Diagnosis and management of protoporphyria-related liver dysfunction in erythropoietic protoporphyria and x-linked protoporphyria: A patient-friendly summary of the 2023 evidence-based consensus guidelines

Download video file ^{(61.3MB, mp4)}

This article will summarize selected sections of the consensus guidelines put forth by the Porphyrias Consortium and the Rare Diseases Clinical Network in an easy-to-read format for patients and their caregivers.¹ The goal of this summary is to help patients and caregivers better understand diagnosis, monitoring, and treatment for liver-related problems in erythropoietic protoporphyria (EPP) and x-linked protoporphyria. But it should not replace expert medical care.

HOW THESE GUIDELINES WERE CREATED

These guidelines were created by experts from the National Institute of Health’s Porphyrias Consortium. A review of the most recent, relevant research and studies related to protoporphyrias was conducted.

WHAT ARE PROTOPORPHYRIAS?

EPP and x-linked protoporphyria are referred to as the protoporphyrias. Both are caused by changes to one of the building blocks that make heme, an important molecule in the body. A change in one of these building blocks causes protoporphyrin (PPIX) to accumulate in red blood cells.

PPIX is activated when light from the sun or other sources passes through the outer layer of the skin, causing pain and other symptoms.

In addition to painful reactions to light, other complications and symptoms include vitamin D deficiency, gallstones, anemia, enlarged spleen, and liver disease. While the frequency of these other complications is not well known, a small number (1%–5% of patients) will develop severe liver disease.

WHAT IS THE CONNECTION BETWEEN PROTOPORPHYRIA AND THE LIVER?

Protoporphyria-related liver disease is likely related to abnormal bile formation. Bile, which is a substance that helps your body digest and absorb food, is made in the liver, then stored in the gallbladder, or passed through the bile ducts to the intestines.

Excess PPIX is deposited in the liver, transported into the bile and intestines, and eliminated with feces. PPIX forms crystals in the bile that can damage or kill cells and impair the formation and flow of bile. Part of the PPIX is reabsorbed into circulation, continuing this damaging cycle.

It is not clear why patients develop liver disease. However, patients with higher levels of PPIX in their blood appear to be at higher risk.

RECOMMENDATIONS FOR SCREENING AND PREVENTING LIVER DISEASE

Screening is important to determine risk and monitor changes to liver health. Such screening should include:

• Liver function tests—at diagnosis and annually

• Genetic testing—at diagnosis to determine if the patient has changed in the EPP gene associated with higher PPIX levels

If liver function is normal, the following is recommended:

• Maintain a healthy body weight

• Avoid excess alcohol

• Get hepatitis A and B immunizations

• Avoid oral contraception with high estrogen content.

Screening ultrasounds are not recommended with normal liver function and no symptoms of gallstones.

IDENTIFYING MILD-TO-MODERATE LIVER PROBLEMS

If a patient has signs of liver problems, it should be determined if they are due to protoporphyria (Figure 1).

FIGURE 1.

Management process for PPIX liver problems. * Other general measures include completing age-appropriate immunizations and maintaining a healthy weight. Abbreviations: ANA, anti-nuclear antibody; ASMA, anti-smooth muscle antibody; PPIX, protoporphyrin; TSH, thyroid stimulating hormone.

It is recommended that patients with suspected liver problems due to protoporphyria be referred to a liver specialist.

Baseline liver function tests should be conducted, and monitoring tests should be done every 6 months, or more frequently if needed. Monitoring should include lab tests, complete blood count, blood clotting time, and PPIX levels. A baseline ultrasound test is also recommended.

Protoporphyria patients are at increased risk of gallstones and blockages in the bile ducts. Gallstones should be treated the same as they would for all people.

HOW ARE MILD-TO-MODERATE LIVER PROBLEMS MANAGED?

The rarity of protoporphyria-related liver disease makes it hard to study treatments. Small studies and case reports show that ursodeoxycholic acid, colestipol and cholestyramine, and vitamin E may be beneficial.

Anemia is common in protoporphyrias. Iron supplementation can help improve anemia, but iron use in EPP is controversial because it may cause increased light sensitivity and liver damage. Therefore, iron supplementation is recommended in EPP only when anemia symptoms are present, along with low ferritin levels. In x-linked protoporphyria, on the other hand, iron supplementation is always recommended and may improve symptoms.

WHAT HAPPENS WHEN YOU HAVE ADVANCED PROTOPORPHYRIA-RELATED LIVER PROBLEMS?

Protoporphyria-related liver disease can progress to where a liver transplant is required. Success rates for protoporphyria-related liver transplants are similar to other liver transplants.

With protoporphyria-related liver transplants, there is the potential for a reaction to operating room lights, causing burns on the skin and internal organs. Special light filters should be used.

Liver transplantations are not curative because the excess PPIX comes from the bone marrow, and there is a chance that, over time, the transplanted liver will again become damaged by excess PPIX. A bone marrow transplant following the liver transplant prevents liver damage from recurring and eliminates light sensitivity. However, it is considered a very risky procedure with a high chance of complications. An evaluation by a bone marrow specialist with expertise in the porphyrias is recommended.

There are other interventions that may help reduce PPIX in the plasma and minimize liver damage and surgery complications. More research is required to understand if these treatments are beneficial:

• Therapeutic plasma exchange: Blood is circulated out of your body where the plasma is separated out and replaced with a plasma substitute, and then returned to your body. The goal is to reduce the amount of PPIX circulating in your body.

• Red blood cell exchange: Similar to therapeutic plasma exchange, only instead of replacing plasma, red blood cells are replaced. The effectiveness of this treatment is uncertain but may be beneficial before a bone marrow transplant to prevent liver injury.

• IV hemin therapy: Hemin is used to treat acute hepatic porphyrias. It has been used in rare situations in protoporphyria and may be beneficial in cases of severe liver damage.

• PRBC transfusion: Red blood cells from a donor are added to the blood. The goal of this intervention is to reduce the body’s need to make its own red blood cells and, therefore, reduce the amount of heme and PPIX produced.

FUTURE RESEARCH AND DIRECTIONS

Additional studies are needed for a better understanding of the protoporphyrias. Patient participation in this research is very important in this process.