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, and Karl E. Anderson, MD, Department of Internal Medicine, Pharmacology and Toxicology, Division of Gastroenterology, The University of Texas Medical Branch at Galveston, for assistance in the preparation of this report.
Acute intermittent porphyria (AIP) is a rare metabolic disorder that is characterized by partial deficiency of the enzyme 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 hormonal changes associated with puberty, the use of certain prescribed or recreational drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms. Symptoms include severe abdominal pain, constipation, a rapid heartbeat and increased blood pressure (tachycardia and hypertension), behavioral changes, seizures, and damage of the nerves to muscles (peripheral neuropathy) which can lead to profound muscle weakness (paralysis). 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.
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 which accumulate 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.
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 rarely 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.
During attacks 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) , high blood pressure (hypertension) 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 liver cancers such as hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC).
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 dieting (e.g. caloric restriction), stress, infections or certain hormonal (endocrine) factors, often in combination.
The HMBS gene mutation that predisposes individuals to developing AIP is inherited in an autosomal dominant pattern. 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 sufficient 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. The risk is the same for males and females.
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.
Symptomatic AIP is always accompanied by increased production and excretion of porphyrin precursors. However, for reasons that are unknown, some affected individuals have elevated porphyrin precursors without 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 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.
In Europe the prevalence of symptomatic AIP is reported to be 5.9 per million people in the general population., It is likely to be similar elsewhere in the world apart from Sweden where it is higher due to a founder effect. Recent population based genetic studies have shown that approximately 1 in 2000 of the population inherit a disease causing (pathogenic) mutation in the HMBS gene. This suggests that only 1% of those who inherit a pathogenic mutation will ever experience porphyria symptoms. AIP can occur in individuals of all ethnic backgrounds, although it may be less frequently 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.
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 from a detailed patient history, a thorough clinical evaluation and certain specialized tests. AIP should be suspected in individuals with unexplained abdominal pain, especially repeated episodes and when occurring along with psychological symptoms, neurological findings with muscle weakness 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 production and 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. This should not delay treatment of acutely unwell patients. 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 does not therefore prove that a patient is having an acute attack.
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 advised 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.
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 human hemin. 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) approved Panhematin for the treatment of recurrent attacks of AIP related to the menstrual cycle in susceptible women, after a trial of glucose therapy and should be administered only by physicians experienced in the management of porphyrias in a hospital setting. Based on much experience, it is used for treating and even preventing acute attacks, often without an initial trial of glucose, and has been found to be safe during pregnancy.
In 2019, the FDA approved Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, including AIP. Givlaari aims to reduce the number of attacks patients experience.
Normosang (heme arginate) is another heme preparation that can be used to treat individuals with AIP. Normosang is not available in the United States, but is used in many 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. The pain is usually very severe and generally requires opiates (e.g. morphine) for adequate relief. 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. The EPNET/NAPOS Database should also be consulted.
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 patients, 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 and 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.
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For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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Deybach JC. Acute Intermittent Porphyria. Orphanet Encyclopedia, February 2009. Available at: http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=11302&Disease_Disease_Search_diseaseGroup=Acute-Intermittent-Porphyria&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Acute-intermittent-porphyria&title=Acute-intermittent-porphyria&search=Disease_Search_SimpleAccessed April 20, 2016.
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