Erythropoietic Protoporphyria and X-linked Protoporphyria

Erythropoietic protoporphyria, which comprises about 90% of EPP phenotypic presentations results from inherited deficiency of the enzyme ferrochelatase. The inheritance pattern is autosomal recessive; thus, clinical manifestations occur only in people with 2 defective FECH alleles, or more commonly, one defective and one low-expressing wild-type allele (1 Etiology references Erythropoietic protoporphyria (EPP) is due to an inherited deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is due to an inherited increase in the activity... read more ).

X-linked protoporphyria, which comprises the remaining 10% of cases, results from gain-of-function mutations that increase the activity of erythroid-specific delta-aminolevulinate synthase (ALAS 2) in the bone marrow; inheritance is X-linked. The phenotype of heterozygous females can vary from asymptomatic to that of affected males (1 Etiology references Erythropoietic protoporphyria (EPP) is due to an inherited deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is due to an inherited increase in the activity... read more ).

Prevalence of EPP phenotype is about 1/75,000. However, a study from the UK Biobank found that the prevalence of EPP was about 1/17,000 (2 Etiology references Erythropoietic protoporphyria (EPP) is due to an inherited deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is due to an inherited increase in the activity... read more ). The authors attributed this higher prevalence to under diagnosis. Protoporphyrin accumulates in bone marrow and red blood cells, enters the plasma, and is deposited in the skin or excreted by the liver into bile. About 10% of patients develop chronic liver disease; a few of these patients develop cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more , which may progress to liver failure. A more common complication is pigment gallstones Cholelithiasis Cholelithiasis is the presence of one or more calculi (gallstones) in the gallbladder. In developed countries, about 10% of adults and 20% of people > 65 years have gallstones. Gallstones... read more due to heavy protoporphyrin excretion.

Symptom severity in erythropoietic protoporphyria and X-linked protoporphyria varies greatly, even among patients within a single family. One study suggests that higher levels of erythrocyte protoporphyrin are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLPP (1 Symptoms and signs reference Erythropoietic protoporphyria (EPP) is due to an inherited deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is due to an inherited increase in the activity... read more ).

Most patients develop symptoms in early childhood. Brief exposure to sunlight can cause severe pain, burning, erythema, and edema of the exposed skin. Usually, an infant or young child cries for hours after even short exposure to sun. Patients are often erroneously said to suffer from "sun allergy." Sometimes skin swelling and erythema may be subtle or absent, and EPP and XLPP may go undiagnosed longer than any other of the porphyrias.

Crusting may develop around the lips and on the back of the hands after prolonged sun exposure. However, blistering and scarring, as are typical in porphyria cutanea tarda Porphyria Cutanea Tarda Porphyria cutanea tarda (PCT) is a comparatively common hepatic porphyria affecting mainly the skin. Liver disease is also common. PCT is due to an acquired or inherited deficiency in the activity... read more , variegate porphyria, and congenital erythropoietic porphyria (see table ), do not occur.

If skin protection is chronically neglected, rough, thickened, and leathery skin (lichenification) may develop, especially over the knuckles. Linear perioral furrows (carp mouth) may develop. Patients with XLPP tend to have more severe photosensitivity and liver disease than those with EPP.

If unrecognized, erythropoietic protoporphyria and X-linked protoporphyria may cause psychosocial problems because children inexplicably refuse to go outdoors. The fear or anticipation of pain may be so distressing that children become nervous, tense, aggressive, or even develop feelings of detachment from the surroundings or suicidal thoughts.

Erythropoietic protoporphyria or X-linked protoporphyria should be suspected in children and adults with painful cutaneous photosensitivity who experience no blisters or scarring. Gallstones in children should prompt testing for EPP and XLPP. Family history is usually negative.

The diagnosis is confirmed by finding increased red blood cell and plasma protoporphyrin levels. The peak plasma fluorescence occurs at 634 nm, following excitation at 410 nm.

Red blood cell protoporphyrin should also be fractionated to determine the proportions of metal-free and zinc protoporphyrin. In EPP, the proportion of red blood cell protoporphyrin that is metal-free is almost always > 85%. The presence of > 15% zinc protoporphyrin suggests XLPP.

If measured, plasma coproporphyrin and urinary porphyrin levels are normal. Stool protoporphyrin may be elevated, but coproporphyrin level is normal.

Potential carriers among relatives can be identified by finding increased red blood cell protoporphyrin levels and by genetic testing if a mutation has been identified in the index case.

Treatment for erythropoietic protoporphyria and X-linked protoporphyria is similar. Patients with erythropoietic protoporphyria or X-linked protoporphyria should avoid sun exposure; protective clothing, hats, and light-opaque titanium dioxide or zinc oxide containing sunscreens should be used.

Afamelanotide, a long-acting congener of melanocyte stimulating hormone which leads to increased production of eumelanin, can be administered once every 60 days as a subcutaneous implant, decreases photosensitivity, allows longer exposure to light, and improves quality of life (1 Treatment reference Erythropoietic protoporphyria (EPP) is due to an inherited deficiency in the activity of the enzyme ferrochelatase. X-linked protoporphyria (XLPP) is due to an inherited increase in the activity... read more ).

Oral beta-carotene, an antioxidant, reduces photosensitivity. However, patient adherence with beta-carotene is often poor because it is not very effective in controlling symptoms and also causes orange skin pigmentation; thus it is often tried but usually not continued. Beta-carotene dose depends on patient’s age (see table Doses of Beta-Carotene in Erythropoietic Protoporphyria Doses of Beta-Carotene in Erythropoietic Protoporphyria and X-Linked Protoporphyria ).

Medications that trigger acute porphyrias need not be avoided (see the Drug Database for Acute Porphyria or the American Porphyria Foundation drug database).

In some patients, acute skin symptoms can be alleviated by cold baths or wet towels, analgesics, and topical and/or oral corticosteroids. However, many patients do not find such measures very effective. Symptoms can take up to a week to resolve.

If these measures are ineffective (eg, patients have increasing photosensitivity, rising porphyrin levels, progressive jaundice), giving hematin and/or red blood cell hypertransfusion (ie, to above-normal hemoglobin levels) may reduce protoporphyrin overproduction. Administration of bile acids may facilitate biliary excretion of protoporphyrin.

Oral cholestyramine or charcoal have been used to interrupt the enterohepatic circulation of protoporphyrin and increase fecal excretion.

Oral vitamin E, 800 units per day, is also used with the hope that it will exert an antioxidant and hepatoprotective effect, although objective evidence of benefit is scant.

Patients who develop decompensated end-stage liver disease require liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more . As with acute intermittent porphyria Treatment Acute porphyrias result from deficiency of certain enzymes in the heme biosynthetic pathway, resulting in accumulation of heme precursors that cause intermittent attacks of abdominal pain and... read more , patients with EPP are not eligible for standardized Model for End-Stage Liver Disease (MELD)-exception points. However, liver transplantation does not correct the underlying metabolic defect and EPP hepatopathy often develops in the transplanted liver.

Hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more is curative for EPP but is not routinely done because the risk typically outweighs the benefits. The strategy of hematopoietic stem cell transplantation after liver transplantation cures EPP and prevents recurrent EPP from damaging the allograft, but the optimal timing of this strategy has not been established. Patients should be protected from operating room lights during liver transplantation or other prolonged surgery to avoid serious phototoxic injury to internal organs. Light sources should be covered with commercially available filters that block wavelengths ~380 to 420 nm. Endoscopy, laparoscopy, and brief (< 1.5 hour) abdominal surgery do not usually cause phototoxic damage.

Regular physician-patient consultations that provide information, discussion, and opportunities for genetic counseling together with physical checkups are important. Liver function and red blood cell and plasma protoporphyrin levels should be checked annually.

Patients with abnormal liver function test results should be evaluated by a hepatologist; a liver biopsy may be needed to stage the degree of fibrosis. Patients with known chronic liver disease should undergo screening liver ultrasonography, CT, or MRI every 6 months to check for hepatocellular carcinoma.

Vitamin D levels should be checked because deficiency is common (patients tend to avoid sun exposure); supplements are given if levels are low.

All patients with EPP and XLPP should receive hepatitis A vaccine Hepatitis A (HepA) Vaccine Both hepatitis A vaccines provide long-term protection against hepatitis A. For more information, see Hepatitis A Advisory Committee on Immunization Practices Vaccine Recommendations and Centers... read more and hepatitis B vaccine Hepatitis B (HepB) Vaccine The hepatitis B vaccine is 80 to 100% effective in preventing infection or clinical hepatitis B in people who complete the vaccine series. For more information, see Hepatitis B Advisory Committee... read more and be advised to avoid alcohol.

The following English-language resources may be useful. Please note that The Manual is not responsible for the content of these resources.