Erythropoietic Protoporphyria (EPP) or Protoporphyria
Erythropoietic Protoporphyria (EPP) or Protoporphyria
Erythropoietic Protoporphyria is characterized by abnormally elevated levels of protoporphyrin IX in erythrocytes (red blood cells) and plasma (the fluid portion of circulating blood), and by sensitivity to visible light that is usually noticed in early childhood and occurs throughout life. EPP can result either from mutations of the ferrochelatase gene (FECH), or less commonly the delta-aminolevulinic acid synthase-2 gene (ALAS2). When EPP is due to an ALAS2 mutation it is termed X-linked protoporphyria (XLP), because that gene is found on the X chromosome.
Protoporphyrin accumulates first in the bone marrow in EPP, and then in red blood cells, plasma and sometimes the liver. Protoporphyrin is excreted by the liver into the bile, after which it enters the intestine and is excreted in the feces. It is not soluble in water, so is not excreted in the urine.
EPP is the third most common type of porphyria, and the most common in childhood. It causes very painful photosensitivity and can greatly impair quality of life. Delay in diagnosis is greater than with any other type of porphyria.
Swelling, burning, itching, and redness of the skin may appear during or after exposure to sunlight, including sunlight that passes through window glass. This can cause mild to severe burning pain on sun-exposed areas of the skin. Usually, these symptoms subside in 12 to 24 hours and heal without significant scarring. Blistering and scarring are characteristic of other types of cutaneous porphyria but are unusual in EPP. Skin manifestations generally begin early childhood and are more severe in the summer.
There is an increased risk of gallstones, which contain protoporphyrin. Excess protoporphyrin can also cause liver damage. Less than 5% of EPP patients’ severe liver damage and a condition caused protoporphyric hepatopathy that sometimes requires liver transplantation.
Diagnosis and Genetic Counseling
EPP should be suspected in anyone with non-blistering photosensitivity especially when is it prolonged and beginning in childhood. It is easy to make a diagnosis, or rule it out, once it is suspected.
The diagnosis of EPP is established by finding an abnormally high level of total erythrocyte protoporphyrin, and showing that this increase is mostly free protoporphyrin rather than zinc protoporphyrin. There is considerable confusion about which test to order. Sometimes laboratories have measured only zinc protoporphyrin and reported results incorrectly as “protoporphyrin” or “free erythrocyte protoporphyrin (FEP)”. Laboratories that measure total erythrocyte protoporphyrin, free protoporphyrin and zinc protoporphyrin and report results reliably are:
- Porphyria Laboratory and Center, University of Texas Medical Branch at Galveston, 1-409-772-4661
- Mayo Medical Laboratories, 1-800-533-1710
- ARUP Laboratories
Porphyrins are almost always elevated in plasma in EPP, but may be normal in mild cases. Fecal porphyrins may be normal or increased.
An experienced biochemical laboratory can usually distinguish between patients with EPP and XLP, because the former have much less zinc protoporphyrin in their erythrocytes. This can be explained because in the marrow the enzyme ferrochelatase not only normally makes heme (iron protoporphyrin) from protoporphyrin and iron, but can also make zinc protoporphyrin, especially when excess protoporphyrin is present or iron is deficient. However, this does not replace DNA studies.
Rarely, EPP develops in adults in the presence of a bone marrow disorder such as polycythemia vera, and is due to expansion of a clone of red blood cell precursors in the marrow that is deficient in ferrochelase.
DNA studies are important for confirming the diagnosis of EPP and XLP and for genetic counseling. This should be completed first in a person known to have the disease, and the information about the mutations in that individual used to guide testing of family members.
When EPP is due to a FECH mutation the inheritance is described as autosomal recessive. It is most common to find that one severe mutation is inherited from one parent and another weak mutation inherited from the other parent. The weak mutation is quite common in normal Caucasians, rare in Blacks and even more common in Japanese and Chinese populations. This mutation is sometime referred to as “hypomorphic” because it results in formation of a less than normal amount of ferrochelatase. But is does not cause EPP unless it is paired with a severe mutation. The severe mutation is characteristic for an EPP family and is present in all affected individuals. “Carriers” of the severe mutation are not affected because they do not have the weak mutation. Affected individuals and unaffected carriers can transmit the severe mutation to the next generation. Some of their children will have EPP if the other parent has a copy of the weak mutation. Rarely, the weak mutation is absent in an EPP family and two severe mutations are found, with at least one producing some ferrochelatase.
In XLP, mutations of the ALAS2 gene, which is found on the X chromosome, causes an increase in the production of the enzyme ALAS2 in the bone marrow. Several of these “gain of function” mutations have been described in different XLP families. In XLP protoporphyrin production exceeds that needed for heme and hemoglobin formation. Like hemophilia and other X linked genetic diseases, XLP is more common in men. Women have two X chromosomes and are usually not affected because they have a normal as well as a mutated ALAS2 gene. Men have only one X chromosome and will be affected if they inherit an ALAS2 mutation. Women with an ALAS2 mutation will, on average, pass that mutation to half of their daughters (who will usually be unaffected carriers) and to half of their sons (who will be affected).
Treatment and Management
1. Sunlight protection
Protection from sunlight is the mainstay of management of EPP, and this is necessary throughout life. Disease severity and porphyrin levels in erythrocytes and plasma probably remain high and relatively constant throughout life in EPP. However, this has been little studied and more longitudinal observations are needed. Life style, employment, travel and recreation require adjustment in order to avoid painful reactions to sunlight and even from exposure to fluorescent lighting. For these reasons EPP can substantially affect quality of life.
Protective clothing, including broad-brimmed hats, long sleeves, gloves and trousers (rather than shorts), is beneficial. Several manufacturers specialize on clothing made of closely woven fabrics for people with photosensitivity.
2. Beta-Carotene (Lumitene Tishcon)
Beta-carotene is an over the counter product that was originally developed in a purified form as a drug for the treatment of EPP, and was shown to be effective by Dr. Micheline Mathews-Roth at Harvard University and others. The pharmaceutical grade formulation is now distributed by Tishcon as Lumitene, and can be ordered by calling 1-800-866-0978 or via the website www.epic4health.com. Other products are less standardized and reliable and are not recommended.
Beta-carotene provides protection by quenching reactive oxygen products that form when protoporphyrin is activated in the skin by light. It is important to take an amount that is adequate to be protective. For more information about Lumitene, including a recommended dosing schedule, please see the Lumitene section of this website.
3. Other considerations
In an occasional patient, protoporphyrin causes liver problems, so monitoring liver function is important. EPP patients should also not use any drug or anesthetic which causes cholestasis (slowing down bile flow), and should also avoid alcohol. Women should avoid medications containing estrogen (birth-control pills, hormone replacement therapy), and men should avoid testosterone supplements, as these substances can also have deleterious effects on the liver of a person with EPP.
Consult a specialist. Because EPP is a rare condition, most physicians are not knowledgeable about it. Primary care or Emergency Room doctors can contact EPP expert: Dr. Micheline Mathews-Roth, Harvard Medical School, 617-525-8249. The American Porphyria Foundation, 713-266-9617 can also provide further information. A Medic Alert bracelet with instructions to contact a specialist if needed is a worthwhile precaution.
Yearly monitoring. Testing to include erythrocyte total protoporphyrin, plasma porphyrin, complete blood counts, ferritin and liver function tests should be done yearly. Porphyry levels are expected to be stable and liver tests to remain normal. EPP patients may have evidence of iron deficiency, and an iron supplement may be advisable if the serum ferritin is below about 20 ng/mL.
Vitamin D. Because they avoid sunlight, EPP patients are likely to be deficient in vitamin D. A vitamin D supplement with calcium is recommended for bone health.
Liver protection. It is important to avoid other causes of liver disease that might promote the development of liver complications from EPP. Patients should avoid alcohol and other substances that might damage the liver, including many herbal preparations, and be vaccinated for hepatitis A and B.
Surgical lights. Strong operating room lights can cause photosensitivity of the skin and even surfaces of internal organs. Flexible membrane filters, such as CL5-200-X from Madico Co., are available to cover surgical lights and offer some protection. This is especially important in EPP patients with liver failure, which causes even greater increases in protoporphyrin levels and photosensitivity.
Drugs. Drugs that are harmful in other porphyrias are not known to make EPP worse, but are best avoided as a precaution. This may include estrogens and other drugs that might reduce bile formation. A short course of a non-steroidal anti-inflammatory drug can provide some pain relief after an episode of photosensitivity, but can cause ulcerations of the digestive track especially with prolonged use.
Laser treatment. According to Dr. Roth, laser treatments for hair removal or eye surgery have not been a problem in EPP people. But the doctor should be made aware of the diagnosis, and that laser output between 400 and 650 nanometers might be harmful. Before hair removal treatment, the doctor may irradiate a small area of the skin to be treated for the length of time it will take to do the hair removal to ascertain if the patient would react within the period of time that a reaction to sunlight would be expected in that patient.
Children with EPP. Avoiding sunlight can be difficult for children with EPP who have less sunlight tolerance than their friends. Camp Discovery is an option for such children. It provides a week-long summer camping experience of fishing, boating, swimming, water skiing, arts and crafts, and just plain fun for young people with skin disorders, and is sponsored by the American Academy of Dermatology. Full scholarships, including transportation, are provided by the American Academy of Dermatology through generous donations of their members and other organizations. Members of the Academy are asked to recommend candidates for Camp Discovery, so ask your child's doctor about sending your child to Camp Discovery.
Disneyland and Disney World are responsive to people with sun sensitivity. They will provide a pass to enable you to enter attractions without waiting in line in the sun.
Go to "Town Hall" and explain your problem with photosensitivity. You should bring a physician's letter with you as well as an APF brochure explaining the type of Porphyria you have. The staff will ask you some questions about your limitations (e.g., whether or not you can climb stairs) and how many are in your group. Next time you return, be sure to bring the old card with you, as it will only take about half as long to go through the process on your next trip.
Proceed to the "Guest Relations" office at any park (Magic Kingdom, EPCOT, etc.) and request the Special Assistance Pass.
Remember to bring a doctor's note and explanation of your condition, because it is not necessarily visible. People on duty may not be familiar with light sensitivity and its consequences.
Patients with EPP and XLP can participate in the research through the Porphyrias Consortium. The American Porphyria Foundation has information on what research protocols are currently open.
* The Porphyrias Consortium is conducting a Longitudinal Study to better define the natural history of the disease. This study is currently open for enrollment of new patients.
* The Porphyrias Consortium will be starting a pilot study soon on a drug that may lower porphyrin levels in EPP.
* Clinuvel Pharmaceuticals is developing afamelanotide (Scenesse®) for the treatment of EPP. This drug is given by injection and increases skin pigmentation. Another study of this drug is expected to open within the next year.
All patients with porphyria are encouraged to enter the Porphyrias Registry at the Porphyrias Consortium website. A link to this website is found on the website of the American Porphyria Foundation. Registration demonstrates to NIH that patients and their families think that research on porphyrias is important. You can also ask that one of the 6 porphyria center in the Consortium contact you.