What is Acute Intermittent Porphyria?
Acute Intermittent Porphyria (AIP) is an inherited genetic condition. The genetic mutations that cause AIP are in the HMBS gene. They result in the production of partially defective hydroxymethylbilane synthase enzymes (also called porphobilinogen deaminase) and decrease the overall functional capacity of this enzyme. Without enough of this enzyme capacity, the body is not able to convert the chemical porphobilinogen (PBG) into hydroxymethylbilane, the first tetra-pyrrole of the heme biosynthetic pathway. In concert with other factors that increase the activity of ALA synthase-1, the first and normally rate-controlling enzyme of the heme biosynthetic pathway, the defect in HMBS leas to a build up in delta-aminolevulinic acid (ALA) and PBG to much higher levels than usual. These chemicals are toxic to nerves and their abnormal buildup can lead to symptomatic episodes called acute attacks. The vast majority (>90%) of people with AIP mutations never develop acute attacks, highlighting the importance of other host and environmental factors in the development of clinical disease.
When patients do suffer an acute attack, they will usually experience severe abdominal pain first and foremost. This is often extremely painful and patients may need to go to the urgent care, emergency rooms or other acute care facilities for help. Because these attacks will often not involve any obvious visible signs of acute illness, such as fever, healthcare providers such as ER staff may not fully understand how much pain patients are experiencing, may think that patients are malingering or are seeking narcotics, and may not know how to diagnose or treat acute attacks, if they lack experience in the evaluation and management of patients with acute porphyria. It is very important for patients to speak with their local hospital and health care provider to make sure a plan is in place before an attack so they are able to receive care as quickly as possible when such attacks do occur.
Patients can also a variety of other symptoms related to nerve damage from high levels of ALA and PBG. This can include numbness, weakness, nausea, constipation, confusion, restlessness, hallucination, seizures, and difficulty with urination during acute attacks. These symptoms can be very severe and hard to treat if health care providers do not know to suspect acute attacks of AIP, or have no experience in its evaluation and management. It is important for family members of AIP patients to get tested even if they have never had an attack before. If they do have a mutation in one of their copies of the HMBS gene, knowing this will allow their doctor to give them the appropriate care if any symptoms arise.
Patients with AIP, especially those with chronic overproduction of ALA, are likely to have been misdiagnosed with acute appendicitis or acute cholecystitis or other intra-abdominal disorders and to have undergo exploratory laparotomies, of with removal of normal appendices or gall bladders without gall stones or acute inflammation. Such surgeries do not prvent further acute attacks, which are due to metabolic disorders that do not have surgical cures. Long-term, patients with AIP also are at increased risk for development of systemic arterial hypertension [high blood pressure], development of chronic kidney disease and kidney failure, development of chronic liver disease, and also have an increased risk of developing liver cancer, called hepatocellular carcinoma.
How is Acute Intermittent Porphyria diagnosed?
There are two things to consider when it comes to AIP diagnosis: 1) who is at risk for developing acute attacks of AIP and 2) who is experiencing acute attacks. Genetic testing is used to determine who is at risk for acute attacks and biochemical testing is used to determine who is experiencing symptoms from acute attacks. Biochemical testing is typically done on blood or urine samples, while genetic tests are done from blood, or saliva samples or from buccal swabs.
Biochemical: Acute attacks of AIP are due to abnormally high levels of ALA and PBG, which cause damage to nerves in the body. These two “biomarkers” can be accurately measured in the urine. It is not necessary for 24 hour or other timed urine samples to be obtained; a single, random urine, with measurement of ALA, PBG, and creatinine will provide diagnostic results. It is best to take samples during an acute attack (e.g. when someone is having abdominal pain, etc), when the levels of both ALA and PBG should be very high (>5X normal). In patients who experience only one or a few attacks in their lifetime, ALA and PBG levels may be normal outside of attack periods. However, in patients who experience frequent, recurrent acute attacks, ALA and PBG levels are usually elevated even in between attacks. It is not necessary for urine samples to have preservatives added, nor that they be handled in very special ways. It is better if they are collected in amber containers or if the containers are wrapped in aluminum foil and if they are kept refrigerated after collection and until the time of chemical analysis. However, even at room temperature, the decrease in levels of ALA and PBG in urine is only about 5-10% per week.
Genetic: A blood sample is used to look at a person’s genes and whether mutations exist that can cause disease in specific genes. The gene that causes AIP is called HMBS. People who have disease-causing mutations in the HMBS gene are at risk for developing acute attacks, though more than 90% of mutation carriers will never experience acute attacks of AIP. If a patient has a mutation, their immediate family members should be tested for that same mutation as well. This includes their parents, their siblings, and any children they may have. This will allow all family members to receive appropriate care and counseling. Because of this, genetic testing is recommended for patients who already have the diagnosis confirmed with very high ALA and PBG levels.
Also see FAQ: What diagnostic tests are available?
What are treatments for Acute Intermittent Porphyria?
Acute attacks in AIP are triggered when the need for heme production in the body, and in particular the liver is increased. This occurs in a number of settings. A mainstain of AIP management is avoidance of these types of triggers that can induce acute attacks.
One known trigger is progesterone, a hormone which naturally increases in women during their menstrual cycle. Female AIP patients are more likely to have attacks in the second half of their menstrual cycle, when their uterine lining is thickening but before it begins to shed (when they begin bleeding). Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance.
Prolonged starvation states is also known to induce liver heme production. Thus dieting can be a trigger and patients should avoid prolonged fasting and crash dieting. Patients with AIP should eat a balanced diet. If weight loss is desired, it is advisable to do this in a slow and gradual manner.
Most drugs are processed, or metabolized by the liver, in a process that requires heme. This is why drugs can be another trigger, especially barbiturates, sulfonamide antibiotics, anti-seizure drugs, and oral contraceptives (progesterone in particular). There is an online drug database to check which medications may be unsafe for people with AIP. The American Porphyria Foundation offers a mobile phone app that pulls up this information online (porphyriadrugs.com).
During an attack, patients may often need to be hospitalized. This will allow them to receive medications to handle their pain and IV fluids if they are unable to stop vomiting or are too nauseous to eat. If the attack was triggered by using drugs for a long time, the muscles which control breathing may be weak and the patient may need respiratory support.
Patients can receive heme therapy through an IV. Panhematin is an FDA approved medication which can help decrease the severity and length of the attack, and is more effective the earlier they receive it.
Patients with recurrent attacks of AIP, more than two per year, and/or with chronic symptoms and signs, such as neuropathic pain, anxiety, delirium, etc, should be offered a trial of givosiran [Givlaari, Alnylam Pharmaceuticals]. Givosiran is an siRNA that selectively and specifically down-regulates hepatic ALA synthase-1, the first and normally rate-controlling enzyme of the heme biosynthetic pathway. Uncontrolled up-regulation of ALA synthase-1 is required for acute porphyric attacks and for the overproduction of ALA and PBG, the former being the chief neurotoxin. In a recent pivotal international, phase-three, placebo-controlled trial of givosiran in patients with AIP with frequent attacks [more than two in the preceding 6 months], givosiran proved highly effective in decreasing the number and severity of acute attacks and in decreasing the need for hospitalizations and administration of IV heme. A limitation to broad use of givosiran is likely to be its high cost and more limited availability, compared to the other treatments outlined above.
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.