Erythropoietic Protoporphyria 

  • Author: Maureen B Poh-Fitzpatrick, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Aug 5, 2010
 

Background

Erythropoietic protoporphyria is a genetic disorder most often arising from impaired activity of ferrochelatase, the ultimate enzyme of heme biosynthesis.[1, 2] The resultant accumulated excess of its substrate, protoporphyrin, causes 2 principal manifestations: (1) a distinctive acute cutaneous photosensitivity typically appearing in childhood and (2) hepatobiliary disease.[1, 3, 4, 5]

The predominant genotype associated with phenotypic expression is one mutant ferrochelatase allele encoding a defective enzyme protein with little or no function, coupled with a normal variant allele with low gene expression.[6, 7] Infrequently, 2 deleterious mutations are found in symptomatic individuals; this recessively inherited form of protoporphyria appears to impart a higher risk for hepatic dysfunction.[8, 9]

A recently described X-linked dominant form of protoporphyria arises from C-terminal deletions in the gene encoding the erythroid-specific enzyme 5-aminolevulinic acid synthase-2; increased function of this enzyme leads to overproduction of protoporphyrin with associated acute photosensitivity and increased risk for liver disease.[10]

Rarely, acquired somatic mutation or deletion of a ferrochelatase gene secondary to myelodysplastic or myeloproliferative disorders leads to an adult-onset protoporphyric disorder.[11, 12, 13]

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Pathophysiology

Protoporphyrin is a lipophilic molecule capable of transformation to excited states by absorption of light energy. Excited-state protoporphyrin mediates photoxidative damage to biomolecular targets in the skin,[14] resulting in immediate phototoxic symptoms variously described as tingling, stinging, or burning that may be followed by the appearance of erythema, edema, and purpura.[3, 14] Excess protoporphyrin is formed during maturation of erythroid cells in the bone marrow and is present at the highest levels in reticulocytes and young erythrocytes.[15] Protoporphyrin escapes from red blood cells into the plasma, from which it is cleared by the liver and secreted into bile. Protoporphyrin-rich bile facilitates gallstone formation.[16] Toxic effects of protoporphyrin deposition in the liver may lead to life-threatening hepatic dysfunction.[16, 17, 18]

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Epidemiology

Frequency

United States

Until a recently established registry for erythropoietic protoporphyria sponsored by the American Porphyria Foundation collects sufficient data, accurate enumeration in the United States cannot be provided, but is probably similar to data from European countries.

International

Estimates of 1 case in 75,000-200,000 population have been reported for some western European populations and in the South African population of European ancestry.[2, 5, 19]

Mortality/Morbidity

Painful cutaneous photosensitivity reduces the sunlight tolerance of individuals with erythropoietic protoporphyria and may influence their lifestyles over entire lifetimes.[3]

An increased prevalence of cholelithiasis in both men and women can result in signs and symptoms of gallstone disease at relatively early ages.[3]

Hepatotoxic effects of excess protoporphyrin deposition have led to liver dysfunction that progressed to life-threatening severity in approximately 2-5% of known cases.[5]

Race

Erythropoietic protoporphyria has been reported most often in people with European heritage, but it has also been reported in people with Japanese, Chinese, East Indian, or north or central African ancestry.

Sex

Protoporphyria occurs equally in males and females.

Age

Photocutaneous symptoms usually appear during childhood,[3] but they also may be noted for the first time in adult life.[11, 12, 13] Gallstones may become symptomatic in young adulthood or in middle age.[3] Liver failure and its complications, sufficiently severe to result in liver transplantation and/or death, may develop in children and adolescents as well as adults.[16, 18, 20, 21, 22]

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Contributor Information and Disclosures
Author

Maureen B Poh-Fitzpatrick, MD  Professor Emerita of Dermatology and Special Lecturer, Columbia University College of Physicians and Surgeons; Professor of Medicine (Dermatology), University of Tennessee Health Science Center College of Medicine

Maureen B Poh-Fitzpatrick, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and New York Academy of Medicine

Disclosure: Lundbeck, Inc. Honoraria Review panel membership; Clinuvel Pharmaceuticals, Ltd. Honoraria Consulting

Specialty Editor Board

Günter Burg, MD  Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland

Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association

Disclosure: Nothing to disclose.

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Edward F Chan, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

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