What is Acute Intermittent Porphyria (AIP)?
AIP an autosomal dominant inherited disorder caused by mutations in the HMBS gene. These mutations reduce the function of an enzyme called hydroxymethylbilane synthase (also known as porphobilinogen deaminase), which is needed for heme production. Without enough of this enzyme, the body can’t properly convert the chemical porphobilinogen (PBG) into hydroxymethylbilane, an essential step in making heme. Certain triggers, such as some medications, fasting, hormonal changes, infections, or stress increase the activity of ALA synthase-1, the first enzyme in the heme production pathway in the liver. This puts extra demand on the deficient HMBS enzyme. As a result, ALA and PBG build up, leading to nerve damage and other manifestations of an acute attack.
During an acute attack, severe abdominal pain is usually the first and most intense symptom, often requiring emergency care. Since AIP patients often have no belly tenderness on physical examination, the symptoms may be misunderstood and the condition not diagnosed. Other accompanying symptoms are also not specific, and can include confusion, constipation, hallucinations, nausea, restlessness, seizures, vomiting, and muscle weakness. To ensure fast and proper treatment, patients known to have AIP should work with their providers to create a care plan for future attacks.
Most people with AIP who develop symptoms will only experience a few attacks in their lifetime. However, a small number suffer from frequent attacks, and some have chronic symptoms between attacks, including pain, mood changes, and sleep problems. Other long-term complications may include chronic kidney disease, high blood pressure, liver disease, and liver cancer.
More than 90% of people with an HMBS mutation never experience an AIP attack, suggesting that other unknown factors contribute to disease development. Symptoms develop most commonly in menstruating people with disease onset after puberty.
How is Acute Intermittent Porphyria diagnosed?
Acute porphyrias, including AIP, are diagnosed using biochemical testing, starting with a urine test to measure porphyrin precursors and porphyrins. This is best done during symptoms, because results may be normal between attacks. A spot urine sample rather than a 24-hour urine sample is recommended. The levels of urinary ALA and PBG during an attack are expected to be markedly elevated. Porphyrins are also elevated, but this finding is not specific for an acute porphyria. Additional blood, urine and stool tests are needed to help determine the specific type of acute porphyria.
Genetic testing can confirm the specific type of porphyria, but it does not replace biochemical testing, which is needed to determine whether the disease might be active and causing symptoms.
Family members of individuals diagnosed with acute porphyria may benefit from testing to see if they have inherited the same mutation. Decisions regarding such testing should consider personal preferences with guidance from a provider with expertise in the porphyrias or genetics.
How is Acute Intermittent Porphyria treated?
Treatment of an attack
For a patient with a confirmed diagnosis of AIP, a spot urine test measuring porphobilinogen (PBG) can help determine whether they are currently experiencing an acute attack. If the PBG level is normal, an acute attack is unlikely.
During an attack, patients may need to stay in the hospital for treatment of severe pain, nausea vomiting and other symptoms and for intravenous fluids and medications. Any known triggers of an attack should be stopped if possible. The main treatment for acute attacks is IV hemin, a medication given through a vein. Hemin works by restoring the heme pool in liver cells and reducing the activity of the first enzyme in the heme production pathway, ALA synthase-1. Types of hemin include heme arginate, available mostly in Europe and lyophilized hemin, used in the United States. IV hemin is usually given once daily for 3-4 days, during which most patients begin to improve, or sometimes longer for more severe or prolonged attacks. Side effects include inflammation of the vein at the injection site, which is less likely with heme arginate or by preparing lyophilized hemin for infusion with albumin. Repeated treatment with hemin over time may lead to iron buildup in the body.
Prevention of future attacks
A key part of managing AIP is avoiding triggers that cause an attack. Triggers include certain medications, fasting, hormonal changes, infections, or stress. Hormonal changes such as the rise in progesterone before menstruation can sometimes trigger attacks. For those with frequent premenstrual attacks, gonadotropin-releasing hormone analogue have been used to suppress ovulation, but results are mixed. Prolonged treatment carries risks, including bone mineral density loss and menopausal symptoms. Fasting or prolonged starvation is another known trigger, so people with AIP should avoid severe restriction of calories and fasting. Certain medications can also trigger attacks by increasing heme production in the liver. People with AIP should consult their healthcare team before starting any new medications. Online drug databases to check which medications may be unsafe for people with AIP are available. Givosiran [Givlaari, Alnylam Pharmaceuticals] is a medication that helps prevent frequent attacks of AIP and is typically given as a monthly injection.
Givosiran works by reducing liver ALA synthase-1 (ALAS-1) and the buildup of ALA and PBG. It does this by blocking the activity of the first enzyme in heme production, ALAS-1. Givosiran is an siRNA therapy, meaning it acts as a switch that turns down the gene responsible for making ALAS-1. This medication is typically given as a monthly injection. It helps lower urinary ALA and PBG levels, reduces the frequency of acute attacks, and can improve quality of life in some people. Side effects include nausea, irritation at the injection site, and others.
Liver transplantation may be considered for people who continue to have severe attacks that are not prevented by medical treatment. This works because the liver is responsible for the disease and where ALA and PBG build up. However, liver transplantation carries significant risk, so it is rarely performed for this indication.
Surveillance and monitoring
People with acute porphyrias have a higher risk of developing liver cancer, especially for those over 50 years of age, so doctors may recommend regular screening for it.
Patients receiving hemin or givosiran need routine lab tests to monitor their health and ensure the treatments are working safely.
How is AIP inherited?
AIP is an autosomal dominant condition. Autosomal means that the defect is not on the chromosomes that determine sex, and dominant means that you only need to inherit one mutated gene to manifest the disease. The gene that causes AIP is called HMBS.
Most AIP patients have one mutated copy and one normal copy. It is random which of these two copies are inherited, so this means that each child of an AIP patient will have a 50% chance of inheriting the mutated copy and 50% chance of inheriting the working copy. Children who are found not to harbor the mutation of their parents with AIP can be assured that they will never develop AIP nor pass the genetic defect on to their children.