Pernicious anemia is a rare blood disorder characterized by the inability of the body to properly utilize vitamin B12, which is essential for the development of red blood cells. Most cases result from the lack of the gastric protein known as intrinsic factor, without which vitamin B12 cannot be absorbed.
The symptoms of pernicious anemia may include weakness, fatigue, an upset stomach, an abnormally rapid heartbeat (tachycardia), and/or chest pains. Recurring episodes of anemia (megaloblastic) and an abnormal yellow coloration of the skin (jaundice) are also common. Pernicious anemia is thought to be an autoimmune disorder, and certain people may have a genetic predisposition to this disorder.
There is a rare congenital form of pernicious anemia in which babies are born lacking the ability to produce effective intrinsic factor. There is also a juvenile form of the disease, but pernicious anemia typically does not appear before the age of 30. The onset of the disease is slow and may span decades. When the disease goes undiagnosed and untreated for a long period of time, it may lead to neurological complications. Nerve cells and blood cells need vitamin B12 to function properly.
Symptoms of pernicious anemia may include fatigue, shortness of breath, rapid heart rate, jaundice or pallor, tingling and numbness of hands and feet, loss of appetite, diarrhea, unsteadiness when walking, bleeding gums, impaired sense of smell, and confusion.
The symptoms of juvenile pernicious anemia are usually obvious between the ages of 4 and 28 months. Most affected infants develop a form of anemia known as megaloblastic anemia. Large, immature red blood cells are found in the blood (megaloblasts), impairing the ability of the blood to deliver oxygen to the tissues of the body. Other types of blood cells (e.g., platelets and white blood cells) may also be deficient (pancytopenia). Symptoms may include vomiting, diarrhea, fatigue, headache, inability to sleep (insomnia), lack of appetite, failure to thrive, a yellow coloration of the skin (jaundice), irritability, and/or a pale complexion. Mental retardation is also common in infants with juvenile pernicious anemia. Affected infants may experience repeated episodes of extreme anemia and jaundice. Some children with the juvenile form of the disease have blood protein present in their urine (persistent proteinuria) and some may have urinary tract malformations.
Individuals with congenital pernicious anemia present with symptoms very similar to the juvenile form. These however progress comparatively slowly; so slowly that the signs of neurological deficits may precede those associated with the decline in blood capacity. The symptoms may include generalized weakness and fatigue, difficulty breathing (dyspnea), an abnormally rapid heartbeat (tachycardia), and/or chest pains (angina). Affected individuals may also have gastrointestinal problems, such as a profound lack of appetite (anorexia), abdominal pain, indigestion, belching, and/or constipation and diarrhea. Weight loss is also common. Some people with Pernicious Anemia may have an abnormally enlarged liver (hepatomegaly) or spleen (splenomegaly). Other problems involving urinary function may also develop.
Because nerve cells need vitamin B12 to function properly, some people with pernicious anemia will display neurological symptoms. Nerves other than those of the brain and spinal cord (peripheral nervous system) are frequently affected. Occasionally, the spinal cord may also be involved. Neurological symptoms may include numbness, tingling, loss of sensation in the arms and/or legs (acroparesthesias). Other neurological symptoms may include impaired ability to coordinate movement (ataxia), a positive Babinski sign (outward motion of the big toe caused by stroking the sole of the foot), and/or exaggerated reflexes (hyperreflexia). Some people with pernicious anemia may also become extremely irritable or depressed and, in some rare cases, even experience paranoia (megaloblastic madness).
Pernicious anemia is thought to be an autoimmune disease. Autoimmune disorders are caused when the body’s natural defenses (e.g., antibodies) against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Pernicious anemia is sometimes seen in association with certain autoimmune endocrine diseases, such as type 1 diabetes, hypoparathyroidism, Addison’s disease, and Graves’ disease.
However, since the disorder also tends to occur with greater frequency in certain families than in others, it is also believed that there may be a genetic component to pernicious anemia. In general, risk factors for pernicious anemia include a family history of the disease, being of Northern European or Scandinavian descent, and a history of autoimmune endocrine disorders.
The congenital and juvenile forms are thought to be inherited as autosomal recessive traits. The gene responsible for anemia due to intrinsic factor deficiency has been tracked to a location on chromosome 11 (11q13). The gene responsible for anemia due to the intestinal malabsorption of vitamin B12 has been tracked to sites on chromosome 14 (14q32) and 10 (10p12.1).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11q13″ refers to band 13 on the long arm of chromosome 11. Similarly gene map loci 14q32 and 10p12.1 refer to a site at band 32 on the long arm of chromosome 14, and at band 12.1 on the short arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Slightly more women than men are affected by pernicious anemia. The adult form is the most common, and diagnosis typically takes place at around 60 years of age.
Pernicious anemia is more common among people from northern Europe, Scandinavia, and North America than among those from other parts of the world. It is believed that a significant number of cases go undiagnosed. This disorder occurs much more frequently among people who have diseases such as multiple myeloma and various other immunoglobulin deficiencies than in the general population.
The diagnosis of pernicious anemia may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized laboratory tests. During a Schilling test, the intestines' ability to absorb vitamin B12 is measured. The vitamin is labeled with radioactive cobalt and is ingested by mouth. X-ray studies can then determine if the body is properly absorbing this vitamin.
If pernicious anemia is ignored, undiagnosed, or left untreated, life-threatening complications can occur. Pernicious anemia is treated by injection of vitamin B12 (hydroxocobalamin or cyanocobalamin) into the muscle. A physician must closely monitor the amount of vitamin that is given and adjust the dosage when necessary. People with pernicious anemia must continue to receive maintenance doses of vitamin B12 throughout life.
Genetic counseling may be of benefit for people with pernicious anemia and their families.
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Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:865-868.
Berkow R, ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:898, 1074.
Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:660, 844.
Al-Alami JR, Tanner SM, Tayeh Mk, et al. Homozygous AMN mutation in hereditary selective malabsorption of vitamin B12 in Jordan. Saudi Med J. 2005;26:1061-64.
Gordon MM, Brada N, Remacha A, et al. A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency. Hum Mutat. 2004;23:85-91.
Hewitt JE, Gordon MM, Taggart RT, et al. Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11. Genomics. 1991;10:432-40.
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McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Intrinsic Factor Deficiency; IFD. Entry Number; 261000: Last Edit Date; 10/19/2005.
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Pernicious Anemia. Entry Number; 170900: Last Edit Date; 1/14/1995.
Hart JA. Pernicious anemia. MedlinePlus. Medical Encyclopedia. Update Date: 1/16/2004. 4pp.
Matsui W. Pernicious anemia. University of Maryland Medical Center. Review date: 5/10/2002. 2pp.