What is Acute Intermittent Porphyria?
‘Porphyria’ is a term derived from the ancient Greek word meaning purple. This relates to porphyrins, substances that are building blocks for heme – an essential part of hemoglobin. Hemoglobin is the part of blood cells that carries oxygen; it contains heme which has an iron atom that binds to oxygen. Heme is made via a complex multi-step process, each step requiring a specific enzyme.
Porphyrias are unique medical conditions that occur due to a deficiency or malfunction in one of these enzymes required for a step in the heme making process. These conditions have traditionally been grouped based on the primary system affected (skin or neurohepatic), but it’s important to note that there’s a significant overlap and many porphyrias exhibit mixed symptoms.
The symptoms, seriousness and future outlook of individual porphyrias rely on the specific enzyme that’s deficient and the buildup of the corresponding heme precursor or porphyrin. The most common and severe form of this condition is Acute Intermittent Porphyria (AIP). Other acute versions of these conditions include Heredity Coproporphyria, Variegate Porphyria and 5-Aminolevulinic Acid Dehydratase Deficiency Porphyria.
Just like most porphyrias, AIP has a gene pattern that’s mainly inherited. Acute conditions like AIP are known to display sudden episodes of symptoms affecting nerves and organs but may not fully appear for a long time. AIP usually exhibits episodes of abdominal pain, nerve problems, and constipation. Unlike in most other porphyrias, a skin rash doesn’t occur in AIP. The main issue in AIP is a deficiency of an enzyme called porphobilinogen-deaminase (or hydroxymethylbilane synthase), the third enzyme needed in producing heme. The acute attacks in AIP are triggered due to the uncontrollable increase of another enzyme involved in heme production called ALA synthase. Diagnosis of AIP often gets delayed due to its nonspecific symptoms and its similarity with other diseases. The only known cure is a liver transplant.
What Causes Acute Intermittent Porphyria?
Acute intermittent porphyria is a condition that is caused by changes in the HMBS gene. This specific gene, found on a particular segment of chromosome 11, is affected by almost 391 known mutations. The issue is, these mutations cause about half of the HMBS deficiencies. This becomes most apparent during acute attacks of the disease when the stored heme (an essential component of hemoglobin) in the liver gets used up.
When this happens, it triggers the production of an enzyme called delta-aminolevulinic acid synthase (ALAS1). This leads to an excess of two things – delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). Both ALA and PBG are important substances that are usually produced prior to HMBS.
Several factors can trigger these acute attacks. These include alcohol consumption, infections, low calorie intake, hormonal changes related to reproduction, and certain medications that are harmful to people with porphyria. Various healthcare groups, including the Norwegian Porphyria Centre (NAPOS) and the European Porphyria Network (Epnet), have compiled a list of medications that should be avoided by people with porphyria. This list includes various antibiotics, seizure medications, and psychiatric medications, among others.
Risk Factors and Frequency for Acute Intermittent Porphyria
Acute porphyrias are not that common with an estimated occurrence of about 5 cases in every 10,000 people. Among these, the most common form is porphyria cutanea tarda (PCT) that mainly affects the skin, and it is found in approximately 1 in every 10,000 individuals. More specifically, acute intermittent porphyria (AIP), another type of porphyria, is more typical in Europe with an incidence rate of approximately 1 in every 2,000 individuals. This type is particularly prevalent in Sweden, where it affects about 1 in every 1,000 people due to a phenomenon known as the founder effect. Recent studies have also pointed to a higher prevalence of AIP among certain ethnic groups in Argentina and Spain, likely due to this same genetic effect.
Acute intermittent porphyria is a genetic disease that doesn’t always manifest symptoms, a concept known as ‘penetrance’. Generally, only about 10% to 20% of people carrying the AIP gene will develop symptoms. In the general population, this is even less common, with less than 1% penetrance. When symptoms like severe abdominal pain and nervous system problems do manifest, it is considered manifest AIP (MAIP). When there are no symptoms, it is known as latent AIP (LAIP). It’s worth noting that some specific mutations may result in higher penetrance, but the overall genetic factors influencing this remain unclear.
Acute intermittent porphyria is more common in women than in men, with about 1.5 to 2 women affected for every man. Symptoms usually don’t occur before puberty and typically start to show between the ages of 18 and 40.
Signs and Symptoms of Acute Intermittent Porphyria
Acute intermittent porphyria, also known as AIP, is a condition that usually has acute attacks lasting up to a week with symptoms progressing in a particular order. The sequence typically begins with severe stomach pain that may cause vomiting and constipation. As the condition progresses, patients may start to display psychiatric symptoms like depression and may even have an increased risk of bipolar disorder or schizophrenia. Lastly, peripheral neuropathies emerge, presenting as a weakness starting in the lower half of the body and moving upwards.
These neuropathies can feel similar to Guillain-Barre syndrome and may lead to high blood pressure and an increased heart rate.
Some severe symptoms related to the central nervous system can also occur, such as delirium, weakening of the muscles leading to quadriplegia and respiratory failure, and in extreme cases, temporary blindness or even coma. Other symptoms may include seizures and changes in urine color to red or brown, which darkens when exposed to air, light, and warmth.
It’s interesting to note that AIP does not have skin-related symptoms, unlike another condition called porphyria cutanea tarda. Also, in between these attacks, patients are often symptom-free, but research suggests that some patients may still experience chronic symptoms, such as stomach pain, fatigue, and loss of sensation.
- Severe stomach pain
- Vomiting and constipation
- Psychiatric symptoms like depression
- Neurologic symptoms that mimic Guillain-Barre syndrome
- High blood pressure
- Increased heart rate
- Delerium
- Weakness leading to quadriplegia and respiratory problems
- Temporary blindness or coma in severe cases
- Seizures
- Changes in urine color
- Chronic pain, fatigue, and loss of sensation even between attacks
Testing for Acute Intermittent Porphyria
If you’re being tested for acute intermittent porphyria (AIP), doctors will try to detect high levels of a substance called PBG in a random urine sample. This test should be done in a light-protected environment. To confirm the diagnosis, the same urine sample is used to measure the quantity of PBG, ALA, and total porphyrins. Normally, levels should be between 0 to 4 mg/L, but during an AIP attack, they can go as high as 25 to 100 mg for ALA and 50 to 200 mg for PBG.
During acute symptoms, if your urinary PBG level is only 0 to 4 mg/L, it’s highly unlikely that acute porphyria is causing your symptoms.
It’s best to collect urine for testing during the height of an AIP attack. However, it can also be collected a few days or weeks after the severe episode. That’s because high levels of urinary ALA and PBG can persist for several months or even years after an attack.
It’s essential to note that increased levels of urine porphyrins, mainly copro porphobilinogen, is usually noticeable. But a nonspecific increase in urine porphyrins is common and not unique to porphyria. Typically, stool porphyrins fall within or slightly above the normal range.
Sometimes, high plasma porphyrin levels are verified by increased fluorescence emission under scanning. Genetic testing for HMBS deficiency isn’t needed to diagnose AIP, but it could be useful for family screening.
During an AIP attack, you may notice several abnormal lab results:
* Low sodium levels – most common
* Low magnesium levels are also common
* Minor increases in liver enzymes
* Slight increase in white blood cell count
It can be challenging to differentiate between various types of acute porphyrias as symptoms overlap significantly. However, genetic testing may help identify the specific type of acute porphyria by sequencing the four genes responsible for these conditions.
Currently, scientists are working to refine this diagnostic strategy using next-generation sequencing. This strategy involves designing a panel containing four genes for precise mutation analysis of AIP and related conditions.
Treatment Options for Acute Intermittent Porphyria
Acute Intermittent Porphyria (AIP) can mimic several other abdominal, metabolic, and neuropsychiatric conditions, making correctly diagnosing the disease crucial to its management. Patients and their families should be educated to avoid anything that could trigger the disease, especially certain medications.
If a patient with confirmed AIP has an attack, the initial response is usually to give the patient a high carbohydrate diet, or dextrose via an IV, to reduce liver enzyme activity. This treatment should be started right away. If the patient isn’t showing signs of weakness, vomiting, or a sodium imbalance, it’s recommended to try a high carbohydrate diet for a couple of days before starting specific treatments.
Pain can be managed with strong painkillers such as morphine, diamorphine, and fentanyl, while nausea and vomiting can be dealt with using drugs like prochlorperazine, promazine, and ondansetron. Typically, these symptoms start to ease in 72 to 96 hours. If the patient has a rapid heart rate and high blood pressure, beta-blockers, ACE inhibitors, and calcium channel blockers are the preferred medicines. Seizures, if present, can be managed with diazepam, magnesium sulfate, or clonazepam.
The specific treatment for AIP is the intravenous administration of heme, which helps replenish the liver’s heme stores, reducing enzyme activity and lessening symptoms. This treatment can be slow to affect the levels of certain compounds in the blood, so it should be started without delay in serious acute attacks and continued for four days. Side effects can include increased clotting time in the first two hours and increased iron production in the liver. The patient can go home when they can tolerate oral drugs and no longer require strong painkillers. While this treatment is usually well-tolerated, it comes with certain risks, especially with repeated use, including a raised risk of clotting and liver diseases, and a reduced response to the treatment over time.
The only known cure for AIP currently is a liver transplant, with a survival rate of about 80%. However, there is a high risk of clotting in the liver’s main artery, so this procedure is typically reserved for patients with severe, recurrent attacks and a severely reduced quality of life.
Research is currently underway to find other potential treatments. These experimental approaches include Enzyme Replacement Therapy, which involves administering a certain enzyme to the patient, and Liver Gene Therapy, which either delivers a specific gene to the patient’s liver cells or uses a small interfering molecule to reduce the production of a particular compound. Both of these methods are in the clinical trial stage and will require further testing before they can be approved.
What else can Acute Intermittent Porphyria be?
In a study of a condition called acute porphyrias, which included 90 patients with a type referred to as AIP, it was found that on average, it took about 15 years to correctly diagnose the condition. This is mainly because the disease often presents itself initially as severe abdominal pain, which is common in numerous conditions. Therefore, patients may undergo surgeries like appendectomy or gallbladder removal before doctors consider and confirm a diagnosis of porphyria.
Due to a wide variety of neurological and internal organ symptoms that AIP can cause, there’s a long list of other conditions that doctors must consider when they’re trying to reach a diagnosis:
- Other kinds of acute porphyrias: These conditions are similar to AIP and can be hard to distinguish from it, including HCP, VP, and Doss porphyria.
- Conditions that could cause severe abdominal pain: These include inflammation of the peritoneum or stomach lining, appendicitis, gallbladder inflammation, pancreatitis, blockage of the intestine, trapped abdominal hernia, lack of blood supply to the intestines, a blockage of the intestine, inflammation of the digestive system, endometriosis, stomach blockage, a form of bowel obstruction, diseases of the pelvic organs, ovarian cysts, kidney inflammation, tear in the aorta’s wall.
- Lead poisoning: Another condition that must be considered. Doctors can distinguish it from AIP by checking for lack of a healthy red blood cell count and testing the blood for lead.
Also, some conditions associated with symptoms of nerve damage or disorders affecting the automatic functions of the body – such as severely high blood pressure, rapid heart rhythms, adrenal gland crisis, familial Mediterranean fever, and fibromyalgia – have to be considered. Additionally, mental health conditions that can resemble the symptoms of AIP – including acute psychotic episodes, delirium, panic attack, and Guillain-Barre syndrome – all should be part of the diagnostic consideration.
What to expect with Acute Intermittent Porphyria
Prognosis is generally positive if acute intermittent porphyria is identified early and treated promptly. Over the years, the mortality rate has fallen to 5% to 20% for acute attacks, due to advances in diagnosis and treatment. However, for those rare instances when the disease doesn’t respond well to heme therapy and reoccurs, the only current approved method to reduce mortality is through a liver transplant.
With active research examining the effectiveness and safety of Enzyme Replacement Therapy (ERT) and liver gene therapy, the future looks even brighter for those with acute intermittent porphyria.
There are potential complications associated with acute intermittent porphyria such as high blood pressure, chronic kidney disease, neurological deficits, and a risk of liver cancer. It’s crucial to keep these under control by regularly monitoring and reviewing the patient’s condition.
Possible Complications When Diagnosed with Acute Intermittent Porphyria
There are several major complications associated with Acute Intermittent Porphyria (AIP). High blood pressure and long-lasting kidney disease are two serious conditions that are often interconnected, seen in up to 30% of individuals with AIP. In its late stages, kidney disease can be life-threatening for those with ongoing active AIP.
Muscle denervation, another serious complication, may leave patients with residual problems following acute attacks – these might include things like foot/wrist drop or shrinkage of the muscles within the hands.
The most dangerous long-term issue related to AIP is a liver cancer known as Hepatocellular Carcinoma (HCC). Research over recent decades has shown a significantly higher occurrence of this cancer in AIP patients compared to the average population. One Swedish study revealed an 80-fold increase in HCC risk for AIP patients over the age of 50. Interestingly, AIP-related HCC often comes without the usual preceding health conditions like Hepatitis B or C infection.
Common Complications:
- Systemic arterial hypertension
- Chronic kidney disease
- End-stage renal disease (in cases of chronic active AIP)
- Muscle denervation
- Residual deficits after acute attacks (foot/wrist drop or muscle wastage)
- Hepatocellular carcinoma (HCC) – A liver cancer with increased risk for AIP patients over 50
Preventing Acute Intermittent Porphyria
AIP, or Acute Intermittent Porphyria, is a rare genetic condition with ongoing symptoms that sometimes become more severe, often affecting the nerves and belly. Fortunately, ongoing research brings hope for a definitive solution to this lifelong illness.
Once a diagnosis of AIP or another type of acute hepatic porphyria is made, it’s crucial that patients be well informed. They should get a list of trigger factors, especially details about drugs that are safe and unsafe. A trigger factor is something that can bring on an attack of symptoms. Avoiding these triggers is essential, as treatment is only available after symptoms have started. The best strategy is to prevent the onset of symptoms by avoiding triggers.
If patients start to experience abdominal pain, they should head straight for the emergency department. It’s also important for them to understand the future outlook of the disease and possible complications. In addition, they are strongly advised to have genetic testing done for their children to know if they can possibly inherit the genetic condition.
