the disease affecting the adrenal glands, see addison's disease. pernicious anemiaother namesvitamin b12 deficiency anemia, biermer's anemia, addison's anemia, addison–biermer anemiamicrograph 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.specialtyhematologysymptomsfeeling tired, shortness of breath, pale skin, numbness in the hands and feet, depression, confusion, poor reflexesusual onset> 60 years oldcausesnot enough intrinsic factordiagnostic methodblood tests, bone marrow teststreatmentvitamin b12 pills or injectionsprognosiswith treatment a normal lifefrequency1 per 1000 people pernicious anemia refers to a type of vitamin b12 deficiency 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 all or part of the stomach or small intestine; from an inherited disorder or illnesses that damage the stomach lining. when suspected, diagnosis is made by blood tests initially a complete blood count, 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. because pernicious anemia is due to a lack of intrinsic factor, it is not preventable. pernicious anemia can be treated with injections or pills of vitamin b12. if the symptoms are serious, injections are typically recommended initially. for those who have trouble swallowing pills, a nasal spray is available. often, treatment may needed for life. pernicious anemia due to autoimmune problems occurs in about one per 1000 people in the us. 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, and can cause harm insidiously and unnoticeably. untreated, it can lead to neurological complications, and in serious cases, death. it can take several years for pernicious anemia to appear, and the disease often goes unrecognized, as the body becomes used to feeling unwell. the onset may be vague and slow, as the same symptoms are often also present with anemia; in 81.1% of cases of cobalamin deficiency, pernicious anemia is not observed. pernicious anemia may be present without a person experiencing symptoms at first, over time, feeling tired and weak, lightheadedness, dizziness, headaches, rapid or irregular heartbeat, breathlessness, glossitis (a sore red tongue), poor ability to exercise, low blood pressure, cold hands and feet, pale or yellow skin, easy bruising and bleeding, low-grade fevers, tremor, cold sensitivity, chest pain, upset stomach, nausea, 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, may occur. anemia may present with a number of further common symptoms, including hair thinning and loss, early greying of the hair, mouth ulcers, bleeding gums, angular cheilitis, 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 cell damage may occur, which can lead to more severe symptoms, including sense loss, difficulty in proprioception, neuropathic pain, difficulty walking, poor balance, loss of sensation in the feet, muscle weakness, blurred vision (either due to retinopathy or optic neuropathy), impaired urination, fertility problems, decreased sense of taste and smell, decreased level of consciousness, changes in reflexes, memory loss, mood swings, depression, irritability, cognitive impairment, trouble talking, confusion, anxiety, clumsiness, psychosis, and, in more severe cases, dementia. anemia may also lead to cardiac murmurs and/or altered blood pressure (low or high). the deficiency may also 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 cause osteoporosis and may lead to bone fractures. pernicious anemia can contribute to a delay in physical growth in children, and may also be a cause for delay in puberty for adolescents. 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 proteases released by the pancreas into 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 enterocytes in the ileum's cubam receptors. pa is characterised by b12 deficiency caused by the absence of intrinsic factor. other disorders that can disrupt the absorption of vitamin b12 in the small intestine include celiac disease, surgical removal of crohn's disease, and hiv. atrophic gastritis showing patchy atrophy of oxyntic mucosa pa may be considered as an end stage of autoimmune atrophic gastritis, a disease characterised by stomach atrophy and the presence of antibodies to parietal cells and intrinsic factor. autoimmune atrophic gastritis, 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. atrophic gastritis is often a precursor to gastric cancer. 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 sodium-potassium pump. in a study, b12 deficiency caused by helicobacter pylori was positively correlated with caga positivity and gastric inflammatory activity, rather than gastric atrophy. less commonly, h. pylori and zollinger-ellison syndrome may cause a form of nonautoimmune 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 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. pathophysiology 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. 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 levomefolic acid 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 levomefolic acid. 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. diagnosis immunofluorescence staining pattern of gastric parietal cell antibodies on a stomach section diagnosis is not always straightforward and can be challenging and can take up to several years to receive a diagnosis from the onset of symptoms and almost 60% of those affected are misdiagnosed or not initially diagnosed at all. 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. the condition may occur without anemia. vitamin b12 serum levels are used to detect its deficiency, but 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, or small intestinal bacterial overgrowth are present. low levels of serum vitamin b12 may be caused by other factors than b12 deficiency, such as folate deficiency, pregnancy, oral contraceptive use, haptocorrin deficiency, and myeloma. high serum levels may caused by supplementing with vitamin b12, present of antibodies to intrinsic factor, or due to underlying condition. 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