Porphyria, Acute Intermittent
Synonyms of Porphyria, Acute Intermittent
- Porphyriam Acute Intermittent
- Porphyria, Swedish Type
- No subdivisions found.
Acute intermittent porphyria (AIP) is a rare metabolic disorder that is characterized by deficiency of the enzyme porphobilinogen deaminase (PBG-D), also known as uroporphyrinogen I-synthase. This enzyme deficiency results in the accumulation of porphyrins or porphyrin precursors in the body. These are natural chemicals that normally do not accumulate in the body. This enzyme deficiency by itself is not sufficient to produce symptoms of the disease (latent). Additional factors must also be present such as hormones, drugs and dietary changes that trigger the appearance of symptoms. Symptoms of AIP may include abdominal pain, constipation, and muscle weakness.
AIP is one of a group of disorders known as the porphyrias. The common feature in all porphyrias is the excess accumulation in the body of porphyrins or porphyrin precursors. Different types of porphyias are characterized by the accumulation of different types of porphyrin chemicals.
Porphyrias can also be classified into two groups: the "hepatic" and "erythropoietic" types. In the hepatic types of porphyria, porphyrins and related substances originate in excess amounts from the liver; in the erythropoietic types, they originate mostly from the bone marrow.
The porphyrias with skin manifestations are sometimes called "cutaneous porphyrias." The "acute porphyrias" are characterized by sudden attacks of pain and other neurological symptoms. These acute symptoms may be severe and often rapidly appear. An individual may be considered latent if he or she has the characteristic enzyme deficiency but has never developed symptoms. There can be a wide spectrum of severity between the latent and active cases of any particular type of porphyria. The symptoms and treatments of the different types of porphyrias are not the same.
The symptoms of AIP generally arise from effects on the central nervous system and/or the skin. In some cases, the cause of the nervous system dysfunctions is not clear, and proper diagnosis is often delayed. Skin manifestations can include burning, blistering and scarring of sun-exposed areas after even minimal exposure to the sun.
Many individuals who inherit the gene for AIP never develop symptoms (asymptomatic). In those who do display symptoms, the disease may become apparent after puberty, and more commonly does so in women than in men. Abdominal pain, which can be severe, is the most common symptom. Additional symptoms may include nausea, vomiting, constipation, and pain in the back, arms and legs. Rapid heart rate (tachycardia), increased blood pressure (hypertension), tremors, confusion, hallucinations or seizures may also be present. Sometimes the level of salt (sodium chloride) in the blood decreases markedly during attacks and contributes to some of these symptoms. Affected individuals may develop disease affecting the nerves outside the central nervous system (peripheral neuropathy). This may result in pain in the arms and legs.
A common symptom of AIP is muscle weakness, which often begins in the proximal muscles of the arms or legs. Muscle weakness may progress to affect other muscles of the body, potentially causing serious complications such as respiratory insufficiency.
The inherited porphyrias are either autosomal dominant or autosomal recessive. Acute intermittent porphyria is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Investigators have determined that AIP results from disruptions or changes (mutations) to the gene that is responsible for regulating the production of the enzyme porphobilinogen (PBG) deaminase (PBGD gene) has been located on the long arm (q) of chromosome 11 (11q23.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Researchers have identified more than 200 different mutations of the PBG deaminase gene, which can cause AIP.
Inheritance of this defective gene, by itself, is not enough for the development of symptoms associated with AIP. Additional factors must also be present such as hormones, drugs and dietary changes that trigger the appearance of symptoms. Triggers that may precipitate an attack of AIP include certain drugs, chemicals, dietary changes, and sun exposure.
Because all porphyrias are uncommon, it is very unlikely that more than one type will occur in the same family, or that someone with one type of porphyria will go on to develop another.
Acute intermittent porphyria is estimated to affect between 2 and 5 per 100,000 people in the general population. It occurs most frequently in people of Scandinavian, Anglo-Saxon, or German ancestry. Prevalence is greatest in northern Sweden. All ethic groups are affected, although it is extremely rare in African Americans. Young or middle-aged adult women are more frequently affected than males.
Symptoms of the following disorders can be similar to those of acute intermittent porphyria. Comparisons may be useful for a differential diagnosis:
The porphyrias are a group of disorders characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes essential to the synthesis of hemoglobin. There are at least seven types of porphyria. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. It is important to note that people who have one type of porphyria do not develop any of the other types. For more information on each of the following types of the disease, choose "porphyria" as your search term in the Rare Disease Database.
ALA-D porphyria symptoms usually arise from effects on the nervous system and/or the skin. Sometimes, the cause of the nervous system symptoms is not clear. Skin manifestations include burning, blistering, and scarring of the sun exposed areas. The disease usually manifests after puberty, and more commonly occurs in women. The most common symptom is severe abdominal pain. Other characteristics are nausea, vomiting, rapid heart rate, increased blood pressure, confusion and/or seizures, and the passing of ALA (delta- aminolevulinic acid) in the urine. (For more information, choose "ALA-D porphyria" as your search term in the Rare Disease Database.)
Porphyria cutanea tarda (PCT) is a type of porphyria in which affected individuals are sensitive to sunlight. Exposed skin shows abnormalities that range from slight fragility of the skin to persistent scarring and disfiguration. Due to fragility of the skin, minor trauma may induce blister formation. Areas of increased and decreased pigment content may be noted on the skin. Blistering of light exposed skin and increased hair growth are also characteristic. PCT is caused by a deficiency of the uroporphyrinogen decarboxylase (URO-D) enzyme in the liver. The disorder can be acquired or can be caused by an inherited gene mutation in the UROD gene. The inherited form of PCT is also called familial PCT and follows autosomal dominant inheritance. Many individuals with a UROD gene mutation never experience symptoms of the disease. PCT becomes active and causes symptoms when triggered by an environmental factor that affects liver cells (hepatocytes). These environmental factors include alcohol, estrogens, hepatitis C, and human immunodeficiency viruses (HIV).
Hereditary coproporphyria is characterized by large amounts of coproporphyrin in the body, which makes affected individuals sensitive to sunlight, but skin disease is rarely severe in this type of porphyria. Clinically it resembles variegate porphyria except that a larger percentage of affected individuals exhibit few symptoms. Other symptoms are similar to those listed for acute intermittent porphyria. (For more information, choose "hereditary coproporphyria" as your search term in the Rare Disease Database.)
Variegate porphyria is characterized by abrasions, blisters, and erosions of the skin which are commonly seen during the second and third decade. These lesions tend to heal slowly, often leaving pigmented or slightly depressed scars. The patients experience sensitivity to light and fragility of skin exposed to the sun. Although in many patients manifestations remain limited to the skin, episodes similar to those of acute porphyria are not uncommon. Therefore, the symptoms, drugs, precautionary measures, and treatment described for acute intermittent porphyria are applicable to variegate porphyria. (For more information, choose "variegate porphyria" as your search term in the Rare Disease Database.)
Tyrosinemia type I is a rare genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system. Symptoms and physical findings associated with tyrosinemia type I include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease. Tyrosinemia type one is inherited as an autosomal recessive trait.
Because acute intermittent porphyria can mimic a host of other more common conditions, its presence is often not suspected. It should be suspected in individuals with unexplained abdominal pain and accompanied by muscle weakness or other neurological symptoms. Tests to determine the levels of porphobilinogen deaminase in the urine may be performed. Elevated levels of PBG confirm a diagnosis of one of the acute porphyrias. Further testing is needed to distinguish AIP from variegate porphyria and hereditary coproporphyria.
When an individual is diagnosed as having AIP, relatives should be examined as well so that latent cases can be identified.
Panhematin (hemin for injection), an orphan drug formerly known as Hematin, is an enzyme inhibitor derived from processed red blood cells that is very potent in suppressing acute attacks of porphyria and has U.S. Food and Drug Administration (FDA) approval for that purpose. Because of its potency, it is usually given after a trial of glucose therapy, and should be administered only by physicians experienced in the management of porphyrias in a hospital setting.
Many types of drugs such as aspirin and certain antibiotics are believed to be safe in individuals with some types of porphyria. Recommendations about drugs for certain types of porphyrias are based on experience with an individual in whom attacks have been caused by drugs, and by tests in animals. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be procured from the American Porphyria Foundation (see the Resources section of this report).
AIP is particularly dangerous if the proper diagnosis has not been made, and if drugs which aggravate this disorder are administered. The prognosis is usually good if the disease is recognized before severe nerve damage has occurred and if treatment and preventive measures are begun. Although symptoms usually resolve after an attack, some individuals may develop chronic pain. Nerve damage and associated muscle weakness can improve over a period of months after a severe attack. Mental symptoms may occur during attacks, but are usually not chronic.
If an affected individual is taking drugs (including barbiturates, sulfonamides, tranquilizers or sedatives, antiseizure drugs, birth control pills or alcohol, etc.), they should be stopped under a physician's supervision.
Attacks of AIP are often precipitated by low intake of carbohydrates in an attempt to lose weight, thus dietary counseling can be very important. Premenstrual attacks often resolve quickly with the onset of menstruation; hormone manipulations may prevent occurrences of such attacks.
AIP patients prone to attacks should eat a normal or high carbohydrate diet and should not greatly restrict their intake of carbohydrates and calories, even for short periods of time. If weight loss is desired, it is advisable to consult a physician who may then request that a dietitian be consulted.
Pregnancy is tolerated much better in women with AIP than was formerly believed. Offspring have a fifty percent chance of inheriting the gene for AIP, but the great majority of those that do, remain "latent" for all or most of their lives. If diagnosed early, the minority of people that eventually develop symptoms will usually benefit from treatment. Given these considerations, most individuals, whether with "latent" or “active” porphyria, usually do not have reservations about family planning. For those who do, genetic counseling may be useful.
Wearing a Medic Alert bracelet is advisable in individuals who have had AIP attacks.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
New treatments for several types of porphyria are under investigation. For the most updated information on research, please contact the organizations listed in the Resources section.
In June of 2006, Zymenex, a Scandinavian biotechnology company, announced that it will not pursue further development of Porphozym, which had received an FDA orphan drug designation in 2002 to treat AIP. The drug had completed phase II clinical trials. Zymenex remains willing to partner the AIP product in the future.
Karl E. Anderson, MD, of the University of Texas Medical Branch, Galveston, TX, received orphan drug designation for Histrelin in 1991 for the treatment of various types of porphyria.
Research is underway on the Finnish product heme arginate (Normasang). Karl Anderson, MD, directed several recently completed (2004) clinical studies in the United States. Information is available at:
Ewing Hall (J-09)
University of Texas Medical Branch
700 Strand St.
Galveston, TX 77555
Organizations related to Porphyria, Acute Intermittent
Anderson KE. Acute Intermittent Porphyria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:490-1.
American Porphyria Foundation Brochure, "Common Questions Asked About Porphyria."
Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medcine. 2004;84:48-60.
Fraunberg MV, Pischik E, Udd L, Kauppinen R. Clinical and biochemical characteristics and genotype-phenotype correlation of 143 Finnish and Russian patients with acute intermittent porphyria. Medicine. 2005;84:35-47.
Kauppinen R. Molecular diagnosis of acute intermittent porphyria. Expert Rev Mol Diagn. 2004;4:243-9.
Suarez JI, Cohen ML, Larkin J, Kernich CA, Hricik DE, Daroff RB. Acute intermittent porphyria: clinicopathologic correlation. Report of a case and review of the literature. Neurology. 1997;48:1678-83.
Kauppinen R, Mustajoki S, Pihlaja H, Peltonen L, Mustajoki P. Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene. Hum Molec Genet. 1995;4:215-2.
Astrin K, Desnick RJ. Molecular basis of acute intermittent porphyria: mutations and polymorphisims in the human hydroxymethylbilane synthase gene. Hum Mutat. (1994; 4). Pp. 243-52.
Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated disease. Medicine. 1992;71:1-13.
FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:176000; Last Update:3/17/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176000 Accessed on: February 1, 2005.
DeLourghery TG. Acute Intermittent Porphyria. Emedicine. 2004. Available at: http://www.emedicine.com/med/topic1880.htm Accessed on: February 1, 2005.
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