Acute Intermittent Porphyria (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.
 

 

Symptoms

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:

  • nausea

  • vomiting

  • constipation

  • 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.

Diagnosis

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. Details are available from the APF or investigators of the national Porphyria Consortium http://rarediseasesnetwork.epi.usf.edu/porphyrias/index.htm.​

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.

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. (Please see the Diet and Nutrition section of our website for more information)

BabyHaving 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.

For more information please see the Healthcare Professionals area of our site.

 

 

PBS Documentary

 

 

 

AIP Diagnosis Stories

 

 

 

**Diagnostic Testing for the Acute Porphyrias - Clarification of Testing Results**
Important Update - Click to view

 

Additional reading on AIP:

 

NORD gratefully acknowledges Dr. Michael Badminton, MBChB, PhD, FRCPath, Honorary Consultant and Clinical Lead, National Acute Porphyria Service (Cardiff), Medical Biochemistry & Immunology, University Hospital of Wales, for assistance in the preparation of this report.

Synonyms of Acute Intermittent Porphyria

AIP
Swedish Porphyria
General Discussion

Summary

Acute intermittent porphyria (AIP) is a rare metabolic disorder that is characterized by deficiency of the enzyme as hydroxymethylbilane synthase (also known as porphobilinogen deaminase). This enzyme deficiency can result in the accumulation of porphyrin precursors in the body. This 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 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 factors (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. Symptoms include severe abdominal pain, constipation, muscle weakness, a rapid heartbeat (tachycardia), behavioral changes, seizures, and damage of the nerves to muscles outside of the central nervous system (peripheral neuropathy). Treatment is focused on preventing attacks by educating patients to avoid potential triggers. Acute attacks usually require hospital care and can be effectively treated with intravenous hematin.

Introduction

AIP belongs to a group of disorders known as the porphyrias. This group of disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins found in all cells. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the "hepatic" and "erythropoietic" types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are often referred to as "cutaneous porphyrias." The term "acute porphyria" is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Two porphyrias can have cutaneous and acute symptoms, sometimes together. Most forms of porphyria are genetic inborn errors of metabolism. AIP is an acute, hepatic form of porphyria.

Signs & Symptoms

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 below. 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.

Abdominal pain, which is usually severe, is the most common symptom associated with AIP and often the initial sign of an attack. Abdominal pain is usually severe, steady (unremitting) and widespread (diffuse). Less often, abdominal pain is described as cramping. Pain may also occur in the neck, lower back, buttocks, or arms and legs.

Gastrointestinal symptoms are also common during an attack and can include nausea, vomiting, constipation or diarrhea, and abdominal swelling (distention). A painful blockage or obstruction (ileus) of part of the small intestines may also occur. Difficulty passing urine (urinary retention) can also occur.

Neurological symptoms may also develop including damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and burning sensations that usually begin in the feet and sometimes the arms. Affected individuals may develop muscle weakness in the legs that may progress to affect the arms and the trunk of the body, eventually causing partial loss or impairment of motor function (motor paralysis). In rare cases, the muscles used to breathe can become involved and potentially cause life-threatening respiratory failure which requires mechanical ventilation.

Some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases, coma.

Affected individuals may also experience a faster than normal heart rate (tachycardia) and irregular heartbeats (cardiac arrhythmias). Seizures have also been reported. Abnormally low sodium levels (hyponatremia) may develop rapidly during an attack and contribute to the onset of seizures.

Individuals with chronic AIP may develop complications that occur after many years (long-term complications) such as high blood pressure (hypertension), kidney damage potentially resulting in kidney failure, and a form of liver cancer known as hepatocellular carcinoma (HCC).

Causes

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. Individuals with AIP have a mutation in the HMBS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

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 dietary (e.g. caloric restriction), stress, infections or certain hormonal (endocrine) factors.

The HMBS gene mutation that predisposes individuals to developing AIP is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and 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.

The HMBS gene creates (encodes) the enzyme porphobilinogen deaminase (PBG-D), which is also known as hydroxymethylbilane synthase or uroporphyrinogen I synthase. This enzyme is the third enzyme is the process of heme biosynthesis. Mutations in the HMBS gene lead to deficient levels of PBG-D in the body, which in turn can lead to the accumulation and release of porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) from the liver.

The elevation of porphyrin precursors alone is not sufficient for the development of symptoms of AIP. As discussed above, triggering factors are required for symptom development. The exact, underlying reasons why symptoms develop in some individuals with 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 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. More research is necessary to determine the exact underlying mechanisms that are involved in the development of symptomatic episodes in individuals with AIP.

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.

Related Disorders

Symptoms of the following disorders can be similar to those of AIP. Comparisons may be useful for a differential diagnosis.

The acute attacks that characterize AIP are similar to those seen in three other forms of porphyria specifically variegate porphyria, hereditary coproporphyria, and ALA-Dehydratase deficiency porphyria. Collectively, these four forms of the porphyria are classified as the acute porphyrias. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)

Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, sometimes progressing to complete paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the patients. This has led to the theory that GBS may be an autoimmune disease (caused by the body’s own immune system). Damage to the covering (myelin) of nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. This causes weakness of the muscles that are supplied by the damaged nerves. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal neuropathy, acute motor axonal neuropathy. (For more information on this disorder, choose “Guillain Barre” as your search term in the Rare Disease Database.)

Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, including a heme precursor ALA, 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 appear in the first months of life and 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, cirrhosis, and hepatocellular carcinoma if left untreated. Untreated children can also suffer neurological crises similar to those seen in acute porphyria. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed. (For more information on this disorder, choose “tyrosinemia” as your search term in the Rare Disease Database.)

Lead toxicity can cause symptoms that mimic acute porphyria (acute abdominal pain, constipation, and neuropathy). Lead inhibits several of the enzymes of haem biosynthesis, which can therefore result in an increase in urine coproporphyrin and 5-aminolevulinic acid excretion, but not porphobilinogen excretion. It can also cause an increase in erythrocyte protoporphyrin concentration, although this is all the zinc-chelate form (zinc-protoporphyrin). The definitive test for lead poisoning is blood lead measurement.

Diagnosis

A diagnosis of AIP can be difficult because most symptoms are nonspecific and occur episodically. A 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.

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.

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.

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.

Standard Therapies

Treatment

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 hematin, 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 medication 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.

Heme arginate (Normosang, Orphan Europe) is another heme preparation that can be used to treat individuals with AIP. Heme arginate is not available in the United States, but is often used in other countries where Panhematin is not available.

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 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 dietician.
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 to suppress ovulation and prevent frequent cyclic attacks. Some individuals who experience recurrent attacks may benefit from regular hematin infusion. This is sometimes recommended for women with severe symptoms during the time of their menses.

If a proper diagnosis has not been made, AIP can be particularly dangerous, especially if drugs 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 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.

Investigational Therapies

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.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov