Acute Hepatic Porphyria

What is acute hepatic porphyria?

Acute hepatic porphyria (AHP) is a group of rare genetic disorders that begin in your liver and go on to affect your nervous system, causing symptoms throughout your body. Symptoms occur when toxic compounds build up in your liver and then pass into your bloodstream, where they come into contact with your nerves. There are four different types of AHP, representing half of the eight types of porphyria that affect different organs.

Porphyria is a deficiency in one of the enzymes that your body needs to make heme (a component of hemoglobin in your blood). During the process of making heme, the absence of specific enzymes causes other compounds to go unused and build up in your body tissues. These leftover compounds — called porphyrin precursors — are toxic when they build up. In acute hepatic porphyria, they build up in your liver first.

What are the different types of acute hepatic porphyria?

The different types of AHP represent different enzymes that are missing. They fall under the sub-type of acute hepatic porphyria because they begin in your liver (hepatic) and because they’re characterized by sudden (acute) attacks of symptoms. In order of most common to least common, they are:

• Acute intermittent porphyria (AIP). A mutation in the HMBS gene causes a deficiency in the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase (PBGD). It can be a new mutation or inherited as an autosomal dominant trait.
• Variegate porphyria (VP). A mutation in the PPOX gene causes a deficiency in the enzyme protoporphyrinogen oxidase (PPO or PPOX). It can be a new mutation or inherited in an autosomal dominant pattern.
• Hereditary coproporphyria (HCP). A mutation in the CPOX gene causes a deficiency in the enzyme coproporphyrinogen oxidase (CPOX). It can be a new mutation or inherited in an autosomal dominant pattern.
• ALAD-deficiency porphyria (ADP). A mutation in the ALAD gene causes a deficiency of the enzyme delta-aminolevulinic acid dehydratase (ALAD). It’s inherited as an autosomal recessive trait.

How does acute hepatic porphyria affect me?

AHP affects people differently. Some people with a gene deficiency associated with AHP do not experience symptoms. Some only experience one to a few “attacks” of symptoms during their lifetimes. Others have more frequent attacks. And some have long-term (chronic) symptoms that affect their day-to-day quality of life. An acute attack of symptoms may be severe enough to bring you to the emergency room. It may involve severe nerve pain, skin changes and neurological symptoms.

Who does acute hepatic porphyria affect?

A person of any race or ethnicity may inherit a gene mutation associated with AHP from one or both parents that carry the mutation. Most never develop symptoms. It takes more than the gene mutation alone to trigger the onset of AHP symptoms. Hormonal changes, certain drugs, alcohol use, smoking and severe stress are some of the factors that can trigger the onset of symptoms. Among those who do develop symptoms, 80% are assigned female at birth and of childbearing age.

How common is acute hepatic porphyria?

It’s difficult to accurately determine the prevalence of AHP because it often goes undiagnosed. It’s estimated to occur in 5 out of every 100,000 people worldwide. Acute intermittent porphyria is the most common type, making up about 80% of documented cases. ALAD-deficiency porphyria is the least common, with only nine documented cases. Only about 1 out of every 10 people with an AHP gene mutation develop symptoms.

What are the symptoms of acute hepatic porphyria?

Symptoms of AHP are often baffling to those who experience them as well as to their healthcare providers. They can strike suddenly and severely and seem to be unconnected to each other. Symptoms can include pain in different areas of the body, problems with your digestive system and severe skin reactions to sunlight. They can also include cognitive and sensory changes related to your nervous system.

Nerve pain may affect different areas of your body, including:

• Abdominal pain.
• Chest pain.
• Back pain.
• Pain in your arms and legs.

Disrupted nerves in your digestive system may cause gastrointestinal symptoms, such as:

• Nausea and vomiting.
• Indigestion.
• Constipation.
• Diarrhea.

Symptoms related to your central nervous system can include:

• Anxiety.
• Insomnia.
• Depression.
• Delirium.
• Hallucinations.
• Seizure.

Symptoms related to your peripheral nervous system can include:

• Muscle weakness.
• Numbness and tingling.
• Fatigue.
• Sensory loss.
• Muscle paralysis
• Respiratory paralysis.

Symptoms related to your autonomic nervous system can include:

• Heart palpitations.
• High blood pressure.

People with variegate porphyria or hereditary coproporphyria may develop skin reactions to sunlight, such as:

• Sensitivity.
• Blistering rash.
• Pigmentation.
• Scarring.

Finally, porphyria can change the color of your urine. Leftover porphyrin precursors that build up in your body and pass through your pee may give it a reddish-purple color. (“Porphyria” comes from the Greek word “porphura,” for purple. Porphyrins in your red blood cells are involved in making your blood red).

What is an acute hepatic porphyria attack?

Most people with symptomatic AHP experience their symptoms as occasional acute “attacks.” These may be more or less frequent or severe for different people. They usually last a few days and get progressively worse before getting better. Severe and frightening symptoms may bring you to the emergency room, and some of these can be medical emergencies. For example, respiratory paralysis can make breathing difficult.

What are the most common symptoms of an AHP attack?

The most common symptom that brings more than 90% of people with AHP to seek medical care is severe unexplained abdominal pain. This is a difficult start for the diagnosis process. Abdominal pain has many causes, and most of them can be traced back to something that healthcare providers can see in an imaging study (such as an X-ray or CT scan). But abdominal pain in AHP is nerve-related and not something they can diagnose on imaging.

Abdominal pain in AHP is often accompanied by nausea, vomiting and constipation. This can mislead healthcare providers to assume you have a gastrointestinal disease. If you also report mental and sensory symptoms related to your nervous system, they might think you have a neurological disorder. It takes a doctor familiar with porphyria to recognize the unconventional combination of symptoms.

What chronic symptoms can occur with acute hepatic porphyria?

People with milder forms of the disease (less prominent enzyme deficiencies) rarely have chronic symptoms and may only have one or two attacks during their lifetimes. Those who are able to identify the factors that triggered their attacks can often successfully avoid them in the future. But others have more frequent attacks, and some symptoms are so frequent that they can be considered chronic. These can include:

• Pain.
• Fatigue.
• Nausea.
• Neuropathy (tingling, numbness or weakness, typically in your hands and feet).

What are the possible complications of acute hepatic porphyria?

Symptoms related to your central nervous system, such as anxiety, hallucinations and seizures, are usually short-lived during an acute attack. Symptoms related to your peripheral nervous system, such as muscle weakness and paralysis, can be more frequent, and a severe attack can cause lasting damage. An overload of porphyrin precursors can also cause cumulative damage to certain organs, leading to:

• Chronic hypertension (high blood pressure).
• Chronic liver disease.
• Chronic kidney disease.
• Primary liver cancer.
• Depression and anxiety.

What causes acute hepatic porphyria?

Genetic mutations are the original cause of AHP, but having the gene mutation isn’t usually enough to trigger the onset of symptoms. Most commonly, hormone changes in puberty trigger them for the first time. Other factors that can trigger them are prescription and recreational drug use, excessive alcohol use, severe calorie restriction and illnesses that cause significant stress to your metabolic system.

What these triggers have in common is that they stimulate the heme production cycle in your liver. However, in a person with AHP, the liver does not have the necessary enzymes to metabolize other byproducts (such as porphyrin precursors) made by the heme production cycle. As a result, leftover porphyrin precursors build up in your liver tissues. They have to build up to a certain level to begin to cause symptoms in your nervous system.

How is acute hepatic porphyria diagnosed?

Getting an accurate diagnosis can be challenging for people with acute hepatic porphyria. The symptoms aren’t specific to this condition and often appear to be unrelated to each other. However, healthcare providers familiar with AHP may recognize it when you have central and peripheral nervous system symptoms together with abdominal pain. This is considered the “classic triad” of AHP symptoms.

When your healthcare provider suspects AHP, they can test for it in a variety of ways. During an acute attack, a urine test is a quick and accessible way. Urine tests may be normal between attacks, but during one they will show elevated levels of porphyrin precursors (PBG and ALA). This isn’t a definitive test for AHP, but it’s a useful first-line screening test that can point healthcare providers in the right direction.

Genetic testing is the gold standard for diagnosing AHP. A genetic test can confirm that you have one of the gene mutations that cause AHP whether or not you’re having symptoms. It can also tell you what type of AHP you have and how severe your enzyme deficiency is. A genetic test uses a sample of your blood or saliva. Your local hospital may have to send the sample away to a specialty lab to have it tested.

How is acute hepatic porphyria treated?

Treatment for AHP is focused on preventing and managing symptom attacks. During an attack, you may need hospital care. You may need various medications to reduce your different symptoms. Between attacks, you may need different medications to keep your triggers in check. Treatment is more effective when you and your healthcare provider are able to identify which triggers affect you the most.

Treatment for an acute attack may include:

• Hemin injection. During a severe attack, a doctor may give you hemin through an injection into your vein to help reduce the porphyrins in your blood. Hemin is a salt derived from red blood cells that inhibits porphyrin production in your body.
• Pain relief. You may need strong pain relievers, such as opioids, during an acute attack.
• Phenothiazines. These drugs can control severe nausea and vomiting.
• IV fluids and nutrition. Symptoms such as abdominal pain, nausea, vomiting, diarrhea and constipation may deprive your body of calories and hydration during an attack. AHP can also cause deficiencies in sodium and magnesium. You may receive IV fluids containing carbohydrates and electrolytes.
• Seizure medications. Up to 20% of people may need treatment for seizures during an attack.

Long-term treatment options may include:

• Prophylactic hemin. People who experience frequent attacks may benefit from a weekly low dose of hemin to prevent porphyrins from building up.
• Givosiran (GIVLAARI®). This medication is a type of gene therapy that inhibits the production of porphyrin precursors. The FDA has recently approved it as a monthly injection to prevent AHP symptoms in people with frequent attacks.
• Hormone therapy. If your menstrual cycle triggers your AHP, your doctor may prescribe GnRH (Gonadotropin-releasing hormone) analogs that inhibit estrogen and progesterone production in your body.
• High blood pressure medication. Those who develop chronic hypertension may need to control it with targeted medications.
• Liver transplantation. People who experience frequent, life-threatening attacks that don’t respond to other treatment options may be eligible for a liver transplant. This can cure them.

Is acute hepatic porphyria preventable?

You can’t prevent inheriting the disease, but you may be able to prevent symptoms from occurring by avoiding triggers. If you’ve never had an attack, you should avoid all possible triggers. If you’ve had attacks and have isolated the triggers that caused them, you may only need to avoid certain ones. Common triggers include:

Medications:

• Antihistamines.
• Sedatives.
• Oral contraceptives.
• Hormone replacement therapy.

Substance use:

• Tobacco.
• Marijuana.
• Alcohol.
• Recreational drugs.

Stress:

• Infections.
• Surgery.
• Calorie deprivation (including carbohydrate deprivation).
• Psychological stress.

What is the prognosis for people with AHP?

It varies widely. Most will never develop symptoms. Among those who do, most will only experience one or a few attacks in their lifetimes. Although attacks can be life-threatening, most people recover completely with prompt medical care. About 5% of people with AHP have frequent or chronic symptoms. For these people, preventative medications are often helpful, and liver transplantation is a possible last resort.

How should I take care of myself while living with AHP?

• Avoid common triggers. Alcohol, smoking and drugs should be at the top of your list to avoid. You might need to consult your doctor about alternatives to certain prescription medications.
• Maintain a healthy, well-balanced diet. Avoid extreme dieting and low-carb diet plans. Consult your doctor before fasting for a medical test or procedure.
• Get your regular checkups. Even if you don’t have symptoms, your healthcare provider will need to check on your liver, kidneys and blood pressure periodically.

A note from Cleveland Clinic

Acute hepatic porphyria is rare, and general awareness of the condition is low. When acute symptoms strike in a sudden attack, they can be confusing and frightening. Some people spend years trying to find out what might be wrong with them and what might help. If you suspect you might have AHP, genetic testing can confirm it. Once you know, you’ll be in a better position to prevent and manage attacks.