Continuing Education Activity

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.

Introduction

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 in nature with symptoms principally occurring in the spring and summer season.

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]

Etiology

EPP is caused by a mutation of ferrochelatase, which is the final enzyme in the heme biosynthesis cycle, adding Fe+2 with protoporphyrin IX (PPIX) to make heme. In patients with EPP, PPIX significantly accumulates in red blood cells, plasma, liver, and skin due to ferrochelatase deficiency.[3][4][3]

PPIX excites and releases its energy to oxygen, which may create free radicals that result in skin damages when the patients with EPP are exposed to light.[4]

Epidemiology

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

Pathophysiology

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

Histopathology

The acute phase presents as visible endothelial damage in superficial vessels of the dermis. 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. Immunofluorescence study shows immunoglobulin G deposition.[7]

Electron microscopy shows replicated hyaline material, a fragmented basement membrane, layered with fine fibrillar material that permeates the capillary connective tissue sheath and extends beyond the vessel wall.

History and Physical

EPP presents with painful photosensitivity in early childhood. The clinical presentation in males and females is similar. Children with EPP may be misdiagnosed as primary angioedema and allergic reaction. Skin findings first appear in early infancy or childhood in the form of photosensitivity shortly after exposure to sunlight, which manifests as intense burning, tingling, and itching of sun-exposed skin, especially the nose, cheeks, and dorsal hands. These symptoms may be followed by redness, swelling, or blanching, lasting from 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 (e.g., milder symptoms in winter). In children with EPP, the risk of gall stones is increased, and EPP must be considered as a leading cause of gall stones 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 increase accumulation of porphyrins. Liver function tests are persistently elevated in chronic hepatopathy. Many individuals with uncomplicated EPP have normal liver function tests. In later stages of hepatopathy, the patient may develop peripheral neuropathy that mimics peripheral neuropathy 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 anemia, which is microcytic and hypochromic. For some unknown reasons, pregnancy is associated with lower levels of protoporphyrin with improved photosensitivity.[9]

Evaluation

The diagnosis of EPP needs to be considered in any patient who presents with acute and non-blistering photosensitivity. The proper diagnosis provides an explanation for years of unexplained pain and impaired quality of life. The specific screening test is measuring 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, but in a patient with EPP, it is elevated up to 300 to 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, i.e., hepatopathy develops. To avoid diagnostic delay, plasma porphyrins should be measured at the same time with erythrocyte protoporphyrin.[10]

Molecular and genetic testing is more important in the case of EPP than other porphyrias because of the familial mutation identification and genetic heterogenicity. Other investigations include liver function testing at the time of diagnosis and then monitor at the interval of 6-12 months. Complete blood count for iron deficiency anemia, vitamin D level, ultrasonography of abdomen, or other imaging in cases of suspected cholelithiasis should also be done. 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 in order to exclude other causes of chronic liver disease.[11]

Treatment / Management

There is no definitive treatment for EPP in order to decrease the circulating porphyrin levels, but patients should avoid sunlight or fluorescent light. Parents should also learn about how to protect their children from sunlight. When going outside, patients must wear protective clothes and broad-brimmed hats and stay 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 as a result of visible light and ultraviolet A (UVA) light in operating rooms. Light filters should be used in operating rooms to protect the patient, especially in case of long surgical procedures like liver transplantation in a patient with hepatopathy.[9]

Afamelanotide, a synthetic analog of alpha-melanocyte-stimulating hormone (MSH), normally increases the skin pigmentation and decreases the production of cytokines and free radicals.[12] It is given subcutaneously as a controlled released implant (16mg), especially in the summer season. Another agent which 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 to 800 mcg/dL, and the serum carotene levels should be checked every three to four weeks. The risk of lung carcinoma is increased with high doses of beta-carotene. Other photoprotection measures with variable success include narrow-band UVB phototherapy and oral cysteine. Calcium and vitamin-D (daily intake of 1000mg of calcium with 800 IU of vitamin D) supplementation is necessary for patients with EPP because of sunlight avoidance. 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 level), plasmapheresis, ursodeoxycholic acid, cholestyramine, vitamin-E (400IU), 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 wit hliver 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 is related to a majority of heme synthesis in the bone marrow, thus allowing for a possibility of curative treatment in some case reports, particularly as some case reports show recrudescence of disease activity leading to fatal outcomes rapidly [16][15][17].

Differential Diagnosis

• Phototoxic drug reaction: There must be a history of the introduction of 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 first three 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 an underlying dermatologic condition, with sensitivity depending on the degree of skin pigmentation and hair and eye color.[18]

Prognosis

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]

Complications

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, which mimics the peripheral neuropathy 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.[19]

Deterrence and Patient Education

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, use long sleeves, a wide-brimmed hat, shoes (avoid sandals) and wear gloves for driving. They should use reflecting sunscreens that are based on zinc dioxide or titanium oxide as they will be 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 very important as EPP is inherited as an autosomal recessive disease. For patients with EPP, the likelihood of having an affected child will depend 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 will inherit the severe FECH mutation (which may be passed on to future generations); however, they will not have EPP because they also inherited one normal FECH allele.

Enhancing Healthcare Team Outcomes

Erythropoietic protoporphyria is an inherited condition due to the mutation of ferrochelatase, which is the final enzyme in the heme biosynthesis cycle.[20] 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 it can be accompanied by a psychiatric disorder. The dermatologist, psychiatrist, primary clinician, and gastroenterologist need to work as a team while treating these patients. Specialty-trained nurses can also help by counseling the patient about photoprotection, providing direction on medical management, and monitoring for any complications. Close communication between different interprofessional team members is important to improve the outcomes.