eMedicine Specialties > Dermatology > Metabolic Diseases

Variegate Porphyria: Differential Diagnoses & Workup

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 18, 2009

Differential Diagnoses

Drug-Induced Photosensitivity
Erythropoietic Protoporphyria
Epidermolysis Bullosa
Lupus Erythematosus, Bullous
Epidermolysis Bullosa Acquisita
Porphyria Cutanea Tarda
Erythropoietic Porphyria
Pseudoporphyria

Other Problems to Be Considered

Hereditary coproporphyria
Acute intermittent porphyria

Workup

Laboratory Studies

  • During active phases of variegate porphyria, urinary porphyrin levels are abnormally high, with the coproporphyrin faction larger than the uroporphyrin fraction.
  • Urinary aminolevulinic acid and porphobilinogen levels are greatly elevated during attacks but often normalize during quiescent phases.20
  • Total fecal porphyrin excretion is often high, with protoporphyrin excretion greater than coproporphyrin excretion.21
  • Erythrocyte porphyrin levels are normal in patients with heterozygosity, but when 2 mutant alleles for the protoporphyrin oxidase gene are present, the zinc protoporphyrin level is elevated.4,14,18
  • Plasma porphyrin levels are always increased in patients who are symptomatic. A fluorescence emission peak maximal at 625-627 nm detected by spectrofluorometry is unique to variegate porphyria and is a rapid means of confirming this specific diagnosis.22 Spectrofluorometry identifies such plasma porphyrin peaks in many, but not all, asymptomatic adult carriers of a protoporphyrin oxidase gene mutation, but it detects only some carriers in childhood.21
  • Porphyrin abnormalities in urine, stool, and plasma may normalize during quiescent phases, or they may remain increased at variable levels.
  • Increased biliary porphyrin levels may be the most sensitive biochemical indicator during quiescence.23
  • Because medical management of an attack is the same for all acute porphyrias, qualitative evidence of elevated porphobilinogen is sufficient to justify initiating therapies in crisis situations while quantitative assays to establish a precise diagnosis are still pending. Rapid qualitative porphobilinogen tests for screening random urine samples include modified Watson-Schwartz and Hoesch assays.24 A commercial test kit with an anion-exchange minicolumn and a color chart for rapid, specific semiquantitative porphobilinogen estimation is available (Trace PBG Kit, Thermo Fisher Scientific; Waltham, Mass).
  • Assays for protoporphyrinogen oxidase enzyme activity are technically difficult, but they are available in a few specialized porphyria  laboratories in several different countries.
  • Mutation analysis of the protoporphyrinogen oxidase gene is performed in several centers with particular interest in porphyrias, and it is commercially available in the United States. Because variegate porphyria in most individuals carrying a mutated gene remains clinically silent and may be biochemically silent, family studies aimed at identifying all adults and children at risk for developing variegate porphyria require mutation analysis for absolute certainty of identifying all carriers.

Histologic Findings

Histologic findings resembling those of porphyria cutanea tarda are well described.25,26 Bullae are subepidermal and cell poor; a mild perivascular lymphocytic inflammatory infiltrate may be present. Thickened, hyalinized superficial dermal blood vessel walls contain periodic acid-Schiff stain–positive, diastase-resistant glycoprotein deposits. Ultrastructural examination of the dermal vasculature and the dermoepidermal junction reveals replicated basement membranes believed to be elaborated by multiple episodes of damage and repair and fine fibrillar material in the surrounding dermis. Immunoglobulin and complement deposits that are present perivascularly and at the dermoepidermal junction are believed to be due to leakage of these proteins from damaged blood vessels rather than to immunologically mediated events.

More on Variegate Porphyria

Overview: Variegate Porphyria
Differential Diagnoses & Workup: Variegate Porphyria
Treatment & Medication: Variegate Porphyria
Follow-up: Variegate Porphyria
References
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References

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  2. Meissner PN, Day RS, Moore MR, Disler PB, Harley E. Protoporphyrinogen oxidase and porphobilinogen deaminase in variegate porphyria. Eur J Clin Invest. Jun 1986;16(3):257-61. [Medline].

  3. Kirsch RE, Meissner PN, Hift RJ. Variegate porphyria. Semin Liver Dis. 1998;18(1):33-41. [Medline].

  4. Whatley SD, Puy H, Morgan RR, et al. Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. Am J Hum Genet. Oct 1999;65(4):984-94. [Medline].

  5. Eales L, Day RS, Blekkenhorst GH. The clinical and biochemical features of variegate porphyria: an analysis of 300 cases studied at Groote Schuur Hospital, Cape Town. Int J Biochem. 1980;12(5-6):837-53. [Medline].

  6. Mustajoki P. Variegate porphyria. Twelve years' experience in Finland. Q J Med. Spring 1980;49(194):191-203. [Medline].

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  9. Meissner P, Adams P, Kirsch R. Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen. A possible mechanism for the acute attack of variegate porphyria. J Clin Invest. Apr 1993;91(4):1436-44. [Medline].

  10. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis. 1998;18(1):43-52. [Medline].

  11. Dean G. The porphyrias. A story of inheritance and environment. London: Pitman Medical; 1971:2nd ed.

  12. Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG. A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet. May 1996;13(1):95-7. [Medline].

  13. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore). Jan 2005;84(1):48-60. [Medline].

  14. Mustajoki P, Tenhunen R, Niemi KM, Nordmann Y, Kaariainen H, Norio R. Homozygous variegate porphyria. A severe skin disease of infancy. Clin Genet. Nov 1987;32(5):300-5. [Medline].

  15. Corrigall AV, Hift RJ, Davids LM, et al. Homozygous variegate porphyria in South Africa: genotypic analysis in two cases. Mol Genet Metab. Apr 2000;69(4):323-30. [Medline].

  16. von und zu Fraunberg M, Timonen K, Mustajoki P, Kauppinen R. Clinical and biochemical characteristics and genotype-phenotype correlation in Finnish variegate porphyria patients. Eur J Hum Genet. Oct 2002;10(10):649-57. [Medline].

  17. Hift RJ, Meissner D, Meissner PN. A systematic study of the clinical and biochemical expression of variegate porphyria in a large South African family. Br J Dermatol. Aug 2004;151(2):465-71. [Medline].

  18. Korda V, Deybach JC, Martasek P, et al. Homozygous variegate porphyria. Lancet. Apr 14 1984;1(8381):851. [Medline].

  19. Hift RJ, Meissner PN, Todd G, et al. Homozygous variegate porphyria: an evolving clinical syndrome. Postgrad Med J. Oct 1993;69(816):781-6. [Medline].

  20. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol. Nov 2006;135(3):281-92. [Medline].

  21. Hift RJ, Davidson BP, van der Hooft C, Meissner DM, Meissner PN. Plasma fluorescence scanning and fecal porphyrin analysis for the diagnosis of variegate porphyria: precise determination of sensitivity and specificity with detection of protoporphyrinogen oxidase mutations as a reference standard. Clin Chem. May 2004;50(5):915-23. [Medline].

  22. Poh-Fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol. May 1980;116(5):543-7. [Medline].

  23. Logan GM, Weimer MK, Ellefson M, Pierach CA, Bloomer JR. Bile porphyrin analysis in the evaluation of variegate porphyria. N Engl J Med. May 16 1991;324(20):1408-11. [Medline].

  24. Zaider E, Bickers DR. Clinical laboratory methods for diagnosis of the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):277-93. [Medline].

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

  26. Timonen K, Niemi KM, Mustajoki P, Tenhunen R. Skin changes in variegate porphyria. Clinical, histopathological, and ultrastructural study. Arch Dermatol Res. 1990;282(2):108-14. [Medline].

  27. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. Mar 15 2005;142(6):439-50. [Medline].

  28. Kalman DR, Bonkovsky HL. Management of acute attacks in the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):299-306. [Medline].

  29. Tschudy DP, Welland FH, Collins A, Hunter G Jr. The effect of carbohydrate feeding on the induction of delta-aminolevulinic acid synthatase. Metabolism. May 1964;13:396-406. [Medline].

  30. Bonkovsky HL, Healey JF, Lourie AN, Gerron GG. Intravenous heme-albumin in acute intermittent porphyria: evidence for repletion of hepatic hemoproteins and regulatory heme pools. Am J Gastroenterol. Aug 1991;86(8):1050-6. [Medline].

  31. Anderson KE, Spitz IM, Sassa S, Bardin CW, Kappas A. Prevention of cyclical attacks of acute intermittent porphyria with a long-acting agonist of luteinizing hormone-releasing hormone. N Engl J Med. Sep 6 1984;311(10):643-5. [Medline].

  32. Stojeba N, Meyer C, Jeanpierre C, et al. Recovery from a variegate porphyria by a liver transplantation. Liver Transpl. Jul 2004;10(7):935-8. [Medline].

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Further Reading

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Keywords

VP, porphyria variegata, South African porphyria, protocoproporphyria, mixed porphyria, porphyria cutanea tarda hereditaria, royal malady, porphyrin-heme metabolism, protoporphyrinogen oxidase, protoporphyrinogen oxidase gene

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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: Lundbeck, Inc. Honoraria Review panel membership

Medical Editor

David Woodley, MD, Co-Chair, Professor, Department of Medicine, Division of Dermatology, University of Southern California
David Woodley, MD is a member of the following medical societies: American Academy of Dermatology, American Association for the Advancement of Science, American College of Emergency Physicians, American College of Physicians, American Federation for Medical Research, American Society for Clinical Investigation, New York Academy of Medicine, Society for Investigative Dermatology, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center
Julia R Nunley, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Society of Nephrology, International Society of Nephrology, Medical Dermatology Society, Medical Society of Virginia, National Kidney Foundation, Phi Beta Kappa, and Women's Dermatologic Society
Disclosure: Johnson and Johnson stock holder dividends; Amgen stock holder dividends; Forest Lab, Inc stock holder dividends; Galaxo Smith Klein stock holder dividends; Covidien stock holder dividends; Novartis Grant/research funds Consulting; Biolex  sub-investigator

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

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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