Acute Intermittent Porphyria (AIP)
AIP is the most common of the acute porphyrias, with a world-wide prevalence of approximately 1 to 2 per 20,000. AIP results from autosomal dominant inheritance of a mutation in the gene for the enzyme hydroxymethylbilane-synthase (HMB-synthase), which is also known as porphobilinogen deaminase or uroporphyrinogen I synthase. The enzyme deficiency alone is not sufficient to produce the symptoms of AIP, and other activating factors, such as drugs, hormones, and dietary changes, must be present. Sometimes, activating factors cannot be identified.
Most people who have a mutation in the gene for AIP never develop symptoms; this is referred to as “latent” AIP. Symptoms may develop after puberty, especially in women. Acute attacks almost always start with severe pain in the abdomen but sometimes in the chest, back, or thighs, and are often accompanied by nausea, vomiting, and constipation. Heart rate and blood pressure are commonly increased. These symptoms and signs are all due to the effects of the disease on the nervous system. Confusion, convulsions, and muscular weakness, due to impairment of the nerves controlling the muscles, may lead to paralysis. An acute attack usually lasts for days or weeks. Recovery from severe paralysis is generally slow.
Acute attacks are often provoked by drugs such as barbiturates, sulfonamide antibiotics, anti-seizure drugs, rifampin, metoclopramide, and alcohol. Attacks in women may occur after ovulation and during the last part of the menstrual cycle when progesterone levels are high. Reduced food intake, often in an effort to lose weight, as well as infections, surgery, and stressful situations may also precipitate attacks. Risk for developing chronic renal disease and liver cancer (hepatocellular carcinoma) is increased in AIP. The skin is not affected, except in some AIP patients who have developed kidney failure.
The finding of a substantial increase of porphobilinogen (PBG) in urine establishes that one of the three most common acute porphyrias (AIP, HCP or VP) is present. Therefore, measuring PBG in urine is the most important test for diagnosing acute porphyria, especially in an acutely ill patient. Deficiency of HMB-synthase activity in red blood cells helps to establish the diagnosis of AIP. However, normal HMB-synthase activity in red blood cells does not exclude AIP. A diagnosis of AIP is established in a patient by DNA studies, which can demonstrate a HMB-synthase gene mutation in almost all cases.
Many different mutations have been identified in the HMB-synthase gene. Almost every family with AIP has a different mutation in this gene. Within one family, however, everyone who inherits a deficiency of HMB-synthase has the same mutation. Knowing the mutation that causes AIP in a particular family member means that others who carry the mutation can be reliably identified and counseled to avoid drugs, dietary practices, etc. that may trigger symptoms. Measuring red blood cell HMB-synthase activity has been useful in family studies but is less accurate than DNA analysis.
Treatment and Prognosis
The prognosis is usually good if the disease is recognized and if treatment is prompt, before severe nerve develops. Although symptoms usually resolve after an attack, repair of nerve damage and associated muscle weakness may require several months or longer. Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.
Hospitalization is often necessary for acute attacks. Medications for pain, nausea, and vomiting and close observation are generally required. During treatment of an attack, attention should be given to sodium (salt) and water balance. Harmful drugs should be stopped.
Attacks are treated with either glucose loading or hemin. These are specific treatments that lower the production of heme pathway intermediates by the liver. Glucose or other carbohydrates are given by mouth if possible, otherwise by vein. Intravenous glucose is usually given as a 10% solution, at least 3 liters daily. However, unless an attack is mild, it is now common practice to begin treatment with hemin, which is more effective than glucose loading. Hemin therapy can be started after a trial of glucose therapy, but the response to hemin therapy is best if started early in an attack.
Hemin must be administered intravenously. Panhematin®, from Lundbeck Pharmaceuticals, is the only hemin preparation available in the United States. Panhematin® is more stable and less likely to produce phlebitis (an inflammation of the vein; a reported possible side effect of Hemin therapy) if it is mixed with human albumin before it is given.
Individuals with AIP who are prone to attacks should eat a normal or high carbohydrate diet and should not greatly restrict their intake of carbohydrate and calories, even for short periods of time. If weight loss is desired, it is advisable to consult a physician and a dietitian to have them prescribe an individualized diet that is approximately 10% below the normal level of calories for the patient. This should result in a gradual weight loss and usually will not cause an attack of porphyria.
Pregnancy is usually well tolerated, but the hormonal changes may exacerbate AIP is some women. Proper nutrition and hydration are important during pregnancy and labor, after delivery, and for the duration of breastfeeding. As always, only drugs and anesthetics classified as safe in porphyria should be used. Acute attacks are treated with glucose or hemin; there is no evidence of adverse effects of hemin therapy on the mother or fetus.
Attacks can be prevented in many cases by avoiding harmful drugs and adverse dietary practices. Wearing a Medic Alert bracelet is advisable for patients who have had attacks, but is probably not warranted in most latent cases. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In selected cases, frequent noncyclic attacks can be prevented by once- or twice-weekly infusions of hemin. Patients with severe renal disease tolerate hemodialysis or kidney transplantation. Liver transplantation has been very effective for patients with AIP who have repeated attacks and who are resistant to other treatments. However, experience with transplantation as a treatment for AIP is still limited.
Because AIP is an autosomal dominant disorder, a person with a mutation in his or her HMB-synthase gene has a 50% chance with each pregnancy of passing that mutation on to his/her offspring. The outlook for such offspring is generally good, since most individuals who inherit an HMB-synthase gene mutation never become ill or have only a few attacks.