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Acute intermittent porphyria
AIP is caused by a genetic change in the HMBS gene, leading to a deficiency in an enzyme involved in haem production. This can result in acute attacks characterised by abdominal pain, neurological issues, and psychiatric symptoms. It typically affects adults, with females often experiencing more severe symptoms.
Overview
Acute intermittent porphyria (AIP) is a rare, inherited metabolic condition belonging to a group of disorders known as porphyrias. These conditions arise from problems in the production of haem, a vital component of haemoglobin in red blood cells. In AIP, the body cannot produce enough of a specific enzyme needed for this process. This can lead to a build-up of certain toxic substances called porphyrin precursors in the body, particularly during an acute attack [PMID:31252192].
While some individuals with a genetic change causing AIP may never experience symptoms, others can have severe, potentially life-threatening acute attacks. These attacks can be triggered by various factors, including certain medications, alcohol, stress, fasting, and hormonal changes. AIP is considered one of the 'acute hepatic porphyrias', meaning it primarily affects the liver and can cause sudden, severe symptoms impacting the nervous system.
The exact prevalence of AIP is estimated to be between 1 in 10,000 and 1 in 20,000 individuals, though many carriers of the genetic change may remain undiagnosed if they never experience symptoms [PMID:20301490]. It typically becomes apparent in adulthood, with symptoms rarely presenting before puberty.
Symptoms & clinical features
The hallmark of AIP is the occurrence of acute attacks, which can vary widely in severity and presentation. The most common symptom during an attack is severe abdominal pain, which can be constant and often disproportionate to physical findings on examination. This pain may be accompanied by nausea, vomiting, and constipation [PMID:31252192].
Neurological symptoms are a significant feature of AIP attacks. These can range from muscle weakness, particularly in the limbs, to more severe paralysis, which can affect breathing muscles in critical cases. Mental health symptoms are also common during attacks, including anxiety, confusion, hallucinations, and paranoia. Rapid heart rate (tachycardia) and high blood pressure (hypertension) can also occur. Between attacks, many individuals do not experience symptoms, though some may report chronic pain, fatigue, or mild neurological issues.
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Affected organs
AIP primarily affects the nervous system, leading to the diverse neurological and psychiatric symptoms observed during acute attacks. The build-up of porphyrin precursors is thought to be toxic to nerve cells, impacting both the peripheral nerves (nerves outside the brain and spinal cord) and the central nervous system (brain and spinal cord).
The liver is also critically involved, as it is the main site where the affected haem-production pathway operates. While the liver is central to the biochemical defect, direct liver damage is less common in AIP compared to some other types of porphyria. However, long-term complications can include an increased risk of liver cancer in older individuals with repeated attacks.
Risks & severity
The severity of AIP can vary significantly, even among individuals within the same family who carry the same genetic change. Many individuals with the genetic predisposition never experience an acute attack, remaining asymptomatic throughout their lives. For those who do experience attacks, the severity can range from mild episodes managed at home to life-threatening crises requiring intensive care.
Acute attacks typically begin after puberty, most commonly affecting adults aged 20 to 50 years. Females are more likely to experience acute attacks than males, often due to hormonal fluctuations, especially those related to menstruation, pregnancy, or oral contraceptives. Long-term risks for individuals with recurrent attacks can include chronic neuropathic pain, kidney problems, and a higher risk of developing hepatocellular carcinoma (a type of liver cancer) in later life.
Genetic causes
Acute intermittent porphyria is caused by pathogenic changes in the HMBS gene. This gene provides instructions for making an enzyme called hydroxymethylbilane synthase, also known as porphobilinogen deaminase (PBGD). This enzyme is crucial for the second step in the biochemical pathway that produces haem.
Haem is an essential molecule found in haemoglobin, which transports oxygen in red blood cells, and in other important proteins. When a genetic change in HMBS reduces the activity of the PBGD enzyme, the pathway can become inefficient. This leads to an accumulation of precursor molecules, specifically delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), especially when the body's demand for haem is high. These accumulated precursors are believed to be neurotoxic, causing the symptoms seen in acute attacks.
- HMBS hydroxymethylbilane synthase
Inheritance pattern
AIP is inherited in an autosomal dominant pattern. This means that only one copy of the altered HMBS gene in each cell is sufficient to cause a predisposition to the condition. An individual with AIP has a 50% chance of passing the altered gene to each of their children, regardless of the child's sex.
It is important to remember that inheriting the altered gene does not mean symptoms will definitely develop. Many individuals who inherit the genetic change remain asymptomatic throughout their lives. The penetrance, which is the likelihood of developing symptoms given the genetic change, is incomplete. Genetic counselling can provide more specific information and support for families concerned about inheritance patterns.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of an acute porphyria attack often begins with clinical suspicion based on the characteristic symptoms, particularly severe unexplained abdominal pain combined with neurological or psychiatric features. Initial biochemical tests involve measuring levels of porphyrin precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), in urine during an acute attack. Significantly elevated levels of these precursors are highly suggestive of an acute porphyria, including AIP.
Confirmation of AIP typically involves genetic testing of the HMBS gene to identify a pathogenic variant. This testing can be accessed via the NHS Genomic Medicine Service (GMS) pathways. Referrals for genetic testing are usually made by a clinical geneticist or a specialist physician (e.g., neurologist or gastroenterologist) after initial biochemical screening. The relevant R-code for testing acute intermittent porphyria in the NHS GMS is R48, 'Acute intermittent porphyria'. Family members at risk may also be offered genetic testing to determine if they carry the pathogenic variant.
Management & lifestyle
Management of AIP focuses on preventing acute attacks and treating symptoms when they occur. Identifying and avoiding triggers is crucial; this includes certain medications (a comprehensive list can be obtained from specialist porphyria centres), alcohol, smoking, dieting or prolonged fasting, and stress. Maintaining adequate nutrition and managing hormonal factors can also be important.
During an acute attack, treatment often involves administering intravenous glucose to suppress the haem synthesis pathway and, in severe cases, intravenous haem arginate. Haem arginate directly replaces the deficient haem and rapidly reduces the levels of toxic precursors. Long-term management may involve regular monitoring for potential complications such, as liver disease or chronic pain. Patients are typically managed in close collaboration with specialist porphyria centres within the NHS, often involving a multidisciplinary team including neurologists, gastroenterologists, and genetic counsellors. Genetic counselling is also available to discuss the condition, inheritance, and implications for family members.
UK care pathway
In the UK, individuals suspected of having or diagnosed with acute intermittent porphyria (AIP) are typically supported through the NHS Genomic Medicine Service (GMS) pathways. Diagnosis involves specialist biochemical tests followed by genetic testing, often requested by a clinical geneticist or relevant specialist. Genetic testing for AIP falls under the R-code R48 in the GMS test directory. Genetic counsellors play a key role in explaining inheritance patterns, testing options for family members, and providing psychological support throughout the diagnostic and management journey.
Ongoing care and management are usually coordinated through highly specialised porphyria centres across the UK, which have expertise in this rare condition. These centres ensure access to appropriate treatments, monitoring, and advice on trigger avoidance, aligning with national guidelines.
Frequently asked questions
What triggers an AIP attack?
Acute intermittent porphyria attacks can be triggered by various factors, including certain medications, alcohol, fasting, stress, and hormonal changes. It is important for individuals with AIP to be aware of and avoid their specific triggers.
Can AIP be cured?
AIP is a genetic condition, meaning it cannot be cured. However, it can be effectively managed by avoiding triggers and using specific treatments during acute attacks, such as intravenous glucose or haem arginate, to alleviate symptoms and prevent complications.
If I have AIP, will my children get it?
AIP is inherited in an autosomal dominant pattern. This means that if you have AIP, each of your children has a 50% chance of inheriting the altered gene. However, inheriting the gene does not guarantee they will develop symptoms, as many carriers remain asymptomatic.
Are there any dietary restrictions for AIP?
While there isn't a strict 'AIP diet', maintaining adequate nutrition is important. Prolonged fasting or restrictive diets can sometimes trigger attacks. Individuals with AIP are often advised to eat regular meals and avoid excessive alcohol consumption. A specialist porphyria centre can provide personalised dietary guidance.
What should I do if I think I'm having an AIP attack?
If you suspect you are having an acute AIP attack, it is crucial to seek immediate medical attention. Contact your specialist porphyria centre or go to your nearest emergency department. Inform medical staff about your diagnosis of AIP and any known triggers.
References
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