Erythropoietic Protoporphyria and X-linked Protoporphyria
Erythropoietic protoporphyria (EPP) is due to an inherited deficiency in the activity of the enzyme ferrochelatase, and X-linked protoporphyria (XLPP) is due to an inherited increase in the activity of delta-aminolevulinic acid synthase-2; both enzymes are in the heme biosynthetic pathway (see Table: Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency). EPP and XLPP are nearly identical clinically. They typically manifest in infancy with itching or burning skin pain after even short exposure to sunlight. Gallstones are common later in life, and chronic liver disease occurs in about 10%. Diagnosis is based on symptoms and increased levels of protoporphyrin in RBCs and plasma. Prevention is by avoidance of triggers (eg, sunlight, alcohol, fasting) and perhaps use of oral beta-carotene. Acute skin symptoms can be alleviated by cold baths or wet towels, analgesics, and topical and/or oral corticosteroids. Patients with liver failure may need liver transplantation, but liver transplantation is not curative because the predominant source of excess protoporphyrin production is the bone marrow.
Because XLPP is so similar to EPP, it is sometimes regarded as a variant of EPP. For porphyria etiology and pathophysiology, see Overview of Porphyrias.
Erythropoietic protoporphyria, which comprises about 90% of EPP phenotypic presentations results from inherited deficiency of the enzyme ferrochelatase (FECH). 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.
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; the inheritance is X-linked. The phenotype of heterozygous females can vary from asymptomatic that of affected males.
Prevalence of EPP phenotype is about 1/75,000. Protoporphyrin accumulates in bone marrow and RBCs, 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, which may progress to liver failure. A more common complication is pigment gallstones due to heavy protoporphyrin excretion.
Symptom severity in erythropoietic protoporphyria and X-linked protoporphyria varies greatly, even among patients within a single family. 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. 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, hereditary coproporphyria, and congenital erythropoietic porphyria (see Table: Some Less Common Porphyrias), 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, EPP and XLPP 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 RBC and plasma protoporphyrin levels. RBC protoporphyrin should also be fractionated to determine the proportions of metal-free and zinc protoporphyrin. In EPP, the proportion of RBC 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 showing increased RBC protoporphyrin and by genetic testing if a mutation has been identified in the index case.
Avoidance of sun exposure through use of protective clothing and opaque sunscreens
Symptomatic treatment for skin burning with cold compresses, NSAIDs, and topical and/or oral corticosteroids
Sometimes oral beta-carotene for prevention
Management of hepatobiliary complications
Afamelanotide for prevention of phototoxic events and relief of symptoms
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.
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. Beta-carotene dose depends on patient’s age (see Table: Doses of Beta-Carotene in Erythropoietic Protoporphyria).
Other drugs that also may decrease photosensitivity include afamelanotide, a synthetic analog of melanocyte stimulating hormone. Afamelanotide is currently available in parts of the European Union. In two multicenter randomized, double-blind, placebo-controlled trials (United States and European Union) in patients with erythropoietic protoporphyria, afamelanotide decreased the number of phototoxic events, decreased recovery time from phototoxic events, and improved quality of life with an acceptable adverse effect profile (1).
Drugs that trigger acute porphyrias need not be avoided (see Table: Drugs and Porphyria*).
Acute skin symptoms can be alleviated by cold baths or wet towels, analgesics, and topical and/or oral corticosteroids. 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 RBC hypertransfusion (ie, to above-normal Hb 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.
Patients who develop decompensated end-stage liver disease require liver transplantation. As with acute intermittent porphyria, 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 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 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 h) 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 RBC 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 ultrasonography every 6 mo 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.
Erythropoietic protoporphyria (EPP) causes burning pain with exposure to sunlight; symptoms are not brought on by drugs that trigger other porphyrias.
Cirrhosis develops in about 10%, sometimes progressing to liver failure.
Brief exposure to sunlight can cause severe pain, burning, erythema, and edema of exposed skin.
Measure RBC and plasma protoporphyrin levels.
Prevent symptoms by avoiding sun exposure and sometimes using drugs (eg, beta-carotene, cysteine).
Hematin and/or RBC hypertransfusion may reduce protoporphyrin overproduction.
X-linked protoporphyria (XLPP) is clinically similar to EPP, but photosensitivity and liver disease are more severe than in EPP.
A useful clue for XLPP is a high proportion of RBC protoporphyrin that is zinc protoporphyrin .