Acute Intermittent Porphyria (AIP) is a rare metabolic disorder that is characterized by deficiency of the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase (PBGD). This enzyme deficiency can result in the accumulation of toxic porphyrin precursors in the body. However, the deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with a HMBS gene mutation do not develop symptoms of AIP. Additional factors such as endocrine influences (e.g. hormonal changes), the use of certain drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms.
The PBGD enzyme deficiency is caused by a mutation in the HMBS gene which is inherited as an autosomal dominant trait (only one HMBS gene copy is affected). However, the majority of people with a mutation in this gene do not develop symptoms of AIP; additional factors, often called “triggers” are also required to cause symptomatic acute Porphyria. These factors are not necessarily the same for each individual, and susceptibility to specific triggers may vary during a patient’s lifetime. Most of these triggers are believed to stimulate increased heme production (synthesis) in the liver and include certain drugs, excessive alcohol consumption, fasting or dieting (e.g. caloric restriction), stress, infections or certain hormonal (endocrine) factors.
AIP is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for developing symptoms of the disorder. The exact, underlying reasons why symptoms only develop in some individuals with the genetic mutation for AIP are not fully understood. There are several theories as to the underlying pathogenesis of AIP. One theory states that a specific porphyrin precursor (most likely ALA) is a hepatic (liver) neurotoxin that damages nerve tissue. This theory is supported by the information obtained from patients who have had liver transplant, which corrects both the clinical and biochemical features of the condition. A second theory suggests that heme deficiency in nerve cells (neurons) contributes to the development of symptoms.
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:
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 in AIP.
AIP can be associated with a range of symptoms and physical findings that can potentially involve multiple organ systems of the body. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can potentially cause life-threatening complications. It is important to note the highly variable nature of AIP and that affected individuals may not have all of the symptoms discussed above. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
The symptoms of AIP usually occur as episodes or “attacks” that develop over course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s but may occur at or just after puberty. Onset before puberty is extremely rare. Attacks are much more common in women than men, probably because of the menstrual cycle hormones. Approximately 3%-5% of affected individuals, predominately women, experience recurrent attacks, which are defined as more than 4 per year, for a period of many years.
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 and avoidance of unsafe medications is essential to good management.
A diagnosis of AIP can be difficult because most symptoms are nonspecific and occur episodically. Diagnosis is usually based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and certain specialized tests. AIP should be suspected in individuals with unexplained abdominal pain, especially when occurring along with muscle weakness, psychological symptoms, neurological findings or unexplained hyponatraemia. Dark or reddish urine in such individuals is also suggestive of AIP. However, absence of this feature does not exclude AIP.
Because the acute Porphyrias are 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. .
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. Details are available from the APF or investigators of the national Porphyria Consortium https://www.rarediseasesnetwork.org/cms/porphyrias
Clinical Testing and Workup: Screening tests to measure the levels of the porphyrin precursor porphobilinogen (PBG) in urine are essential to confirm a diagnosis of acute Porphyria. Acute attacks are always accompanied by increased excretion of PBG in AIP. If urinary PBG excretion is increased, then further testing (fecal and blood porphyrin measurement) is necessary to distinguish AIP from Variegate Porphyria or Hereditary Coproporphyria. Delta-aminolevulinic acid (ALA) excretion will also be elevated in urine samples from individuals with AIP, but measurement is less widely available and is not essential. These tests can be performed on a random (spot) urine sample that should be protected from light after collection and during transport to the laboratory. There is now good evidence that once urine PBG excretion is increased in AIP it takes many years to return to normal. Increased urine PBG excretion in a known AIP patient is therefore not necessarily diagnostic of an acute attack.
Affected Populations: The exact incidence and prevalence of symptomatic AIP is unknown. In Europe the prevalence is estimated to be approximately 5.9 per million people in the general population. Prevalence is greatest in Sweden due to a founder effect. AIP can occur in individuals of all racial and ethnic backgrounds, although it is rarely reported in African-American individuals. Women are affected by symptomatic AIP more often than men. The disorder is most common in young or middle-aged women.
Family Testing: Molecular genetic testing is not essential to confirm a diagnosis as the porphyrin biochemical findings are characteristic. However molecular genetic testing to detect a mutation in the HMBS gene is usually required so that family members can be offered testing for this mutation. Genetic testing is available mainly from laboratories specializing in Porphyria diagnosis.
Having Children: 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.
Patients and family members who have inherited AIP should be counseled on how to limit their risk of any future acute attacks. This should include information about AIP and what causes attacks, how to check if a prescribed medication is safe or unsafe and details of relevant patient support groups.
Hospitalization is often necessary for acute attacks, particularly if nausea and vomiting have prevented adequate oral intake of calories and nutrition, especially carbohydrates. 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. In the United States, heme is sold as Panhematin®, from Recordati Rare Diseases. Most hospitals do not stock it. Therefore, the pharmacy must be notified at the time of 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 heme 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. Porphyria experts at times suggest adding human albumin to the heme solution to reduce the risk of phlebitis. (Directions for preparing Panhematin® in this manner can be obtained from Porphyria specialists and is included in the Emergency Room Kit/Primary Care Physician Kit from the APF. Directions for reconstituting Panhematin® and a dosing calculator are included in the instructional video with a step-by-step tutorial on administering Panhematin® to a patient with an acute Porphyria at panhematin.com). 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 (Safe/Unsafe Drug List). Attacks are often precipitated by low intake of carbohydrates and calories in an attempt to lose weight. Thus, dietary counseling is very important (Diet and Nutrition). 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 medications 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.
The treatment of AIP is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hematologists, hepatologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected patient’s treatment. Genetic counseling may benefit affected individuals and their families.
The objective of treatment is to manage symptoms, prevent complications and to suppress heme creation (synthesis) in the liver with Panhematin®, which reduces the production of porphyrin precursors. Initial treatment steps also include stopping any medications that can potentially worsen AIP or cause an attack and ensuring proper caloric intake, which can include intravenous infusion of sufficient nutrients (glucose and salt). Carbohydrate loading in conjunction with good pain management may be sufficient for mild attacks.
An acute neurovisceral attack often necessitates hospitalization and may require treatment with hematin. In the United States, affected individuals may be treated with Panhematin® (hemin for injection), an enzyme inhibitor derived from red blood cells that is potent in suppressing acute attacks of porphyria. Panhematin almost always returns porphyrin and porphyrin precursor levels to normal values. The U.S. Food and Drug Administration (FDA) originally approved panhematin for the treatment of recurrent attacks of AIP in related to the menstrual cycle in susceptible women. 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. Panhematin® is manufactured by Recordati.
Treatment for AIP also includes drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness. Medications to treat any infections that may occur at the same time as an attack (intercurrent infection) may also be necessary. Although many types of drugs are believed to be safe in individuals with AIP, recommendations about drugs for treating AIP are based upon experience and clinical study. 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 obtained from the American Porphyria Foundation (see the Resources section of this report). The Foundation also maintains an Acute Porphyria Drug Safety Database.
Additional treatment for individuals undergoing an attack including monitoring fluid and electrolyte balances. For example, if individuals develop hyponatremia, which can induce seizures, they should be treated by saline infusion.
In some cases, an attack is precipitated by a low intake of carbohydrates in an attempt to lose weight. Consequently, dietary counseling is very important. Affected individuals who are prone to attacks should eat a normal balanced diet and should not greatly restrict their intake of carbohydrates or calories, even for short periods of time. If weight loss is desired, it is advisable to contact a physician and dietitian.
Premenstrual attacks often resolve quickly with the onset of menstruation. Hormone manipulation may be effective in preventing such attacks and some affected women have been treated with gonadotropin-releasing hormone analogues (GnRH or LHRH treatments such as Lupron) to suppress ovulation and prevent frequent, cyclic attacks. Some individuals who experience recurrent attacks may benefit from regular, prophylactic hematin infusion. This is sometimes recommended for women with severe symptoms before or during the time of their menses.
If a proper diagnosis has not been made, AIP can be particularly dangerous, especially if unsafe medications which aggravate the disorder are administered. The prognosis of AIP is usually good if the disorder 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 from a severe attack improves over time, but such improvement may take many months to resolve fully.
Liver transplantation has been used to treat some individuals with AIP, specifically individuals with severe disease with frequent hospitalizations who have failed to respond to other treatment options. A liver transplant in individuals with AIP is an option of last resort. Affected individuals who experience kidney failure may require a kidney transplant. Some individuals have required a combined kidney/liver transplant.
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 web site.
MEDICAL ALERT BRACELET Wearing a Medical Alert bracelet is advisable for patients who have had attacks.
DIET 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. (Diet and Nutrition)
WALLET CARD The use of a wallet card is advisable in individuals who have AIP. Please contact the APF office for more information.