UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Porphyria cutanea tarda and hepatoerythropoietic porphyria: Clinical manifestations and diagnosis

Authors
Ashwani K Singal, MD, MS
Karl E Anderson, MD, FACP
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

The porphyrias are metabolic disorders caused by altered activity of enzymes in the heme biosynthetic pathway. Porphyria cutanea tarda (PCT; previously called symptomatic porphyria, chemical porphyria, toxic porphyria) is the most common of the porphyrias. PCT was named by Waldenström in 1937 to emphasize the predominant cutaneous manifestations and relatively late onset of disease [1]. An earlier name for PCT was chronic hematoporphyria (assigned by Günther in 1911) [2].

This topic review discusses the pathogenesis, clinical manifestations, and diagnostic evaluation for PCT, caused by deficient activity of uroporphyrinogen decarboxylase (UROD) in the liver, with heterozygous UROD mutation sometimes contributing, and hepatoerythropoietic (HEP), an extremely rare condition caused by biallelic UROD mutation.

The management and prognosis of PCT and HEP are discussed in detail separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis".)

Additional topic reviews discuss the other cutaneous, neurovisceral, and combined cutaneous/neurovisceral porphyrias:

Cutaneous – (See "Congenital erythropoietic porphyria" and "Erythropoietic protoporphyria and X-linked protoporphyria".)

                           

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Apr 2017. | This topic last updated: Oct 05, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Waldenstrom J. Studien über porphyrie. Acta Med Scand 1937; Suppl82.
  2. Gunther H. Die hämatoporphyrie. Dtsh Arch Klin Med 1911; 105:89.
  3. Elder GH, Smith SG, Herrero C, et al. Hepatoerythropoietic porphyria: a new uroporphyrinogen decarboxylase defect or homozygous porphyria cutanea tarda? Lancet 1981; 1:916.
  4. de Verneuil H, Sassa S, Kappas A. Purification and properties of uroporphyrinogen decarboxylase from human erythrocytes. A single enzyme catalyzing the four sequential decarboxylations of uroporphyrinogens I and III. J Biol Chem 1983; 258:2454.
  5. Jackson AH, Sancovich HA, Ferramola AM, et al. Macrocyclic intermediates in the biosynthesis of porphyrins. Philos Trans R Soc Lond B Biol Sci 1976; 273:191.
  6. Elder GH. Porphyria cutanea tarda and related disorders. In: The Porphyrin Handbook, Kadish K, Smith K, Guilard R (Eds), Elsevier Science, San Diego 2003. Vol 14, p.67.
  7. Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: The Metabolic and Molecular Basis of Inherited Disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, et al. (Eds), McGraw-Hill, New York 2001. p.2991.
  8. Magnus IA. Cutaneous porphyria. Clin Haematol 1980; 9:273.
  9. Lim HW, Poh-Fitzpatrick MB, Gigli I. Activation of the complement system in patients with porphyrias after irradiation in vivo. J Clin Invest 1984; 74:1961.
  10. Lançoni G, Ravinal RC, Costa RS, Roselino AM. Mast cells and transforming growth factor-beta expression: a possible relationship in the development of porphyria cutanea tarda skin lesions. Int J Dermatol 2008; 47:575.
  11. Jalil S, Grady JJ, Lee C, Anderson KE. Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin Gastroenterol Hepatol 2010; 8:297.
  12. Badenas C, To-Figueras J, Phillips JD, et al. Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives. Clin Genet 2009; 75:346.
  13. Meguro K, Fujita H, Ishida N, et al. Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria. J Invest Dermatol 1994; 102:681.
  14. Cantatore-Francis JL, Cohen-Pfeffer J, Balwani M, et al. Hepatoerythropoietic porphyria misdiagnosed as child abuse: cutaneous, arthritic, and hematologic manifestations in siblings with a novel UROD mutation. Arch Dermatol 2010; 146:529.
  15. Méndez M, Poblete-Gutiérrez P, García-Bravo M, et al. Molecular heterogeneity of familial porphyria cutanea tarda in Spain: characterization of 10 novel mutations in the UROD gene. Br J Dermatol 2007; 157:501.
  16. Garey JR, Hansen JL, Harrison LM, et al. A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda. Blood 1989; 73:892.
  17. McManus JF, Begley CG, Sassa S, Ratnaike S. Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria. Blood 1996; 88:3589.
  18. Moran-Jimenez MJ, Ged C, Romana M, et al. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J Hum Genet 1996; 58:712.
  19. Mendez M, Sorkin L, Rossetti MV, et al. Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles. Am J Hum Genet 1998; 63:1363.
  20. Phillips JD, Whitby FG, Stadtmueller BM, et al. Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Transl Res 2007; 149:85.
  21. Phillips JD, Bergonia HA, Reilly CA, et al. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci U S A 2007; 104:5079.
  22. Gorman N, Zaharia A, Trask HS, et al. Effect of an oral iron chelator or iron-deficient diets on uroporphyria in a murine model of porphyria cutanea tarda. Hepatology 2007; 46:1927.
  23. Nakano K, Ishizuka M, Sakamoto KQ, Fujita S. Absolute requirement for iron in the development of chemically induced uroporphyria in mice treated with 3-methylcholanthrene and 5-aminolevulinate. Biometals 2009; 22:345.
  24. Ajioka RS, Phillips JD, Weiss RB, et al. Down-regulation of hepcidin in porphyria cutanea tarda. Blood 2008; 112:4723.
  25. Turnbull A, Baker H, Vernon-Roberts B, Magnus IA. Iron metabolism in porphyria cutanea tarda and in erythropoietic protoporphyria. Q J Med 1973; 42:341.
  26. Grossman ME, Bickers DR, Poh-Fitzpatrick MB, et al. Porphyria cutanea tarda. Clinical features and laboratory findings in 40 patients. Am J Med 1979; 67:277.
  27. Stölzel U, Köstler E, Koszka C, et al. Low prevalence of hepatitis C virus infection in porphyria cutanea tarda in Germany. Hepatology 1995; 21:1500.
  28. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998; 27:1661.
  29. HALLEN J, KROOK H. Follow-up studies on an unselected ten-year material of 360 patients with liver cirrhosis in one community. Acta Med Scand 1963; 173:479.
  30. Harrison-Findik DD, Klein E, Crist C, et al. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 2007; 46:1979.
  31. Ohtake T, Saito H, Hosoki Y, et al. Hepcidin is down-regulated in alcohol loading. Alcohol Clin Exp Res 2007; 31:S2.
  32. Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepatol 2003; 39:620.
  33. Gumber SC, Chopra S. Hepatitis C: a multifaceted disease. Review of extrahepatic manifestations. Ann Intern Med 1995; 123:615.
  34. Sinclair PR, Bement WJ, Bonkovsky HL, Sinclair JF. Inhibition of uroporphyrinogen decarboxylase by halogenated biphenyls in chick hepatocyte cultures. Essential role for induction of cytochrome P-448. Biochem J 1984; 222:737.
  35. Smith AG, Francis JE. Chemically-induced formation of an inhibitor of hepatic uroporphyrinogen decarboxylase in inbred mice with iron overload. Biochem J 1987; 246:221.
  36. Korenaga M, Okuda M, Otani K, et al. Mitochondrial dysfunction in hepatitis C. J Clin Gastroenterol 2005; 39:S162.
  37. Miura K, Taura K, Kodama Y, et al. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 2008; 48:1420.
  38. Wissel PS, Sordillo P, Anderson KE, et al. Porphyria cutanea tarda associated with the acquired immune deficiency syndrome. Am J Hematol 1987; 25:107.
  39. Drobacheff C, Derancourt C, Van Landuyt H, et al. Porphyria cutanea tarda associated with human immunodeficiency virus infection. Eur J Dermatol 1998; 8:492.
  40. Castanet J, Lacour JP, Bodokh J, et al. Porphyria cutanea tarda in association with human immunodeficiency virus infection: it is related to hepatitis C virus infection? Arch Dermatol 1994; 130:664.
  41. Mansourati FF, Stone VE, Mayer KH. Porphyria cutanea tarda and HIV/AIDS: a review of pathogenesis, clinical manifestations and management. Int J STD AIDS 1999; 10:51.
  42. Rajka G. Pregnancy and porphyria cutanea tarda. Acta Derm Venereol 1984; 64:444.
  43. Goerz G, Hammer G. Porphyria cutanea tarda and pregnancy. Dermatologica 1983; 166:316.
  44. Egger NG, Goeger DE, Payne DA, et al. Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Dig Dis Sci 2002; 47:419.
  45. Roenigk HH Jr, Gottlob ME. Estrogen-induced porphyria cutanea tarda. Report of three cases. Arch Dermatol 1970; 102:260.
  46. Wang MY, Liehr JG. Identification of fatty acid hydroperoxide cofactors in the cytochrome P450-mediated oxidation of estrogens to quinone metabolites. Role and balance of lipid peroxides during estrogen-induced carcinogenesis. J Biol Chem 1994; 269:284.
  47. Fontanellas A, Martínez-Fresno M, Garrido-Astray MC, et al. Smoking but not homozygosity for CYP1A2 g-163A allelic variant leads to earlier disease onset in patients with sporadic porphyria cutanea tarda. Exp Dermatol 2010; 19:e326.
  48. Christiansen L, Bygum A, Jensen A, et al. Association between CYP1A2 polymorphism and susceptibility to porphyria cutanea tarda. Hum Genet 2000; 107:612.
  49. Wickliffe JK, Abdel-Rahman SZ, Lee C, et al. CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda. Mol Med 2011; 17:241.
  50. Bulaj ZJ, Phillips JD, Ajioka RS, et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 2000; 95:1565.
  51. Stuart KA, Busfield F, Jazwinska EC, et al. The C282Y mutation in the haemochromatosis gene (HFE) and hepatitis C virus infection are independent cofactors for porphyria cutanea tarda in Australian patients. J Hepatol 1998; 28:404.
  52. Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology 2007; 46:1071.
  53. Rossmann-Ringdahl I, Olsson R. Porphyria cutanea tarda in a Swedish population: risk factors and complications. Acta Derm Venereol 2005; 85:337.
  54. Lee SC, Yun SJ, Lee JB, et al. A case of porphyria cutanea tarda in association with idiopathic myelofibrosis and CREST syndrome. Br J Dermatol 2001; 144:182.
  55. Anderson KE, Goeger DE, Carson RW, et al. Erythropoietin for the treatment of porphyria cutanea tarda in a patient on long-term hemodialysis. N Engl J Med 1990; 322:315.
  56. Seubert S, Seubert A, Rumpf KW, Kiffe H. A porphyria cutanea tarda-like distribution pattern of porphyrins in plasma, hemodialysate, hemofiltrate, and urine of patients on chronic hemodialysis. J Invest Dermatol 1985; 85:107.
  57. SCHMID R. Acquired porphyria. JAMA 1963; 183:133.
  58. CAN C, NIGOGOSYAN G. Acquired toxic porphyria cutanea tarda due to hexachlorobenzene. Report of 348 cases caused by this fungicide. JAMA 1963; 183:88.
  59. Jones RE, Chelsky M. Further discussion concerning porphyria cutanea tarda and TCDD exposure. Arch Environ Health 1986; 41:100.
  60. Collins AG, Nichol AW, Elsbury S. Porphyria cutanea tarda and agricultural pesticides. Australas J Dermatol 1982; 23:70.
  61. Bleakley P, Nichol AW, Collins AG. Diazinon and porphyria cutanea tarda. Med J Aust 1979; 1:314.
  62. Harber LC, Bickers DR. Photosensitivity diseases: principles of diagnosis and treatment, WB Saunders, Philadelphia 1981. p.189.
  63. Mykletun M, Aarsand AK, Støle E, et al. Porphyrias in Norway. Tidsskr Nor Laegeforen 2014; 134:831.
  64. Brady JJ, Jackson HA, Roberts AG, et al. Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda. J Invest Dermatol 2000; 115:868.
  65. Horina JH, Wolf P. Epoetin for severe anemia in hepatoerythropoietic porphyria. N Engl J Med 2000; 342:1294.
  66. Mascaro JM. The porphyrias: a brief overview based on 25 years of experience (1969-1994) by the Department of Dermatology of the Hospital Clinic and Faculty of Medicine of Barcelona, Spain. J Dermatol 1995; 22:823.
  67. Andersen J, Gjengedal E, Sandberg S, Råheim M. A skin disease, a blood disease or something in between? An exploratory focus group study of patients' experiences with porphyria cutanea tarda. Br J Dermatol 2015; 172:223.
  68. Stevens HP, Ostlere LS, Black CM, Rustin MH. Generalized morphoea secondary to porphyria cutanea tarda. Br J Dermatol 1993; 129:455.
  69. Khayat R, Dupuy A, Pansé I, et al. [Sclerodermatous changes in porphyria cutanea tarda: six cases]. Ann Dermatol Venereol 2013; 140:589.
  70. Cortés JM, Oliva H, Paradinas FJ, Hernandez-Guío C. The pathology of the liver in porphyria cutanea tarda. Histopathology 1980; 4:471.
  71. Kordac V. Frequency of occurrence of hepatocellular carcinoma in patients with porphyria cutanea tarda in long-term follow-up. Neoplasma 1972; 19:135.
  72. Linet MS, Gridley G, Nyrén O, et al. Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol 1999; 149:1010.
  73. Fakan F, Chlumská A. Demonstration of needle-shaped hepatic inclusions in porphyria cutanea tarda using the ferric ferricyanide reduction test. Virchows Arch A Pathol Anat Histopathol 1987; 411:365.
  74. Chlumska A, Chlumsky J, Malina L. Liver changes in porphyria cutanea tarda patients treated with chloroquine. Br J Dermatol 1980; 102:261.
  75. Bygum A, Brandrup F. Iron overload in porphyria cutanea tarda. Br J Dermatol 2000; 143:1116.
  76. Bonkovsky HL, Lambrecht RW, Shan Y. Iron as a co-morbid factor in nonhemochromatotic liver disease. Alcohol 2003; 30:137.
  77. Lundvall O, Weinfeld A, Lundin P. Iron storage in porphyria cutanea tarda. Acta Med Scand 1970; 1-2:37.
  78. Elder GH. Porphyrin metabolism in porphyria cutanea tarda. Semin Hematol 1977; 14:227.
  79. Sampietro M, Fiorelli G, Fargion S. Iron overload in porphyria cutanea tarda. Haematologica 1999; 84:248.
  80. Dereure O, Jumez N, Bessis D, et al. Measurement of liver iron content by magnetic resonance imaging in 20 patients with overt porphyria cutanea tarda before phlebotomy therapy: a prospective study. Acta Derm Venereol 2008; 88:341.
  81. Anderson KE, Goeger DE, Bessman JD. Asymptomatic erythrocyte disorder presenting as increased porphobilinogen deaminase and uroporphyrinogen decarboxylase. Clin Chem 1995; 41:1670.
  82. Day RS, Strauss PC. Severe cutaneous porphyria in a 12-year-old boy: hepatoerythropoietic or symptomatic porphyria? Arch Dermatol 1982; 118:663.
  83. Maynard B, Peters MS. Histologic and immunofluorescence study of cutaneous porphyrias. J Cutan Pathol 1992; 19:40.
  84. Deacon AC, Elder GH. ACP Best Practice No 165: front line tests for the investigation of suspected porphyria. J Clin Pathol 2001; 54:500.
  85. Lim HW, Poh-Fitzpatrick MB. Hepatoerythropoietic porphyria: a variant of childhood-onset porphyria cutanea tarda. Porphyrin profiles and enzymatic studies of two cases in a family. J Am Acad Dermatol 1984; 11:1103.
  86. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol 2006; 135:281.
  87. Boudghène-Stambouli O, Mérad-Boudia A. [Hepato-erythropoietic porphyria]. Ann Dermatol Venereol 1995; 122:615.
  88. Hindmarsh JT, Oliveras L, Greenway DC. Plasma porphyrins in the porphyrias. Clin Chem 1999; 45:1070.
  89. O'Reilly K, Snape J, Moore MR. Porphyria cutanea tarda resulting from primary hepatocellular carcinoma. Clin Exp Dermatol 1988; 13:44.
  90. Ochiai T, Morishima T, Kondo M. Symptomatic porphyria secondary to hepatocellular carcinoma. Br J Dermatol 1997; 136:129.