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Erythropoietic protoporphyria (EPP) is an inherited porphyria resulting in the accumulation of protoporphyrins in red blood cells that causes acute, painful photosensitivity and potential liver disease. It typically presents in early childhood with immediate pain and crying upon exposure to bright sunlight. This activity reviews the evaluation and treatment of erythropoietic protoporphyria and highlights the role of the interprofessional team in the care of patients with this condition. Objectives: Describe the pathogenesis of erythropoietic protoporphyria. Review the appropriate history and physical exam findings of erythropoietic protoporphyria. Outline the management options available for erythropoietic protoporphyria. Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients presenting with erythropoietic protoporphyria. Access free multiple choice questions on this topic.

Erythropoietic protoporphyria (EPP) is an inherited condition resulting in the accumulation of protoporphyrins in red blood cells that causes acute, painful, non-blistering photosensitivity and potential liver disease.[1] It typically presents in early childhood with immediate pain and crying upon exposure to bright sunlight. It is seasonal, with symptoms primarily occurring in spring and summer. EPP is a lifelong disease, and repeated phototoxic reactions eventually lead to thickening of the skin and wax-like scarring on the face. In a small number of patients, the accumulation of protoporphyrins in the liver leads to cirrhosis and liver failure. Onset in adulthood is rare, but an acquired form has been identified, in which clones of cells with mutated ferrochelatase expand in the setting of the myelodysplastic or myeloproliferative syndrome.[2]

A mutation in ferrochelatase causes EPP, the final enzyme in the heme biosynthesis cycle, which adds Fe2+ to protoporphyrin IX (PPIX) to form heme. In patients with EPP, PPIX significantly accumulates in red blood cells, plasma, liver, and skin due to ferrochelatase deficiency.[3][4] PPIX is excited and then transfers its energy to oxygen, potentially generating free radicals that cause skin damage when patients with EPP are exposed to light.[4]

In 1961, erythropoietic protoporphyria was first comprehensively described, and since then, it has been reported worldwide. It is recognized as the third most common porphyria in adults and the commonest porphyria in children. EPP affects both males and females equally. It is more common in East Asian people than in Whites and is rare in Africa. The incidence in European countries varies.[5]

EPP results from a deficiency of ferrochelatase, the enzyme responsible for the final step in heme biosynthesis. Insufficient ferrochelatase enzyme activity results in increased accumulation of protoporphyrin that lacks Fe+2 or other metals, particularly zinc (ie, metal-free protoporphyrin). In EPP, the main source of production of increased red cell and plasma protoporphyrin is bone marrow reticulocytes. Conditions that increase erythropoiesis may result in increased formation of protoporphyrins by the bone marrow.[6]

The acute phase is characterized by visible endothelial damage in superficial dermal vessels. However, in the chronic phase, there are repeated episodes of small vessel damage in the upper epidermis and deposition of periodic acid-Schiff (PAS) positive diastase-resistant specific hyaline material in the blood vessel wall of both upper and papillary dermal vascular plexuses. An immunofluorescence study shows immunoglobulin G deposition.[7] Electron microscopy shows replicated hyaline material, a fragmented basement membrane, and a layer of fine fibrillar material that permeates the capillary connective tissue sheath and extends beyond the vessel wall.

EPP presents with painful photosensitivity in early childhood. The clinical presentation in males and females is similar. Children with EPP may be misdiagnosed as having primary angioedema or an allergic reaction. Skin findings first appear in early infancy or childhood as photosensitivity, which manifests as intense burning, tingling, and itching of sun-exposed skin, especially the nose, cheeks, and dorsal hands, shortly after exposure to sunlight. These symptoms may be followed by redness, swelling, or blanching, which may last for minutes to days. Papulovesicles may form after prolonged sun exposure. Repeated exposure to light leads to loss of lunulae of the fingernails, ecchymoses, petechiae, and minor scarring on the face and vertical grooving of the lips. Skin manifestations vary and are primarily related to the degree of sun exposure (eg, milder symptoms in winter). In children with EPP, the risk of gallstones is increased, and EPP must be considered as a leading cause of gallstones in children.[8] Protoporphyric hepatopathy, which is a cholestatic form of liver disease, is a serious and rare complication of EPP. It is more likely to occur in patients with high levels of protoporphyrins and presents acutely as jaundice, nausea, right upper quadrant pain, and vomiting. Patients with a chronic history of previously unexplained photosensitivity with severe hepatopathy may lead to a diagnosis of EPP. Skin findings become worse in hepatopathy due to increased accumulation of porphyrins. Liver function tests are persistently elevated in chronic hepatopathy. Many individuals with uncomplicated EPP have normal liver function tests. In the later stages of hepatopathy, the patient may develop peripheral neuropathy that mimics that of acute porphyria and may lead to respiratory failure.[5] Because of sunlight avoidance, patients with EPP are more prone to develop a vitamin D deficiency, which leads to osteoporosis. Some individuals present with mild microcytic, hypochromic anemia. For some unknown reasons, pregnancy is associated with lower levels of protoporphyrin with improved photosensitivity.[9]

The diagnosis of EPP should be considered in any patient presenting with acute, non-blistering photosensitivity. The proper diagnosis explains years of unexplained pain and impaired quality of life. The specific screening test measures the total blood protoporphyrin levels followed by fractionation. A 5 to 50 times higher than the normal range of protoporphyrins confirms the diagnosis of EPP. The normal total protoporphyrin level in erythrocytes is 80 mcg/dL, whereas in a patient with EPP it is elevated to 300-8000 mcg/dL. There is an increased percentage of erythrocyte metal-free protoporphyrin rather than zinc protoporphyrin. In patients with EPP, the urinary porphyrin levels are normal, but with liver complications, ie, hepatopathy develops. To avoid diagnostic delay, plasma porphyrins should be measured concurrently with erythrocyte protoporphyrin.[10] Molecular and genetic testing is more important in EPP than in other porphyrias because of the identification of familial mutations and genetic heterogeneity. Other investigations include liver function testing at diagnosis, followed by monitoring at 6-12-month intervals. A complete blood count for iron-deficiency anemia, serum vitamin D level, abdominal ultrasonography, or other imaging in cases of suspected cholelithiasis should also be performed. Osteoporosis or osteopenia due to vitamin D deficiency may be revealed by bone mineral density testing. A tissue biopsy (skin and bone marrow) is rarely indicated except for a liver biopsy to exclude other causes of chronic liver disease.[11]

There is no definitive treatment for EPP that reduces circulating porphyrin levels; however, patients should avoid sunlight and fluorescent light. Parents should also learn about how to protect their children from sunlight. When outdoors, patients must wear protective clothing and a broad-brimmed hat and remain in shaded areas. The use of broad-spectrum sunscreen is also important. Cars and house windows should be equipped with protective tinted glass. Phototoxic reactions may occur due to visible and ultraviolet A (UVA) light in operating rooms. Light filters should be used in operating rooms to protect the patient, especially in cases of lengthy surgical procedures like liver transplantation in a patient with hepatopathy.[9] Afamelanotide, a synthetic analog of alpha-melanocyte-stimulating hormone (MSH), typically increases skin pigmentation and reduces cytokine and free radical production.[12] It is administered subcutaneously as a controlled-release implant (16mg), particularly during the summer. Another agent that increases the sunlight tolerance is beta-carotene, with oral doses of 30 to 300 mg/day for adults and 30 to 150 mg/day for children. It maintains plasma carotene levels in the range between 600 and 800 mcg/dL, and the serum carotene levels should be checked every 3 to 4 weeks. The risk of lung carcinoma is increased with high doses of beta-carotene. Other photoprotection measures, with variable success, include narrowband UVB phototherapy and oral cysteine. Calcium and vitamin D supplementation (daily intake of 1000mg of calcium with 800 IU of vitamin D) is necessary for patients with EPP due to the avoidance of sunlight. Nonsteroidal anti-inflammatory drugs (NSAIDs) or even opioids may give relief in acute painful episodes along with cold compresses.

Afamelanotide, a synthetic analog of alpha-melanocyte-stimulating hormone (MSH), typically increases skin pigmentation and reduces cytokine and free radical production.[12] It is administered subcutaneously as a controlled-release implant (16mg), particularly during the summer. Another agent that increases the sunlight tolerance is beta-carotene, with oral doses of 30 to 300 mg/day for adults and 30 to 150 mg/day for children. It maintains plasma carotene levels in the range between 600 and 800 mcg/dL, and the serum carotene levels should be checked every 3 to 4 weeks. The risk of lung carcinoma is increased with high doses of beta-carotene. Other photoprotection measures, with variable success, include narrowband UVB phototherapy and oral cysteine. Calcium and vitamin D supplementation (daily intake of 1000mg of calcium with 800 IU of vitamin D) is necessary for patients with EPP due to the avoidance of sunlight. Nonsteroidal anti-inflammatory drugs (NSAIDs) or even opioids may give relief in acute painful episodes along with cold compresses. Rapidly progressive and severe hepatopathy can be treated with a regimen that includes intravenous hemin (to reduce plasma porphyrin levels), plasmapheresis, ursodeoxycholic acid, cholestyramine, vitamin E (400 IU), and correction of anemia. Liver transplantation is the treatment choice for severe protoporphyric hepatopathy or for patients who develop liver cirrhosis.[13] Bone marrow transplant is a newer treatment that may be done in conjunction with liver transplantation to prevent the recurrence of EPP, and reports show that it may be able to reverse or treat both photosensitivity and protoporphyric hepatopathy.[14][15] The presumed mechanism involves predominantly heme synthesis in the bone marrow, thereby allowing curative treatment in some case reports, particularly because some case reports show rapid recrudescence of disease activity leading to fatal outcomes.[15][16]

Phototoxic drug reaction: There must be a history of exposure to any new drug. Patients experience painful erythema immediately after sun exposure.[7] Hydroa vacciniforme: It is a rare photosensitivity disorder. It is characterized by recurrent fluid-filled blisters over sun-exposed sites that heal with pox-like scars. Solar urticaria: Solar urticaria is a condition in which exposure to sunlight causes urticaria. Like EPP, symptoms often develop within minutes. Symptoms of solar urticaria are often pruritic rather than painful. Polymorphic light eruption: It is also called a sun allergy or sun poisoning. It is a common photodermatosis that typically occurs during the 1st 3 decades of life. Symptoms occur in sun-exposed areas. Patients present with discrete lesions such as pruritic papules, vesicles, or plaques on sun-exposed areas. Discoid lupus erythematosus: It presents as scaly erythematous plaques on sun-exposed areas. Sunburn: It is a transient inflammatory skin response to ultraviolet radiation from sunlight or artificial sources. Sunburn can occur in individuals without underlying dermatologic conditions, with sensitivity varying with skin pigmentation and hair and eye color.[17]

Life expectancy is usually normal in patients with EPP unless hepatopathy develops due to hepatotoxic effects of protoporphyrins that lead to liver dysfunction. EPP generally does not decrease life expectancy but does have a great influence on the quality of life. Since the pain after photosensitivity is intense and acute, it is necessary for the patient to modify lifestyle and employment.[8]

The main serious complication associated with EPP is protoporphyrin-related hepatopathy, which may be fatal. In the later stages of hepatopathy, the patient may develop peripheral neuropathy that mimics that of acute porphyria and may lead to respiratory failure. On repeated exposure to sunlight, the skin over the face, dorsum of hands (knuckles), can become thickened or lichenified, along with loss of lunulae of fingernails. Due to regular sunlight avoidance, patients with EPP are more prone to develop a vitamin D deficiency, which can lead to osteoporosis.[18]

Parents and patients must be educated about the nature of the disease and should be aware of all the precautionary methods to protect themselves. The patient is advised to avoid unnecessary sun exposure. They should wear protective clothing, including long sleeves, a wide-brimmed hat, and gloves, and should wear shoes (avoid sandals) when driving. They should use sunscreens containing zinc oxide or titanium dioxide, as these are more effective against UVA, UVB, and visible light. During surgery, extra caution is required because these individuals are at risk of burn injuries to the skin and internal organs exposed to the strong lights of operating rooms. Light filters should be used in operating rooms to protect the patient. Patients may need to modify their jobs/employment.[1] Genetic counseling is important because EPP is inherited as an autosomal recessive disorder. For patients with EPP, the likelihood of having an affected child depends on whether the other parent carries the hypomorphic IVS3-48T/C allele, which is more common in some populations than others. Testing the other parent can determine this likelihood. If the other parent's FECH genes are both normal, half the children inherit the severe FECH mutation (which may be passed on to future generations); however, they do not have EPP because they also inherited 1 normal FECH allele.

Erythropoietic protoporphyria is an inherited condition caused by mutations in ferrochelatase, the final enzyme in the heme biosynthesis pathway.[19] There is no definitive treatment for EPP (though there are upcoming possibilities of curative treatments, such as bone marrow transplant, being explored), and it is best managed by an interprofessional team to deal with all the complications. The impact of EPP on the psychosocial functioning and quality of life of these patients should be considered, and a psychiatric disorder can accompany it. The dermatologist, psychiatrist, primary care clinician, and gastroenterologist must work as a team when treating these patients. Specialty-trained nurses can also help by counseling the patient on photoprotection, providing guidance on medical management, and monitoring for complications. Close communication among interprofessional team members is important for improving outcomes.