Acute intermittent porphyria

Synonyms

8

Overview

Acute intermittent porphyria is one of the liver (hepatic) porphyrias. AIP is caused by low levels of porphobilinogen deaminase (PBGD), an enzyme also often called hydroxymethylbilane synthase. The low levels of PBGD are generally not sufficient to cause symptoms; however, activating factors such as hormones, drugs, and dietary changes may trigger symptoms. Although most individuals with AIP never develop symptoms, symptomatic individuals typically present with abdominal pain with nausea. Treatment is dependent on the symptoms.

Symptoms

Some people who inherit the gene for AIP never develop symptoms and are said to have "latent" AIP. Those individuals that present with symptoms usually do so after puberty, probably because of hormonal influences, although other activating factors include: alcohol, drugs (e.g., barbiturates, steroids, sulfa-containing antibiotics), chemicals, smoking, reduced caloric intake, stress, and travel. Symptoms usually last several days, but attacks for which treatment is not received promptly may last weeks or months.

Abdominal pain, which is associated with nausea and can be severe, is the most common symptom and usually the first sign of an attack.

Other symptoms may include:

  • Gastrointestinal issues (e.g., nausea, vomiting, constipation, diarrhea, abdominal distention, ileus)
  • Urinary tract issues (e.g., urinary retention, urinary incontinence, or dysuria)
  • Neurological issues (e.g., muscle weakness in the arms or legs, paralysis)
  • Psychiatric issues (e.g., insomnia, hysteria, anxiety, apathy or depression, phobias, psychosis, agitation, delirium, somnolence, or coma)

Individuals with AIP have an increased risk of developing hepatocellular carcinoma; some develop kidney failure.

Causes

AIP is caused by the deficiency of an enzyme called porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase (HMBS) and formerly known as uroporphyrinogen I-synthase, one of the enzymes required in the synthesis of the red blood pigment heme. When production is impaired, many heme functions are affected. One of these is to assist the liver in metabolizing medical substances.The deficiency of PBGD is caused by a mutation in the HMBS gene. The HMBS gene is the only gene known to be associated with AIP. However, the deficiency of PBGD alone is not enough to cause AIP. Other activating factors (e.g., hormones, drugs, dietary changes) must also be present.

The gene governing the production of PBGD enzyme was identified in the late 1980s, and during the 1990s several gene mutations causing the enzyme deficiency were detected. More than 300 different mutations associated with the disease have hitherto been identified. Forty-two of these have been found in Sweden.

Porphyrins are involved in the biosynthesis of heme. This process involves eight steps, each requiring the presence of a specific enzyme. PBGD acts as a catalyst in the third step. In acute intermittent porphyria, PBGD activity is reduced by about 50 per cent, but the residual activity is normally sufficient to maintain heme production, and the AIP carrier will remain asymptomatic.

Problems associated with AIP present in situations when the liver attempts to accelerate heme production, but is impeded by the defective third step. When there is not sufficient PBGD to catalyse the conversion of heme precursors PBG (porphobilinogen) and ALA (aminolaevulinic acid), they accumulate in the body. Characteristic AIP symptoms, such as neuropathy and reddish urine, result from raised PBG and ALA levels. Over time, the liver and kidney may also be affected.

Certain drugs, hormones, alcohol and chemical solvents boost heme synthesis and trigger symptoms. Infections, physical or psychological stress and fasting may also precipitate an attack.

Prevention

It is possible to avoid or considerably reduce the risk of attacks by consistently avoiding precipitating factors. A person with acute intermittent porphyria should therefore be well informed about the condition. An essential part of the treatment is therefore to provide the patient with information and knowledge. The whole family should learn how to identify potential triggers of an attack and know what to do if symptoms present.

  • Stress. Physical or psychological strain is one of the most common triggers of attacks.
  • Medication. Lists of safe and unsafe drugs are available from the Swedish Porphyria Association (see under “Information material”).
  • Sex hormones. Oral contraceptives are a common cause of attacks in young women. Although new low-dose birth control pills are less likely to provoke an attack, they should be prescribed restrictively, preferably after consultation with both a gynaecologist and a porphyria specialist.
  • Infections. Common colds, flu, urinary tract infections or other infections increase the risk of an attack. In cases of infection it is strongly recommended to avoid other precipitating factors.
  • Alcohol. All carriers of an AIP mutation should restrict their intake of alcohol.
  • Fasting, dieting. Prolonged periods with little food may trigger an attack. Meals should be regular and rich in carbohydrates. If weight loss is desired, a dietician with experience of working with AIP should be consulted. Sporting events or physical activities requiring exertion over long periods of time and no access to nutrition should be avoided.
  • Solvents. Jobs involving the use of solvents are not suitable for AIP carriers. All exposure to solvents should be avoided.

Preventive hormone therapy:

Many women have attacks related to their menstrual cycle. Oral contraceptives or hormones down-regulating sex hormone production can be used to reduce hormone fluctuations and prevent attacks. These treatments must be carried out under the close supervision of a gynaecologist in cooperation with a porphyria specialist.

Diagnosis

Diagnosis of AIP is suspected in individuals with otherwise unexplained severe, acute abdominal pain without physical signs. The finding of increased levels of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine establishes that one of the acute porphyrias is present. If PBGD is deficient in normal red blod cells, the diagnosis of AIP is established. The diagnosis is confirmed in individuals with a disease-causing mutation in theHMBS gene, the only gene known to be associated with AIP, which encodes the erythrocyte hydroxymethylbilane synthase enzyme. Molecular genetic testing of the HMBS gene detects more than 98% of affected individuals and is available in clinical laboratories. To obtain a list of clinical laboratories offering genetic testing for AIP, 

This disease is rare and can mimic a host of other more common conditions, its presence is often not suspected. On the other hand, the diagnosis of AIP and other types of porphyria is sometimes made incorrectly in patients who do not have porphyria at all, particularly if laboratory tests are improperly done or misinterpreted. The finding of increased levels of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine establishes that one of the acute porphyrias is present. If PBGD is deficient in normal red blood cells, the diagnosis of AIP is established. However, measuring PBGD in red blood cells should not be relied upon by itself to exclude AIP in a sick patient, because the enzyme is not deficient in red blood cells of all AIP patients.

If it is known that someone in a family has AIP, and their enzyme value is low in red blood cells, other family members who have inherited a deficiency of PBGD can be identified by measuring the enzyme in their red blood cells. Latent cases so identified can avoid agents known to cause attacks. However, in some AIP families, PBGD is normal in red blood cells and is deficient only in the liver and other tissues. Falsely low values sometimes occur due to problems with collecting and transporting the sample.

DNA is the material in cells that encodes all the genetic information of an individual. Many different mutations have been identified in the portion of DNA that comprises the gene for PBGD. Almost every family with AIP has a different mutation in this gene. Within one family, however, everyone who inherits a deficiency of PBGD has the same mutation. It is advantageous to know the precise mutation in a family, because that knowledge enables the identification of AIP gene carriers by DNA testing. This approach is much more precise than measuring PBGD enzyme activity in red blood cells. At present, DNA testing for AIP and other porphyrias is available only through a few research laboratories.

Prognosis

AIP is particularly dangerous if the diagnosis has not been made and if harmful drugs are administered. The prognosis is usually good if the disease is recognized and if treatment and preventive measures are begun before severe nerve damage has occurred. Although symptoms usually resolve after an attack, some patients develop chronic pain. Nerve damage and associated muscle weakness can improve over a period of months or longer after a severe attack. Mental symptoms may occur during attacks, but are usually not chronic.

Wearing a Medic Alert bracelet is advisable for patients who have had attacks but is probably not warranted in most latent cases. It should be remembered that AIP patients can develop other diseases, and symptoms may not always be due to porphyria.

Treatment

Treatment of AIP may vary based on the trigger of the attack and the symptoms present. Treatment may include stopping medications that cause or worsen the symptoms, treating any infections which may be present, administration of pain medication, monitoring fluid balance and/or correcting electrolyte disturbances, monitoring neurologic status and administering respiratory support. Mild attacks can be manged with increased caloric intake and fluid replacement. Recurrent acute attacks should be managed by a porphyria specialist. Hospitalization is often necessary. Panhematin, an intravenous medication used to correct heme deficiency, may also be prescribed.

Resources

  • American Porphyria Foundation
  • The Swedish Information Centre for Rare Diseases
  • NIH