eMedicine Specialties > Dermatology > Metabolic Diseases

Erythropoietic Protoporphyria

Author: Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee
Contributor Information and Disclosures

Updated: Feb 23, 2009

Introduction

Background

Erythropoietic protoporphyria is a genetic disorder 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: a distinctive cutaneous photosensitivity and hepatobiliary disease.1,3,4,5 The predominant genotype associated with phenotypic expression is one mutant ferrochelatase allele encoding a defective protein, with little or no function coupled with a normal variant allele with low gene expression.6,7 Uncommonly, 2 deleterious mutations have been found in symptomatic individuals.8,9 Rarely, acquired somatic mutation or deletion of a ferrochelatase gene secondary to myelodysplastic or myeloproliferative disorders leads to adult-onset protoporphyric disease.10,11,12

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,13 resulting in immediate phototoxic symptoms variously described as tingling, stinging, or burning that may be followed by the appearance of erythema, edema, and purpura.3,13 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.14 Protoporphyrin escapes from red blood cells into the plasma, from which it is cleared by the liver and secreted into bile. Protoporphyrin-rich bile predisposes the person to gallstone formation.15 Toxic effects of protoporphyrin deposition in the liver may lead to life-threatening hepatic dysfunction.15,16,17

Frequency

United States

No registry for erythropoietic protoporphyria is kept for the United States; therefore, accurate data are lacking.

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

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 ancestry, but also in Japanese, Chinese, East Indian, and African American people.

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.10,11,12 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.15,17,18,19,20

Clinical

History

Uncomfortable sensations in skin exposed to sunlight typically begin during infancy or childhood, most often involving dorsal hands, the face and ears, and, occasionally, legs and dorsal feet, after short periods of exposure. If exposure is promptly discontinued, visible skin lesions may not ensue. Longer exposure, or multiple exposures on sequential days, can elicit swelling with or without redness in the exposed skin that evolves into sheets of petechiae. This exquisitely painful reaction resolves over several days to leave skin that may appear normal. Eventually, chronic changes may develop that are highly suggestive, but, when subtle, can be overlooked.

Individuals with protoporphyria who report skin pain but have minimal objective findings may be considered malingerers until an acute reaction is observed. Gallstones may remain silent or evoke reports of indigestion and/or right upper quadrant abdominal pain consistent with symptomatic cholelithiasis. Individuals with protoporphyria associated with hepatotoxicity may report loss of appetite, nausea, vomiting, weakness and fatigue, anorexia, malaise, weight changes, increasing abdominal girth, pain in the epigastrium or right upper quadrant and back, jaundice, and increasing photosensitivity.

Physical

The acute phototoxic reaction typically includes edema, erythema, and petechiae. Blisters, crusted erosions, and scarring may occur but are less florid and less frequent than in other porphyrias. Chronic changes include shallow, elongated depressions in facial skin, especially over the nose; perioral furrowing; and prematurely aged, thickened, or coarsely textured skin of the dorsal hands, often most prominent over the knuckles. In more severe cases, sclerodermalike waxy induration or a cobblestone texture of the face and hands develops. Mechanical fragility, when present, is less severe than in other porphyrias; hypertrichosis is infrequent.

With progressive liver dysfunction, hepatosplenomegaly and jaundice may develop, as may signs of increasing cutaneous photosensitivity. End-stage liver disease is signaled by intense jaundice, ascites, vomiting, fever, encephalopathy, axonal polyneuropathy that may progress to paresis and respiratory failure, hemorrhage from esophageal varices, and extreme photosensitivity.

Causes

The ferrochelatase gene is located on band 18q21.3.21 Ferrochelatase mutations listed at the Human Gene Mutation Database numbered 112 as of November 2008.

Loss of ferrochelatase activity by as much as 50% as the result of 1 mutant gene is generally insufficient to cause overt disease when its complementary allele has normal function.6 Ferrochelatase genotypes composed of either 2 mutant alleles (approximately 4% of cases) or 1 mutation and a nonmutant allele with a specific intronic single nucleotide polymorphism (IVS3-48C) (approximately 95% of cases) have been found in most symptomatic individuals.8,9  This polymorphism enhances aberrant splicing and rapid degradation of ferrochelatase mRNA, with resultant low expression.7

The prevalence of this polymorphism in populations studied varies widely, as follows:

  • Japanese - 43%
  • Southeast Asian - 31%
  • White French - 11%
  • North African - 2.7%
  • Black West African - <1%9
  • American - 7%22
  • South Africans of European descent - 9%2

The pairing of a mutated allele encoding a severely impaired enzyme protein with this low-expressing polymorphic allele typically yields enzyme activity diminished to less than 30% of normal, low enough to cause protoporphyrin accumulation. Individuals heteroallelic or homoallelic for this polymorphism do not have sufficiently diminished ferrochelatase activity to cause clinical abnormalities, although their erythrocyte protoporphyrin levels may be mildly abnormal.2

Adult-onset protoporphyric photosensitivity and increased protoporphyrin levels have been associated with an acquired somatic mutation or deletion of a ferrochelatase gene due to myelodysplastic or myeloproliferative disorders.10,11,12

More on Erythropoietic Protoporphyria

Overview: Erythropoietic Protoporphyria
Differential Diagnoses & Workup: Erythropoietic Protoporphyria
Treatment & Medication: Erythropoietic Protoporphyria
Follow-up: Erythropoietic Protoporphyria
References
[ CLOSE WINDOW ]

References

  1. Cox TM. Erythropoietic protoporphyria. J Inherit Metab Dis. Jun 1997;20(2):258-69. [Medline].

  2. Parker M, Corrigall AV, Hift RJ, Meissner PN. Molecular characterization of erythropoietic protoporphyria in South Africa. Br J Dermatol. Jul 2008;159(1):182-91. [Medline].

  3. DeLeo VA, Poh-Fitzpatrick M, Mathews-Roth M, Harber LC. Erythropoietic protoporphyria. 10 years experience. Am J Med. Jan 1976;60(1):8-22. [Medline].

  4. Baart de la Faille H, Bijlmer-Iest JC, van Hattum J, Koningsberger J, Rademakers LH, van Weelden H. Erythropoietic protoporphyria: clinical aspects with emphasis on the skin. Curr Probl Dermatol. 1991;20:123-34. [Medline].

  5. Todd DJ. Erythropoietic protoporphyria. Br J Dermatol. Dec 1994;131(6):751-66. [Medline].

  6. Gouya L, Puy H, Lamoril J, et al. Inheritance in erythropoietic protoporphyria: a common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation. Blood. Mar 15 1999;93(6):2105-10. [Medline].

  7. Gouya L, Puy H, Robreau AM, et al. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet. Jan 2002;30(1):27-8. [Medline].

  8. Whatley SD, Mason NG, Khan M, et al. Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease. J Med Genet. Aug 2004;41(8):e105. [Medline].

  9. Gouya L, Martin-Schmitt C, Robreau AM, et al. Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Am J Hum Genet. Jan 2006;78(1):2-14. [Medline].

  10. Goodwin RG, Kell WJ, Laidler P, et al. Photosensitivity and acute liver injury in myeloproliferative disorder secondary to late-onset protoporphyria caused by deletion of a ferrochelatase gene in hematopoietic cells. Blood. Jan 1 2006;107(1):60-2. [Medline].

  11. Poh-Fitzpatrick MB, Wang X, Anderson KE, Bloomer JR, Bolwell B, Lichtin AE. Erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations. J Am Acad Dermatol. Jun 2002;46(6):861-6. [Medline].

  12. Aplin C, Whatley SD, Thompson P, et al. Late-onset erythropoietic porphyria caused by a chromosome 18q deletion in erythroid cells. J Invest Dermatol. Dec 2001;117(6):1647-9. [Medline].

  13. Poh-Fitzpatrick MB. Porphyrin-sensitized cutaneous photosensitivity: pathogenesis and treatment. Clin Dermatol. Apr-Jun 1985;3(2):41-82. [Medline].

  14. Piomelli S, Lamola AA, Poh-Fitzpatrick MF, Seaman C, Harber LC. Erythropoietic protoporphyria and lead intoxication: the molecular basis for difference in cutaneous photosensitivity. I. Different rates of disappearance of protoporphyrin from the erythrocytes, both in vivo and in vitro. J Clin Invest. Dec 1975;56(6):1519-27. [Medline].

  15. Bloomer JR. The liver in protoporphyria. Hepatology. Mar-Apr 1988;8(2):402-7. [Medline].

  16. Gross U, Frank M, Doss MO. Hepatic complications of erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. Apr 1998;14(2):52-7. [Medline].

  17. Anstey AV, Hift RJ. Liver disease in erythropoietic protoporphyria: insights and implications for management. Gut. Jul 2007;56(7):1009-18. [Medline].

  18. Cripps DJ, Gilbert LA, Goldfarb SS. Erythropoietic protoporphyria: juvenile protoporphyrin hepatopathy cirrhosis and death. J Pediatr. Nov 1977;91(5):744-8. [Medline].

  19. Rand EB, Bunin N, Cochran W, Ruchelli E, Olthoff KM, Bloomer JR. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics. Dec 2006;118(6):e1896-9. [Medline].

  20. McGuire BM, Bonkovsky HL, Carithers RL Jr, et al. Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl. Dec 2005;11(12):1590-6. [Medline].

  21. Brenner DA, Didier JM, Frasier F, Christensen SR, Evans GA, Dailey HA. A molecular defect in human protoporphyria. Am J Hum Genet. Jun 1992;50(6):1203-10. [Medline].

  22. Risheg H, Chen FP, Bloomer JR. Genotypic determinants of phenotype in North American patients with erythropoietic protoporphyria. Mol Genet Metab. Sep-Oct 2003;80(1-2):196-206. [Medline].

  23. Gross U, Frank M, Doss MO. Hepatic complications of erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. Apr 1998;14(2):52-7. [Medline].

  24. Doss MO, Frank M. Hepatobiliary implications and complications in protoporphyria, a 20-year study. Clin Biochem. Jun 1989;22(3):223-9. [Medline].

  25. Poh-Fitzpatrick MB, Whitlock RT, Leftkowitch JH. Changes in protoporphyrin distribution dynamics during liver failure and recovery in a patient with protoporphyria and Epstein-Barr viral hepatitis. Am J Med. May 1986;80(5):943-50. [Medline].

  26. Mathews-Roth MM. Letter: Anemia in erythropoietic protoporphyria. JAMA. Nov 11 1974;230(6):824. [Medline].

  27. Wahlin S, Aschan J, Bjornstedt M, Broomé U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol. Jan 2007;46(1):174-9. [Medline].

  28. Wolff K, Honigsmann H, Rauschmeier W, Schuler G, Pechlaner R. Microscopic and fine structural aspects of porphyrias. Acta Derm Venereol Suppl (Stockh). 1982;100:17-28. [Medline].

  29. Epstein JH, Tuffanelli DL, Epstein WL. Cutaneous changes in the porphyrias. A microscopic study. Arch Dermatol. May 1973;107(5):689-98. [Medline].

  30. Bloomer JR, Rank JM, Payne WD, et al. Follow-up after liver transplantation for protoporphyric liver disease. Liver Transpl Surg. Jul 1996;2(4):269-75. [Medline].

  31. Johnson JA, Fusaro RM. Broad-spectrum photoprotection: the roles of tinted auto windows, sunscreens and browning agents in the diagnosis and treatment of photosensitivity. Dermatology. 1992;185(4):237-41. [Medline].

  32. Roelandts R. Photo(chemo)therapy and general management of erythropoietic protoporphyria. Dermatology. 1995;190(4):330-1. [Medline].

  33. Mathews-Roth MM, Pathak UA, Fitzpatrick TB, Harber LC, Kass EH. Beta-carotene as an oral photoprotective agent in erythropoietic protoporphyria. JAMA. May 20 1974;228(8):1004-8. [Medline].

  34. Mathews-Roth MM. Carotenoid functions in photoprotection and cancer prevention. J Environ Pathol Toxicol Oncol. Jul-Oct 1990;10(4-5):181-92. [Medline].

  35. Mathews-Roth MM, Rosner B. Long-term treatment of erythropoietic protoporphyria with cysteine. Photodermatol Photoimmunol Photomed. Dec 2002;18(6):307-9. [Medline].

  36. Ross JB, Moss MA. Relief of the photosensitivity of erythropoietic protoporphyria by pyridoxine. J Am Acad Dermatol. Feb 1990;22(2 Pt 2):340-2. [Medline].

  37. Farr PM, Diffey BL, Matthews JN. Inhibition of photosensitivity in erythropoietic protoporphyria with terfenadine. Br J Dermatol. Jun 1990;122(6):809-15. [Medline].

  38. Yamamoto S, Hirano Y, Horie Y. Cimetidine reduces erythrocyte protoporphyrin in erythropoietic protoporphyria. Am J Gastroenterol. Sep 1993;88(9):1465-6. [Medline].

  39. McCullough AJ, Barron D, Mullen KD, et al. Fecal protoporphyrin excretion in erythropoietic protoporphyria: effect of cholestyramine and bile acid feeding. Gastroenterology. Jan 1988;94(1):177-81. [Medline].

  40. Gorchein A, Foster GR. Liver failure in protoporphyria: long-term treatment with oral charcoal. Hepatology. Mar 1999;29(3):995-6. [Medline].

  41. van Wijk HJ, van Hattum J, Baart de la Faille H, van den Berg JW, Edixhoven-Bosdijk A, Wilson JH. Blood exchange and transfusion therapy for acute cholestasis in protoporphyria. Dig Dis Sci. Dec 1988;33(12):1621-5. [Medline].

  42. Dellon ES, Szczepiorkowski ZM, Dzik WH, et al. Treatment of recurrent allograft dysfunction with intravenous hematin after liver transplantation for erythropoietic protoporphyria. Transplantation. Mar 27 2002;73(6):911-5. [Medline].

  43. Do KD, Banner BF, Katz E, Szymanski IO, Bonkovsky HL. Benefits of chronic plasmapheresis and intravenous heme-albumin in erythropoietic protoporphyria after orthotopic liver transplantation. Transplantation. Feb 15 2002;73(3):469-72. [Medline].

  44. Gordeuk VR, Brittenham GM, Hawkins CW, Mukhtar H, Bickers DR. Iron therapy for hepatic dysfunction in erythropoietic protoporphyria. Ann Intern Med. Jul 1986;105(1):27-31. [Medline].

  45. McClements BM, Bingham A, Callender ME, Trimble ER. Erythropoietic protoporphyria and iron therapy. Br J Dermatol. Mar 1990;122(3):423-4. [Medline].

  46. Komatsu H, Ishii K, Imamura K, et al. A case of erythropoietic protoporphyria with liver cirrhosis suggesting a therapeutic value of supplementation with alpha-tocopherol. Hepatol Res. Nov 2000;18(3):298-309. [Medline].

  47. Eichbaum QG, Dzik WH, Chung RT, Szczepiorkowski ZM. Red blood cell exchange transfusion in two patients with advanced erythropoietic protoporphyria. Transfusion. Feb 2005;45(2):208-13. [Medline].

  48. Shehade SA, Chalmers RJ, Prescott RJ. Predictable and unpredictable hazards of erythropoietic protoporphyria. Clin Exp Dermatol. May 1991;16(3):185-7. [Medline].

  49. Herbert A, Corbin D, Williams A, Thompson D, Buckels J, Elias E. Erythropoietic protoporphyria: unusual skin and neurological problems after liver transplantation. Gastroenterology. Jun 1991;100(6):1753-7. [Medline].

  50. Meerman L, Verwer R, Slooff MJ, et al. Perioperative measures during liver transplantation for erythropoietic protoporphyria. Transplantation. Jan 1994;57(1):155-8. [Medline].

  51. Morris SD, Mason NG, Elder GH, Hawk JL, Sarkany RP. Ferrochelatase gene polymorphism analysis for accurate genetic counselling in erythropoietic protoporphyria. Br J Dermatol. Sep 2002;147(3):572-4. [Medline].

  52. Schneider-Yin X, Gouya L, Meier-Weinand A, Deybach JC, Minder EI. New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care. Eur J Pediatr. Oct 2000;159(10):719-25. [Medline].

  53. Redeker AG, Sterling RE. The "glucose effect" in erythropoietic protoporphyria. Arch Intern Med. May 1968;121(5):446-8. [Medline].

  54. Bonkovsky HL, Schned AR. Fatal liver failure in protoporphyria. Synergism between ethanol excess and the genetic defect. Gastroenterology. Jan 1986;90(1):191-201. [Medline].

  55. Rank JM, Carithers R, Bloomer J. Evidence for neurological dysfunction in end-stage protoporphyric liver disease. Hepatology. Dec 1993;18(6):1404-9. [Medline].

  56. Poh-Fitzpatrick MB. Human protoporphyria: reduced cutaneous photosensitivity and lower erythrocyte porphyrin levels during pregnancy. J Am Acad Dermatol. Jan 1997;36(1):40-3. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

erythropoietic protoporphyria, erythrohepatic protoporphyria, congenital erythropoietic protoporphyria, protoporphyria, porphyria, light sensitivity, photoprotection, end-stage liver disease, endstage liver disease, ESLD, ferrochelatase, FECH

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee
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: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

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
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.

Managing Editor

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.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine 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.

RELATED MEDSCAPE ARTICLES
Articles
 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.