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Erythropoietic protoporphyria
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
In this metabolic disorder, a genetically determined ferrochelatase enzyme deficiency in bone marrow erythroid cells causes excessive protoporphyrin levels in erythrocytes, plasma, liver, bile, and feces. Protoporphyrin is a photoactive heme synthesis intermediary. In the skin, its exposure to long-wave ultraviolet (UV) or visible-light radiation can elicit oxygen-dependent acute cutaneous phototoxicity. Protoporphyrin undergoes hepatobiliary excretion, facilitating cholelithiasis. Protoporphyrin hepatotoxicity may progress to irreversible liver failure. Hypochromic microcytic anemia, when present, is typically mild and infrequently requires treatment. A rare, phenotypically similar disorder, X-linked dominant protoporphyria (XLP), caused by gain-of-function mutations in the erythroid-specific 5-aminolevulinic acid synthase gene, has a larger ratio of erythrocyte zinc-protoporphyrin to metal-free protoporphyrin than does erythropoietic protoporphyria (EPP). It is generally amenable to the same therapies.
Management Strategy
Protoporphyric photosensitivity typically requires sun avoidance (lifestyle changes, protective clothing, physical barriers), which may lead to vitamin D deficiency. Topical sunscreens containing titanium dioxide , zinc oxide , iron oxide , or dihydroxyacetone block or filter long-wave ultraviolet (UV) and visible-light spectra but offer limited relief. Patients sensitive to light from computer, television, or phone screens or room lighting may benefit from eliminating or filtering offending devices ( https://en.wikipedia.org/wiki/Erythropoietic_protoporphyria ).
Epidermal melanization and hyperplasia achieved with ultraviolet B (UVB) phototherapy, or an α-melanocyte–stimulating hormone analog (afamelanotide), can increase sunlight tolerance. Oral agents believed to photoprotect by quenching excited oxygen species include β - carotene, cysteine, vitamin E, and vitamin C . Antihistamines may attenuate phototoxic flaring. Gallstones are managed surgically. Exacerbators of protoporphyrin-induced hepatotoxicity (alcohol, cholestatic drugs [including medicinal estrogens], dietary carbohydrate restriction) are best avoided. Vaccination against hepatitis A and B is recommended. Deteriorating liver function is only sporadically reversible by enteric sorbents ( cholestyramine, activated charcoal ) that interrupt enterohepatic porphyrin circulation, bile acids (to stimulate biliary protoporphyrin secretion), blood transfusion or exchange , hematin infusion, glucose loading (to retard endogenous porphyrinogenesis), iron (to increase protoporphyrin conversion to heme), or various combinations thereof. Cimetidine is postulated to inhibit porphyrinogenesis. End-stage liver disease warrants liver transplantation, aided by measures to reduce preoperative, intraoperative, and postoperative porphyrin levels ( exchange transfusion, hematin infusion, plasmapheresis, vitamin E ). Operating room lamps should be filtered to exclude wavelengths damaging to porphyrin-photosensitized skin and internal organs. Hematopoietic cell transplantation has been curative in highly selected cases and is optimal prevention for protoporphyric hepatopathy in native or transplanted livers.
Specific Investigations
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Liver failure occurs in <5% of all cases. Because urine is typically free of excess porphyrins in uncomplicated protoporphyria, surveillance for coproporphyrinuria may discover patients with asymptomatic hepatic dysfunction.
Erythropoietic protoporphyria
Lecha M, Puy H, Deybach JC. Orphanet J Rare Dis 2009. doi: 10.1186/1750-1172-4-19.
Erythropoietic protoporphyria and X-linked protoporphyria: pathophysiology, genetics, clinical manifestations, and management
Balwani M. Mol Genet Metab 2019. doi.org/10.1016/j.ymgme.2019.01.020 [Epub ahead of print].
Efficiency of opaque photoprotective agents in the visible light range
Kaye ET, Levin JA, Blank IH, et al. Arch Dermatol 1991; 127: 351–5.
Efficacy and cosmetic quality of sunscreens containing zinc oxide, titanium dioxide, and iron oxide.
Erythropoietic protoporphyria: IV. Protection from sunlight
Fusaro RM, Runge WJ. Br Med J 1970; 1: 730–1.
Seven patients had prolonged sunlight tolerance after applying a 3% dihydroxyacetone and 0.13% lawsone skin cream causing stratum corneum browning.
Beta-carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases
Mathews-Roth MM, Pathak MA, Fitzpatrick TB, et al. Arch Dermatol 1977; 113: 1229–32.
Of 133 patients with EPP, 84% had a threefold increase in sunlight tolerance after ingesting pharmaceutical-grade β-carotene now available without prescription (Lumitene, Tishcon Corp.).
Doses producing serum levels of ≈800 mcg/dL (children: 30–120 mg/day, adults: 120–300 mg/day, in 2–3 mealtime doses) should be started 4–6 weeks before seasonal symptoms are anticipated. Efficacy varies and is often nil. Contraindicated in smokers due to increased lung cancer among heavy smokers treated with β-carotene in cancer prevention trials.
Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria
Biolcati G, Marchesini E, Sorge F, et al. Br J Dermatol 2015; 172: 1601–12.
Afamelanotide for erythropoietic protoporphyria
Langendonk JG, Balwani M, Anderson KE, et al. N Engl J Med 2015; 373: 48–59.
Afamelanotide increases skin melanization and may have other beneficial effects. Clinical trials of a subcutaneously implantable form have involved ≈3 00 protoporphyria patients worldwide. Approved for prevention of phototoxicity in adults with EPP by the European Medicines Agency (2014), and by the US Food and Drug Administration (2019).
Osteoporosis in patients with erythropoietic protoporphyria
Biewenga M, Matawlie RHS, Friesema ECF, et al. Br J Dermatol 2017; 177: 1693–8.
Among 44 EPP patients, 50% had low plasma vitamin D and 59% had low bone mineral density. Osteopenia/osteoporosis mitigation by following fracture-prevention measures including vitamin D and calcium supplementation and increased bone-strengthening physical activity is recommended.
Narrow-band (TL-01) UVB phototherapy: an effective preventative treatment for the photodermatoses
Collins P, Ferguson J. Br J Dermatol 1995; 132: 956–63.
Six EPP patients had increased sunlight tolerance after serial narrowband UVB treatments.
Long-term treatment of erythropoietic protoporphyria with cysteine
Mathews-Roth MM, Rosner B. Photodermatol Photoimmunol Photomed 2002; 18: 307–9.
Forty-seven patients received cysteine 500 mg twice daily in this phase III 3-year trial. Patient history and light exposure diaries were kept; some patients were phototested. Cysteine significantly increased light tolerance subjectively and objectively.
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