Porphyrias – An Overview and Update for Physicians and their Staffs
Main Article Content
Abstract
Abstract
Heme is an essential molecule involved in various biochemical processes in many species. It is used in the formation of cytochromes P-450, mitochondrial cytochromes, hemoproteins, catalase, peroxidase, myoglobin, and hemoglobin. Formation of the heme molecule involves a multistep process using eight enzymes. Biosynthesis of heme occurs in the mitochondria and in the cytoplasm. Most tissues in the human body synthesize heme, but the main sites of formation are in the bone marrow (erythroblasts) and in the liver (hepatocytes). Porphyrias are a unique group of disorders mainly due to inborn errors of metabolism of the heme synthetic pathway. The deficient activity of the enzymes can lead to a build-up of heme precursors, resulting in wide heterogeneity of clinical symptoms. To date, there are nine described porphyrias: aminolevulinic acid dehydratase deficient porphyria (ALADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLPP). The classification of porphyrias is based on 1) the main sites of heme precursor synthesis (hepatic, erythropoietic), 2) acute or chronic porphyria, and 3) cutaneous involvement. In this review, we focus on AIP, PCT, and EPP, the three most common forms of porphyria in the United States. A case vignette for each of the three is provided and followed by a discussion regarding the clinical features, pathogenesis, diagnosis/management, and prognosis of each. Management of AIP currently revolves around avoidance of drugs and chemicals and severe caloric deprivation, which may trigger acute attacks, and use of intravenous heme for acute attacks. Exciting new therapies, particularly siRNA to down regulate hepatic 5-aminolevulinic acid synthase, are under active development. Management of EPP currently involves protection from sunlight, but implants of afamelanotide have shown good efficacy and are already approved by the European Medicines Agency.
Article Details
How to Cite
MARION, Brandon et al.
Porphyrias – An Overview and Update for Physicians and their Staffs.
Medical Research Archives, [S.l.], v. 5, n. Issue 9, sep. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1528>. Date accessed: 13 nov. 2024.
Keywords
5 [delta]-aminolevulinic acid, 5-aminolevulinic acid synthase, heme, hepatitis C, iron, photosensitivity, porphobilinogen, porphyria, porphyrins
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Macalpine I, Hunter R. George III and the Mad Business. London: Allen Lane, 1969.
2. Sherman IW. Twelve Diseases that Changed Our World. Washington, DC: ASM Press, 2007.
3. Arnold WN. Vincent van Gogh: Chemicals, Crises, and Creativity. Berlin, Boston, Basel: Birkhauser, 1992.
4. Loftus LS, ArnoldWN. Vincent van Gogh’s illness: Acute intermittent porphyria? BMJ 303: 1589-1591, 1991.
5. Bonkovsky HL, Cable EE, Cable JW, Donohue SE, White EC, Greene YJ, Lambrecht RW, Srivastava KK, Arnold WN. Porphyrogenic properties of the terpenes camphor, pinene, and thujone (with a note on historic implications for absinthe and the illness of Vincent van Gogh). Biochem Pharmacol 43: 2359-2368, 1992.
6. Waldenström J. Some observations on acute porphyria and other conditions with a change in the excretion of porphyrins. Acta Medica Scandinavica. 1934;83(1-4):281-316.
7. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017: In press.
8. Stein JA, Tschudy DP. Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine (Baltimore). 1970;49(1):1-16.
9. Bonkovsky HL, Guo JT, Hou W, Li T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. Compr Physiol. 2013;3[1]:365-401.
10. Innala E, Bäckström T, Bixo M, Andersson C. Evaluation of gonadotropin-releasing hormone agonist treatment for prevention of menstrual-related attacks in acute porphyria. Acta Obstet Gynecol Scand. 2010;89(1):95-100.
11. Bonkovsky HL, Siao P, Roig Z, Hedley-whyte ET, Flotte TJ. Case records of the Massachusetts General Hospital. Case 20-2008. A 57-year-old woman with abdominal pain and weakness after gastric bypass surgery. N Engl J Med. 2008;358(26):2813-25.
12. Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014;127(12):1233-41.
13. Goldberg A. Acute intermittent porphyria. A study of 50 cases. Q J Med. 1959:28(110):183-209.
14. Waldenstrom J. The porphyrias as inborn errors of metabolism. Am J Med. 1957;22(5):758-73.
15. Cavanagh JB, Mellick RS. On the nature of the peripheral nerve lesions associated with acute intermittent porphyria. J Neurol Neurosurg Psychiatr. 1965;28:320-7.
16. Balwani M, Wang B, Anderson KE, et al. Acute Hepatic Porphyrias: Recommendations for Evaluation and Long Term Management. Hepatology. 2017: In press.
17. Magnussen C, Doherty J, Hess R, Tschudy D. Grand mal seizures and acute intermittent porphyria: the problem of differential diagnosis and treatment. Neurology. 1975;25(12):1121.
18. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142(6):439-50.
19. Bylesjö I, Wikberg A, Andersson C. Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. Scand J Clin Lab Invest. 2009;69(5):612-8.
20. Marsden JT, Chowdhury P, Wang J, et al. Acute intermittent porphyria and chronic renal failure. Clin Nephrol. 2008;69(5):339-46.
21. Pallet N, Mami I, Schmitt C, et al. High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria. Kidney Int. 2015;88(2):386-95.
22. Tchernitchko D, Tavernier Q, Lamoril J, et al. A Variant of Peptide Transporter 2 Predicts the Severity of Porphyria-Associated Kidney Disease. J Am Soc Nephrol. 2017;28(6):1924-1932.
23. Goetsch CA, Bissell DM. Instability of hematin used in the treatment of acute hepatic porphyria. N Engl J Med. 1986;315(4):235-8.
24. Poh-fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol. 1980;116(5):543-7.
25. Andant C, Puy H, Bogard C, et al. Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors. J Hepatol. 2000;32(6):933-9.
26. Sardh E, Wahlin S, Bjornstedt M, Harper P, Andersson DE. High risk of primary liver cancer in a cohort of 179 patients with acute hepatic porphyria. J Inherit Metab Dis. 2013; 36(6):1063-1071.
27. D'avola D, López-franco E, Sangro B, et al. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol. 2016;65(4):776-83.
28. Biessen EA, Vietsch H, Rump ET, et al. Targeted delivery of oligodeoxynucleotides to parenchymal liver cells in vivo. Biochem J. 1999;340 ( Pt 3):783-92.
29. Chan A, Liebow A, Yasuda M, et al. Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification. Mol Ther Nucleic Acids. 2015;4:e263.
30. Soonawalla ZF, Orug T, Badminton MN, et al. Liver transplantation as a cure for acute intermittent porphyria. Lancet. 2004;363(9410):705-6.
31. Waldenström J. Neurological symptoms caused by so-called acute porphyria. Acta Psychiatrica Scandinavica. 1939;14(1-2):375–379.
32. Sanders AR, Rincon-limas DE, Chakraborty R, et al. Association between genetic variation at the porphobilinogen deaminase gene and schizophrenia. Schizophr Res. 1993;8(3):211-21.
33. Cederlöf M, Bergen SE, Larsson H, Landén M, Lichtenstein P. Acute intermittent porphyria: comorbidity and shared familial risks with schizophrenia and bipolar disorder in Sweden. Br J Psychiatry. 2015;207(6):556-7.
34. Bonkovsky HL, Schady W. The neurological manifestations of acute porphyria. Semin Liver Dis. 1982;2: 108-124.
35. Jiménez-monreal AM, Murcia MA, Gómez-murcia V, et al. Anthropometric and Quality-of-Life Parameters in Acute Intermittent Porphyria Patients. Medicine (Baltimore). 2015;94(30):e1023.
36. Elder GH. The cutaneous porphyrias. Semin Dermatol. 1990;9(1):63-9.
37. Badminton MN, Elder GH. Molecular mechanisms of dominant expression in porphyria. J Inherit Metab Dis. 2005;28(3):277-86.
38. Lambrecht RW, Bonkovsky HL. Hemochromatosis and porphyria. Semin Gastrointest Dis. 2002;13: 109-119.
39. Cruz-rojo J, Fontanellas A, Morán-jiménez MJ, et al. Precipitating/aggravating factors of porphyria cutanea tarda in Spanish patients. Cell Mol Biol (Noisy-le-grand). 2002;48(8):845-52.
40. Mukerji SK. Haem biosynthesis and human porphyria cutanea tarda: effects of alcohol intake. Indian J Exp Biol. 2000;38(7):635-42.
41. Daniell WE, Stockbridge HL, Labbe RF, et al. Environmental chemical exposures and disturbances of heme synthesis. Environ Health Perspect. 1997;105 Suppl 1:37-53.
42. Mor Z, Caspi E. Cutaneous complications of hormonal replacement therapy. Clin Dermatol. 1997;15(1):147-54.
43. Bonkovsky HL, Lambrecht RW, Shan Y. Iron as a co-morbid factor in nonhemochromatic liver disease. Alcohol. 2003;30: 137-144.
44. Sterling RK, Bralow S. Extrahepatic manifestations of hepatitis C virus. Curr Gatroenterol Rep. 206;8: 53-59.
45. Almehmi A, Deliri H, Szego GG, Teague AC, Pfister AK, Martin SA. Porphyria cutanea tarda in a patient with HIV-infection. W V Med J. 2005;101(1):19-21.
46. Shehan JM, Huerter CJ. Porphyria cutanea tarda associated with an acute gastrointestinal bleed: The roles of supplemental iron and blood transfusion. Cutis. 2001;68: 147-150.
47. Lockwood WH, Poulos V, Rossi E, Curnow DH. Rapid procedure for fecal porphyrin assay. Clin Chem. 1985;31(7):1163-7.
48. Freesemann A, Frank M, Sieg I, Doss MO. Treatment of porphyria cutanea tarda by the effect of chloroquine on the liver. Skin Pharmacol. 1995;8(3):156-61.
49. Hift RJ, Corrigall AV, Hancock V, Kannemeyer J, Kirsch RE, Meissner PN. Porphyria cutanea tarda: the etiological importance of mutations in the HFE gene and viral infection is population-dependent. Cell Mol Biol (Noisy-le-grand). 2002;48(8):853-9.
50. Armstrong DK, Sharpe PC, Chambers CR, Whatley SD, Roberts AG, Elder GH. Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol. 2004;151(4):920-3.
51. Elder GH, Smith SG, Herrero C, et al. Hepatoerythropoietic porphyria: a new uroporphyrinogen decarboxylase defect or homozygous porphyria cutanea tarda?. Lancet. 1981;1(8226):916-9.
52. Balwani M, Naik H, Anderson KE, et al. Clinical, biochemical, and genetic characterization of North American patients with erythropoietic protoporphyria and X-linked protoporphyria. JAMA Dermatol. 2017: In press.
53. Todd DJ. Erythropoietic protoporphyria. Br J Dermatol. Dec 1994;131[6]:751-766.
54. Balwani M, Bloomer J, Desnick R. Erythropoietic protoporphyria, autosomal recessive. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. Gene Reviews. Seattle [WA]1993.
55. Lecha M, Puy H, Deybach JC. Erythropoietic protoporphyria. Orphanet J Rare Dis. 2009;4:19.
56. Milligan A, Graham-brown RA, Sarkany I, Baker H. Erythropoietic protoporphyria exacerbated by oral iron therapy. Br J Dermatol. 1988;119(1):63-6.
57. Holme SA, Thomas CL, Whatley SD, Bentley DP, Anstey AV, Badminton MN. Symptomatic response of erythropoietic protoporphyria to iron supplementation. J Amer Acad Dermatol. 2007;56[6]:1070-1072.
58. Bentley DP, Meek EM. Clinical and biochemical improvement following low-dose intravenous iron therapy in a patient with erythropoietic protoporphyria. Br J Haematol. 2013;163[2]:289-291.
59. Barman-Aksözen J, Minder EI, Schubiger C, Biolcati G, Schneider-Yin X. In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability. Blood Cells, Molec, Dis. 2015;54[1]:71-77.
60. Bonkowsky HL, Bloomer JR, Ebert PS, Mahoney MJ. Heme synthetase deficiency in human protoporphyria. Demonstration of the defect in liver and cultured skin fibroblasts. J Clin Invest , 1975;56: 1139-1148.
61. Whitcombe DM, Carter NP, Albertson DG, Smith SJ, Rhodes DA, Cox TM. Assignment of the human ferrochelatase gene [FECH] and a locus for protoporphyria to chromosome 18q22. Genomics 1991;11[4]: 1152-1154.
62. Whatley SD, Ducamp S, Gouya L, et al. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet. 2008;83[3]:408-414.
63. Bishop DF, Tchaikovskii V, Nazarenko I, Desnick RJ. Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria. Mol Med. 2013;19:18-25.
64. Elder GH, Gouya L, Whatley SD, Puy H, Badminton MN, Deybach JC. The molecular genetics of erythropoietic protoporphyria. Cell Mol Biol [Noisy-le-grand]. 2009;55[2]:118-126.
65. Whatley SD, Mason NG, Holme SA, Anstey AV, Elder GH, Badminton MN. Molecular epidemiology of erythropoietic protoporphyria in the U.K. Br J Dermatol. 2010;162[3]:642-646.
66. Balwani M, Doheny D, Bishop DF, et al. Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. Mol Med. 2013; 19:26-35.
67. Lane AM, McKay JT, Bonkovsky HL. Advances in the management of erythropoietic protoporphyria - role of afamelanotide. Appl Clin Genet. 2016; 9:179-189.
68. Mathews-Roth MM. The consequences of not diagnosing erythropoietic protoporphyria. Arch Dermatol 1980;116: 407.
69. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, Harber LH, Kass EH. Beta carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases. Arch Dermatol 1977; 113: 1229-1232.
70. Mathews-Roth MM, Rosner B. Long-term treatment of erythropoietic protoporphyria with cysteine. Photodermatol Photoimmunol Photomed 2002; 18: 307-309.
71. McCullough AJ, Barron D, Mullen KD, Petrelli M, Park MC, Mukhtar H, Bickers DR. Fecal protoporphyrin excretion in erythropoietic protoporphyria: Effect of cholestyramine and bile acid feeding. Gastroenterology 1988; 94: 177-181.
72. Gorchein A, Foster GR. Liver failure in protoporphyria: Long-term treatment with oral charcoal. Hepatology 1999; 29: 995-996.
73. 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. 2002;73(3):469-72.
74. Reichheld JH, Katz E, Banner BF, Szymanski IO, Saltzman JR, Bonkovsky HL. The value of intravenous heme-albumin and plasmapheresis in reducing postoperative complications of orthotopic liver transplantation for erythropoietic protoporphyria. Transplantation. 1999;67(6):922-8.
75. Rand EB, Bunin N, Cochran W, Ruchelli E, Olthoff KM, Bloomer JR. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics. 2006;118(6):e1896-9.
76. Wahlin S, Aschan J, Björnstedt M, Broomé U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol. 2007;46(1):174-9.
77. Harms J, Lautenschlager S, Minder CE, Minder EI. An alpha-melanocyte-stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med. 2009;360(3):306-7.
78. Harms JH, Lautenschlager S, Minder CE, Minder EI. Mitigating photosensitivity of erythropoietic protoporphyria patients by an agonistic analog of alpha-melanocyte stimulating hormone. Photochem Photobiol. 2009;85(6):1434-9.
79. Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med. Jul 2 2015;373[1]:48-59.
2. Sherman IW. Twelve Diseases that Changed Our World. Washington, DC: ASM Press, 2007.
3. Arnold WN. Vincent van Gogh: Chemicals, Crises, and Creativity. Berlin, Boston, Basel: Birkhauser, 1992.
4. Loftus LS, ArnoldWN. Vincent van Gogh’s illness: Acute intermittent porphyria? BMJ 303: 1589-1591, 1991.
5. Bonkovsky HL, Cable EE, Cable JW, Donohue SE, White EC, Greene YJ, Lambrecht RW, Srivastava KK, Arnold WN. Porphyrogenic properties of the terpenes camphor, pinene, and thujone (with a note on historic implications for absinthe and the illness of Vincent van Gogh). Biochem Pharmacol 43: 2359-2368, 1992.
6. Waldenström J. Some observations on acute porphyria and other conditions with a change in the excretion of porphyrins. Acta Medica Scandinavica. 1934;83(1-4):281-316.
7. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017: In press.
8. Stein JA, Tschudy DP. Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine (Baltimore). 1970;49(1):1-16.
9. Bonkovsky HL, Guo JT, Hou W, Li T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. Compr Physiol. 2013;3[1]:365-401.
10. Innala E, Bäckström T, Bixo M, Andersson C. Evaluation of gonadotropin-releasing hormone agonist treatment for prevention of menstrual-related attacks in acute porphyria. Acta Obstet Gynecol Scand. 2010;89(1):95-100.
11. Bonkovsky HL, Siao P, Roig Z, Hedley-whyte ET, Flotte TJ. Case records of the Massachusetts General Hospital. Case 20-2008. A 57-year-old woman with abdominal pain and weakness after gastric bypass surgery. N Engl J Med. 2008;358(26):2813-25.
12. Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014;127(12):1233-41.
13. Goldberg A. Acute intermittent porphyria. A study of 50 cases. Q J Med. 1959:28(110):183-209.
14. Waldenstrom J. The porphyrias as inborn errors of metabolism. Am J Med. 1957;22(5):758-73.
15. Cavanagh JB, Mellick RS. On the nature of the peripheral nerve lesions associated with acute intermittent porphyria. J Neurol Neurosurg Psychiatr. 1965;28:320-7.
16. Balwani M, Wang B, Anderson KE, et al. Acute Hepatic Porphyrias: Recommendations for Evaluation and Long Term Management. Hepatology. 2017: In press.
17. Magnussen C, Doherty J, Hess R, Tschudy D. Grand mal seizures and acute intermittent porphyria: the problem of differential diagnosis and treatment. Neurology. 1975;25(12):1121.
18. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142(6):439-50.
19. Bylesjö I, Wikberg A, Andersson C. Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. Scand J Clin Lab Invest. 2009;69(5):612-8.
20. Marsden JT, Chowdhury P, Wang J, et al. Acute intermittent porphyria and chronic renal failure. Clin Nephrol. 2008;69(5):339-46.
21. Pallet N, Mami I, Schmitt C, et al. High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria. Kidney Int. 2015;88(2):386-95.
22. Tchernitchko D, Tavernier Q, Lamoril J, et al. A Variant of Peptide Transporter 2 Predicts the Severity of Porphyria-Associated Kidney Disease. J Am Soc Nephrol. 2017;28(6):1924-1932.
23. Goetsch CA, Bissell DM. Instability of hematin used in the treatment of acute hepatic porphyria. N Engl J Med. 1986;315(4):235-8.
24. Poh-fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol. 1980;116(5):543-7.
25. Andant C, Puy H, Bogard C, et al. Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors. J Hepatol. 2000;32(6):933-9.
26. Sardh E, Wahlin S, Bjornstedt M, Harper P, Andersson DE. High risk of primary liver cancer in a cohort of 179 patients with acute hepatic porphyria. J Inherit Metab Dis. 2013; 36(6):1063-1071.
27. D'avola D, López-franco E, Sangro B, et al. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol. 2016;65(4):776-83.
28. Biessen EA, Vietsch H, Rump ET, et al. Targeted delivery of oligodeoxynucleotides to parenchymal liver cells in vivo. Biochem J. 1999;340 ( Pt 3):783-92.
29. Chan A, Liebow A, Yasuda M, et al. Preclinical Development of a Subcutaneous ALAS1 RNAi Therapeutic for Treatment of Hepatic Porphyrias Using Circulating RNA Quantification. Mol Ther Nucleic Acids. 2015;4:e263.
30. Soonawalla ZF, Orug T, Badminton MN, et al. Liver transplantation as a cure for acute intermittent porphyria. Lancet. 2004;363(9410):705-6.
31. Waldenström J. Neurological symptoms caused by so-called acute porphyria. Acta Psychiatrica Scandinavica. 1939;14(1-2):375–379.
32. Sanders AR, Rincon-limas DE, Chakraborty R, et al. Association between genetic variation at the porphobilinogen deaminase gene and schizophrenia. Schizophr Res. 1993;8(3):211-21.
33. Cederlöf M, Bergen SE, Larsson H, Landén M, Lichtenstein P. Acute intermittent porphyria: comorbidity and shared familial risks with schizophrenia and bipolar disorder in Sweden. Br J Psychiatry. 2015;207(6):556-7.
34. Bonkovsky HL, Schady W. The neurological manifestations of acute porphyria. Semin Liver Dis. 1982;2: 108-124.
35. Jiménez-monreal AM, Murcia MA, Gómez-murcia V, et al. Anthropometric and Quality-of-Life Parameters in Acute Intermittent Porphyria Patients. Medicine (Baltimore). 2015;94(30):e1023.
36. Elder GH. The cutaneous porphyrias. Semin Dermatol. 1990;9(1):63-9.
37. Badminton MN, Elder GH. Molecular mechanisms of dominant expression in porphyria. J Inherit Metab Dis. 2005;28(3):277-86.
38. Lambrecht RW, Bonkovsky HL. Hemochromatosis and porphyria. Semin Gastrointest Dis. 2002;13: 109-119.
39. Cruz-rojo J, Fontanellas A, Morán-jiménez MJ, et al. Precipitating/aggravating factors of porphyria cutanea tarda in Spanish patients. Cell Mol Biol (Noisy-le-grand). 2002;48(8):845-52.
40. Mukerji SK. Haem biosynthesis and human porphyria cutanea tarda: effects of alcohol intake. Indian J Exp Biol. 2000;38(7):635-42.
41. Daniell WE, Stockbridge HL, Labbe RF, et al. Environmental chemical exposures and disturbances of heme synthesis. Environ Health Perspect. 1997;105 Suppl 1:37-53.
42. Mor Z, Caspi E. Cutaneous complications of hormonal replacement therapy. Clin Dermatol. 1997;15(1):147-54.
43. Bonkovsky HL, Lambrecht RW, Shan Y. Iron as a co-morbid factor in nonhemochromatic liver disease. Alcohol. 2003;30: 137-144.
44. Sterling RK, Bralow S. Extrahepatic manifestations of hepatitis C virus. Curr Gatroenterol Rep. 206;8: 53-59.
45. Almehmi A, Deliri H, Szego GG, Teague AC, Pfister AK, Martin SA. Porphyria cutanea tarda in a patient with HIV-infection. W V Med J. 2005;101(1):19-21.
46. Shehan JM, Huerter CJ. Porphyria cutanea tarda associated with an acute gastrointestinal bleed: The roles of supplemental iron and blood transfusion. Cutis. 2001;68: 147-150.
47. Lockwood WH, Poulos V, Rossi E, Curnow DH. Rapid procedure for fecal porphyrin assay. Clin Chem. 1985;31(7):1163-7.
48. Freesemann A, Frank M, Sieg I, Doss MO. Treatment of porphyria cutanea tarda by the effect of chloroquine on the liver. Skin Pharmacol. 1995;8(3):156-61.
49. Hift RJ, Corrigall AV, Hancock V, Kannemeyer J, Kirsch RE, Meissner PN. Porphyria cutanea tarda: the etiological importance of mutations in the HFE gene and viral infection is population-dependent. Cell Mol Biol (Noisy-le-grand). 2002;48(8):853-9.
50. Armstrong DK, Sharpe PC, Chambers CR, Whatley SD, Roberts AG, Elder GH. Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol. 2004;151(4):920-3.
51. Elder GH, Smith SG, Herrero C, et al. Hepatoerythropoietic porphyria: a new uroporphyrinogen decarboxylase defect or homozygous porphyria cutanea tarda?. Lancet. 1981;1(8226):916-9.
52. Balwani M, Naik H, Anderson KE, et al. Clinical, biochemical, and genetic characterization of North American patients with erythropoietic protoporphyria and X-linked protoporphyria. JAMA Dermatol. 2017: In press.
53. Todd DJ. Erythropoietic protoporphyria. Br J Dermatol. Dec 1994;131[6]:751-766.
54. Balwani M, Bloomer J, Desnick R. Erythropoietic protoporphyria, autosomal recessive. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. Gene Reviews. Seattle [WA]1993.
55. Lecha M, Puy H, Deybach JC. Erythropoietic protoporphyria. Orphanet J Rare Dis. 2009;4:19.
56. Milligan A, Graham-brown RA, Sarkany I, Baker H. Erythropoietic protoporphyria exacerbated by oral iron therapy. Br J Dermatol. 1988;119(1):63-6.
57. Holme SA, Thomas CL, Whatley SD, Bentley DP, Anstey AV, Badminton MN. Symptomatic response of erythropoietic protoporphyria to iron supplementation. J Amer Acad Dermatol. 2007;56[6]:1070-1072.
58. Bentley DP, Meek EM. Clinical and biochemical improvement following low-dose intravenous iron therapy in a patient with erythropoietic protoporphyria. Br J Haematol. 2013;163[2]:289-291.
59. Barman-Aksözen J, Minder EI, Schubiger C, Biolcati G, Schneider-Yin X. In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability. Blood Cells, Molec, Dis. 2015;54[1]:71-77.
60. Bonkowsky HL, Bloomer JR, Ebert PS, Mahoney MJ. Heme synthetase deficiency in human protoporphyria. Demonstration of the defect in liver and cultured skin fibroblasts. J Clin Invest , 1975;56: 1139-1148.
61. Whitcombe DM, Carter NP, Albertson DG, Smith SJ, Rhodes DA, Cox TM. Assignment of the human ferrochelatase gene [FECH] and a locus for protoporphyria to chromosome 18q22. Genomics 1991;11[4]: 1152-1154.
62. Whatley SD, Ducamp S, Gouya L, et al. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet. 2008;83[3]:408-414.
63. Bishop DF, Tchaikovskii V, Nazarenko I, Desnick RJ. Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria. Mol Med. 2013;19:18-25.
64. Elder GH, Gouya L, Whatley SD, Puy H, Badminton MN, Deybach JC. The molecular genetics of erythropoietic protoporphyria. Cell Mol Biol [Noisy-le-grand]. 2009;55[2]:118-126.
65. Whatley SD, Mason NG, Holme SA, Anstey AV, Elder GH, Badminton MN. Molecular epidemiology of erythropoietic protoporphyria in the U.K. Br J Dermatol. 2010;162[3]:642-646.
66. Balwani M, Doheny D, Bishop DF, et al. Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. Mol Med. 2013; 19:26-35.
67. Lane AM, McKay JT, Bonkovsky HL. Advances in the management of erythropoietic protoporphyria - role of afamelanotide. Appl Clin Genet. 2016; 9:179-189.
68. Mathews-Roth MM. The consequences of not diagnosing erythropoietic protoporphyria. Arch Dermatol 1980;116: 407.
69. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, Harber LH, Kass EH. Beta carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases. Arch Dermatol 1977; 113: 1229-1232.
70. Mathews-Roth MM, Rosner B. Long-term treatment of erythropoietic protoporphyria with cysteine. Photodermatol Photoimmunol Photomed 2002; 18: 307-309.
71. McCullough AJ, Barron D, Mullen KD, Petrelli M, Park MC, Mukhtar H, Bickers DR. Fecal protoporphyrin excretion in erythropoietic protoporphyria: Effect of cholestyramine and bile acid feeding. Gastroenterology 1988; 94: 177-181.
72. Gorchein A, Foster GR. Liver failure in protoporphyria: Long-term treatment with oral charcoal. Hepatology 1999; 29: 995-996.
73. 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. 2002;73(3):469-72.
74. Reichheld JH, Katz E, Banner BF, Szymanski IO, Saltzman JR, Bonkovsky HL. The value of intravenous heme-albumin and plasmapheresis in reducing postoperative complications of orthotopic liver transplantation for erythropoietic protoporphyria. Transplantation. 1999;67(6):922-8.
75. Rand EB, Bunin N, Cochran W, Ruchelli E, Olthoff KM, Bloomer JR. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics. 2006;118(6):e1896-9.
76. Wahlin S, Aschan J, Björnstedt M, Broomé U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol. 2007;46(1):174-9.
77. Harms J, Lautenschlager S, Minder CE, Minder EI. An alpha-melanocyte-stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med. 2009;360(3):306-7.
78. Harms JH, Lautenschlager S, Minder CE, Minder EI. Mitigating photosensitivity of erythropoietic protoporphyria patients by an agonistic analog of alpha-melanocyte stimulating hormone. Photochem Photobiol. 2009;85(6):1434-9.
79. Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med. Jul 2 2015;373[1]:48-59.