AIP Disease characteristics
Acute intermittent porphyria results from half-normal activity of the enzyme hydroxymethylbilane synthase (HMBS). It is characterized clinically by life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs, often accompanied by nausea, vomiting, tachycardia, and hypertension. Attacks may be complicated by neurologic findings (mental changes, convulsions, and peripheral neuropathy that may progress to respiratory paralysis), and hyponatremia.
Acute attacks, which may be provoked by certain drugs, alcoholic beverages, endocrine factors, calorie restriction, stress, and infections, usually resolve within two weeks. Most individuals with AIP have one or a few attacks; about 5% (mainly women) have recurrent attacks (defined as >4 attacks/year) that may persist for years.
Other long-term complications are chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. Attacks, which are very rare before puberty, are more common in women than men. All individuals with a genetic change in the gene HMBS that predisposes to AIP are at risk of developing acute attacks; however, most never have symptoms and are said to have latent (or presymptomatic) AIP.
This is one of the hereditary hepatic porphyrias. Its inheritance is autosomal dominant. The deficient enzyme is porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase (HMB synthase). This enzyme was formerly known as uroporphyrinogen I-synthase, and this term is still used by some clinical laboratories. A deficiency of PBGD is not sufficient by itself to produce AIP, and other activating factors must also be present. These include hormones, drugs and dietary changes. Sometimes, activating factors cannot be identified.
Most people who inherit the gene for AIP never develop symptoms. However, experts recommend that all relatives of someone with AIP obtain testing, to determine who has the genetic trait and who does not. Those who test positive for the trait should be educated as to measures that will help avoid attacks. Prevention is essential to good management.
AIP manifests after puberty, especially in women (due to hormonal influences). Symptoms usually come as discrete attacks that develop over two or more days. Abdominal pain, which is associated with nausea, can be severe and occurs in most cases. Other symptoms may include:
- pain in the back, arms and legs
- muscle weakness (due to effects on nerves supplying the muscles)
- urinary retention
- palpitation (due to a rapid heart rate and often accompanied by increased blood pressure)
- confusion, hallucinations and seizures
Sometimes the level of salt (sodium and chloride) in the blood decreases markedly and contributes to some of these symptoms. The skin is not affected.
Because 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. However, within a given family, everyone has the same mutation. When that mutation is known for one member, screening of the relatives is straightforward and can be done on DNA from saliva (spit) or a swab of the inside of the cheek. This is now the gold standard of diagnosis and is available through specialty labs.
Treatment and Prognosis
Hospitalization is often necessary for acute attacks, particularly if nausea and vomiting have prevented adequate oral intake. Medications for pain, nausea and vomiting, IV hydration, and close observation are generally required.
Glucose and other carbohydrates can help suppress disease activity, are given by vein or by mouth, and are part of initial treatment. Intravenous heme, however, is both more specific and effective than glucose and should be started if the patient’s symptoms fail to improve within 36 hours. Heme is sold as Panhematin®, from Recordati Rare Diseases. Most hospitals do not stock it. Therefore the pharmacy must be notified at the time the patient’s admission to initiate a request for air-freighting enough medication for 5 days of treatment. Generally, shipping will take at least 24 hours.
Panhematin, is the only commercially available form of heme for treatment and prevention of acute porphyric attacks in the United States. Heme arginate, which is marketed in other countries as Normosang® (Orphan Europe), is another preparation for intravenous administration. The main side-effect of Panhematin® is irritation of the vein used for infusion (phlebitis). This is avoided by slow infusion through a large caliber vein or central line. Adding human albumin to the heme solution also may reduce the risk of phlebitis. (Directions for preparing Panhematin® in this manner can be obtained from porphyria specialist and is included in the Primary Care Physician/Emergency Room Kit.) Heme therapy is indicated only if an acute attack of porphyria is proven by a marked increase in urine PBG. It may be useful also as preventive therapy for people with frequent recurrent attacks.
During treatment of an attack, attention should be given to salt and water balance. Harmful drugs should be stopped. These include barbiturates, sulfonamides, and many others (see the Acute Porphyria Drug Database). Attacks are often precipitated by low intake of carbohydrates and calories in an attempt to lose weight. Thus dietary counseling is very important (see below). Premenstrual attacks often resolve quickly with the onset of menses; hormone manipulations may prevent such attacks.
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. People who are asymptomatic carriers of the genetic trait may choose not to wear a bracelet but should be prepared in any medical encounter to advise their care-givers of medications that are risky in AIP. It should be remembered that AIP patients can develop other diseases, and symptoms will not always be due to porphyria.
AIP patients prone to attacks should eat a normal or high carbohydrate diet and should not greatly restrict their intakes of carbohydrate and calories, even for short periods of time. If weight loss is desired, it is advisable to consult a physician, who may request that a dietitian estimate an individual’s normal caloric intake, which varies greatly from one person to another. It may be appropriate to prescribe a 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 tolerated much better than was formerly believed. Offspring have a 50% chance of inheriting the gene for AIP, but the great majority of them remain “latent” for all or most of their lifetimes. The minority that eventually have symptoms usually benefit from treatment. Given these considerations, most patients or individuals with “latent” porphyria elect to have children for the same reasons as anyone else.
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