Abstract
Porphyrias are a group of metabolic disorders, which result from a specific abnormality in one of the eight enzymes of the heme biosynthetic pathway. These have been subdivided based on the predominant site of enzyme defect into hepatic and erythropoietic types and based on clinical presentation into acute neurovisceral and cutaneous blistering porphyrias. This review focuses on hepatic porphyrias, which include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), aminolevulinic acid dehydratase deficiency porphyria (ADP), and porphyria cutanea tarda (PCT). Of these, AIP and ADP are classified as acute porphyria, PCT as cutaneous, while VP and HCP present with both acute and cutaneous clinical manifestations. Porphobilinogen levels in a spot urine sample is the initial screening test for the diagnosis of acute hepatic porphyria, and plasma with spot urine porphyrin levels is the initial screening test to approach patients suspected of cutaneous porphyria. Specific biochemical porphyrin profile for each porphyria helps in determining the specific diagnosis. Pain relief and elimination of triggering agents are the initial steps in managing a patient presenting with an acute attack. Intravenous glucose administration terminates the mild episode of acute porphyria, with intravenous hemin needed for management of moderate to severe episodes. Liver transplantation is curative and may be needed for patients with a life-threatening acute porphyria attack or for patients with recurrent acute attacks refractory to prophylactic treatment. Of the cutaneous porphyrias, PCT is the most common and is frequently associated with a combination of multiple susceptibility factors such as alcohol use, smoking, hepatitis C virus infection, HIV infection, estrogen use, and mutations of the hemochromatosis gene. Regular phlebotomy schedule and low-dose hydroxychloroquine are effective and safe treatment options for management of PCT.
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References
Karim Z, Lyoumi S, Nicolas G, Deybach JC, Gouya L, Puy H. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;9:412–25.
Besur S, Schmeltzer P, Bonkovsky HL. Acute porphyrias. J Emerg Med. 2015;49:305–12.
Singal, AK, Anderson, KE. Variegate porphyria. In: Gene Reviews. Pagon RA, Adam MP, Ardinger HH, et al. Eds. 1993: Seattle (WA).
Singal AK, Phillips J. Porphyria cutanea tarda. Handbook of Porphyrin Science. Ed. Smith KM, Kadish KM, Guilard R. Vol. 29. 2013, Singapore World Scientific Publishing Co Pte. Ltd. . 219–262.
Jalil S, Grady JJ, Lee C, Anderson KE. Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin Gastroenterol Hepatol 2010;8:297–302, 302 e1.
Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014;127:1233–41.
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). 2005;84:48–60.
Lin CS, Park SB, Krishnan AV. Porphyric neuropathy. Handb Clin Neurol. 2013;115:613–27.
Bissell DM, Lai JC, Meister RK, Blanc PD. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med. 2015;128:313–7.
Homedan C, Laafi J, Schmitt C, et al. Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a mouse model. Int J Biochem Cell Biol. 2014;51:93–101.
Singal AK, Anderson KE.Variegate porphyria. In: Pagon RA, Adam MP, Ardinger HH, et al. editors. GeneReviews [Internet] Seattle (WA): University of Washington, Seattle; 1993–2016. 2013 Feb 14.
Hasanoglu A, Balwani M, Kasapkara CS, et al. Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R. J Inherit Metab Dis. 2011;34:225–31.
Nordmann Y, Grandchamp B, de Verneuil H, Phung L, Cartigny B, Fontaine G. Harderoporphyria: a variant hereditary coproporphyria. J Clin Invest. 1983;72:1139–49.
Doss MO, Stauch T, Gross U, et al. The third case of doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany. J Inherit Metab Dis. 2004;27:529–36.
Rossetti MV, Granata BX, Giudice J, Parera VE, Batlle A. Genetic and biochemical studies in Argentinean patients with variegate porphyria. BMC Med Genet. 2008;9:54.
Szlendak U, Lipniacka A, Bianketti J, Podolak-Dawidziak M, Bykowska K. Porphobilinogen deaminase gene mutations in Polish patients with non-erythroid acute intermittent porphyria. Adv Clin Exp Med. 2015;24:63–8.
Sassa S, Kondo M, Taketani S, et al. Molecular defects of the coproporphyrinogen oxidase gene in hereditary coproporphyria. Cell Mol Biol (Noisy-le-grand). 1997;43:59–66.
Elder G, Harper P, Badminton M, Sandberg S, Deybach JC. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis. 2013;36:849–57.
Bissell DM, Wang B, Lai J. Hereditary coproporphyria. In: GeneReviews(R), Pagon RA, Adam MP, Ardinger HH, et al. Eds. 1993: Seattle (WA).
Plewinska M, Thunell S, Holmberg L, Wetmur JG, Desnick RJ. Delta-aminolevulinate dehydratase deficient porphyria: identification of the molecular lesions in a severely affected homozygote. Am J Hum Genet. 1991;49:167–74.
Thunell S, Holmberg L, Lundgren J. Aminolaevulinate dehydratase porphyria in infancy. A clinical and biochemical study. J Clin Chem Clin Biochem. 1987;25:5–14.
Fujita H, Sassa S, Lundgren J, Holmberg L, Thunell S, Kappas A. Enzymatic defect in a child with hereditary hepatic porphyria due to homozygous delta-aminolevulinic acid dehydratase deficiency: immunochemical studies. Pediatrics. 1987;80:880–5.
Akagi R, Nishitani C, Harigae H, et al. Molecular analysis of delta-aminolevulinate dehydratase deficiency in a patient with an unusual late-onset porphyria. Blood. 2000;96:3618–23.
Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439–450. Erratum in: Ann Intern Med. 2005;143:316.
Ramanujam VM, Anderson KE. Porphyria diagnostics-part 1: a brief overview of the porphyrias. Curr Protoc Hum Genet. 2015;86:17.20.1–26.
Ahangari A, Bckstrm T, Innala E, Andersson C, Turkmen S. Acute intermittent porphyria symptoms during the menstrual cycle. Intern Med J. 2015;45:725–31.
Collantes M, Serrano-Mendioroz I, Benito M, et al. Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency. Hum Mol Genet. 2016;25:1318–27.
Bissell DM, Wang B. Acute hepatic porphyria. J Clin Transl Hepatol. 2015;3:17–26.
Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439–50.
Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120:4496–504.
Akagi R, Kato N, Inoue R, Anderson KE, Jaffe EK, Sassa S. Delta-aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations. Mol Genet Metab. 2006;87:329–36.
Anderson KE, Collins S. Open-label study of hemin for acute porphyria: clinical practice implications. Am J Med. 2006;119:801. e19–24.
Stein P, Badminton M, Barth J, Rees D, Stewart MF. British and Irish Porphyria Network. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013;50 Pt 3:217–23.
Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375:924–37.
Frei P, Minder EI, Corti N, et al. Liver transplantation because of acute liver failure due to heme arginate overdose in a patient with acute intermittent porphyria. Case Rep Gastroenterol. 2012;6:190–6.
Marsden JT, Rees DCA. Retrospective analysis of outcome of pregnancy in patients with acute porphyria. J Inherit Metab Dis. 2010;33:591–6.
Handschin C, Lin J, Rhee J, et al. Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell. 2005;122:505–15.
Chacko BK, Kramer PA, Ravi S, et al. The bioenergetic health index: a new concept in mitochondrial translational research. Clin Sci (Lond). 2014;127:367–73.
Ferrer MD, Tauler P, Sureda A, Palacin C, Tur JA, Pons A. Antioxidants restore protoporphyrinogen oxidase in variegate porphyria patients. Eur J Clin Invest. 2013;43:668–78.
Singal AK, Parker C, Bowden C, Thapar M, Liu L, McGuire BM. Liver transplantation in the management of porphyria. Hepatology. 2014;60:1082–9.
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. 1984;311:643–5.
Anderson KE, Spitz IM, Bardin CW, Kappas AA. Gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria. Arch Intern Med. 1990;150:1469–74.
Dowman JK, Gunson BK, Mirza DF, et al. Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl. 2012;18:195–200.
Yasuda M, Erwin AL, Liu LU, et al. Liver transplantation for acute intermittent porphyria: biochemical and pathologic studies of the explanted liver. Mol Med. 2015;21:487–95.
Sullenger BA, Nair S. From the RNA world to the clinic. Science. 2016;352:1417–20.
Yasuda M, Gan L, Chen B, et al. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proc Natl Acad Sci U S A. 2014;111:7777–82.
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.
Paneda A, Lopez-Franco E, Kaeppel C, et al. Safety and liver transduction efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute intermittent porphyria. Hum Gene Ther. 2013;24:1007–17.
D'Avola D, Lopez-Franco E, Sangro B, et al. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol. 2016;65:776–83.
Yin Z, Wahlin S, Ellis EC, Harper P, Ericzon BG, Nowak G. Hepatocyte transplantation ameliorates the metabolic abnormality in a mouse model of acute intermittent porphyria. Cell Transplant. 2014;23:1153–62.
Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore). 1992;71:1–13.
Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015;8:201–14.
Herrero C, Badenas C, Aguilera P, To-Figueras J. Acute intermittent porphyria: long-term follow up of 35 patients. Med Clin (Barc). 2015;145:332–7.
Bonkovsky HL, Guo JT, Hou W, Li T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. Compr Physiol. 2013;3:365–401.
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;88:386–95.
Innala E, Andersson C. Screening for hepatocellular carcinoma in acute intermittent porphyria: a 15-year follow-up in northern Sweden. J Intern Med. 2011;269:538–45.
Lang E, Schafer M, Schwender H, Neumann NJ, Frank J. Occurrence of malignant tumours in the acute hepatic porphyrias. JIMD Rep. 2015;22:17–22.
Stewart MF. Review of hepatocellular cancer, hypertension and renal impairment as late complications of acute porphyria and recommendations for patient follow-up. J Clin Pathol. 2012;65:976–80.
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;36:1063–71.
Bruix J, Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.
Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JPA. Porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci U S A. 2007;104:5079–84.
Singal AK, Kormos-Hallberg C, Lee C, et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2012;10:1402–9.
Darwich E, To-Figueras J, Molina-Lopez RA, et al. Increased serum hepcidin levels in patients with porphyria cutanea tarda. J Eur Acad Dermatol Venereol. 2013;27:e68–74.
Frank J, Poblete-Gutierrez P. Porphyria cutanea tarda—when skin meets liver. Best Pract Res Clin Gastroenterol. 2010;24:735–45.
Maynard B, Peters MS. Histologic and immunofluorescence study of cutaneous porphyrias. J Cutan Pathol. 1992;19:40–7.
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;11:1103–11.
Boudghene-Stambouli O, Merad-Boudia A. Hepato-erythropoietic porphyria. Ann Dermatol Venereol. 1995;122:615–7.
Schulenburg-Brand D, Katugampola R, Anstey AV, Badminton MN. The cutaneous porphyrias. Dermatol Clin. 2014;32:369–84 ix.
Ippen H. Treatment of porphyria cutanea tarda by phlebotomy. Semin Hematol. 1977;14:253–9.
Stolzel U, Kostler E, Schuppan D, et al. Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda. Arch Dermatol. 2003;139:309–13.
Miyauchi S, Shiraishi S, Miki Y. Small volume plasmapheresis in the management of porphyria cutanea tarda. Arch Dermatol. 1983;119:752–5.
Poux JM, Demontis R, Cadranel JF, Ghazali A, Fievet P, Nordmann Y. Porphyria cutanea tarda in a dialyzed patient with hepatitis C virus infection: dramatic efficacy of small repeated phlebotomies. Am J Med. 1997;103:163–4.
Vasconcelos P, Luz-Rodrigues H, Santos C, Filipe P. Desferrioxamine treatment of porphyria cutanea tarda in a patient with HIV and chronic renal failure. Dermatol Ther. 2014;27:16–8.
Ryan Caballes F, Sendi H, Bonkovsky HL, Hepatitis C. Porphyria cutanea tarda and liver iron: an update. Liver Int. 2012;32:880–93.
Hisamuddin K, Veluru C, Mullen KD. Skin lesions in a patient on therapy for chronic hepatitis. Clin Gastroenterol Hepatol. 2009;7:A24C.
Dedania B, Wu GY. Dermatologic extrahepatic manifestations of hepatitis C. J Clin Transl Hepatol. 2015;3:127–33.
Singal AKGE, Gou E, Albuerne M, Hallberg CK, Anderson KEA. Relapse of PCT after achieving remission with phlebotomy or low dose hydroxychloroquine. Hepatology. 2013;58:299A.
Fracanzani AL, Taioli E, Sampietro M, et al. Liver cancer risk is increased in patients with porphyria cutanea tarda in comparison to matched control patients with chronic liver disease. J Hepatol. 2001;35:498–503.
Tollanes MC, Aarsand AK, Sandberg S. Risk of adverse pregnancy outcomes in women with porphyria: a population-based cohort study. J Inherit Metab Dis. 2011;34:217–23.
Acknowledgments
This study was supported by grant funding U54DK083909 to the Porphyria Consortium, a part of the NIH Rare Diseases Clinical Research Network, supported through collaboration between the NIH office of Rare Diseases Research at the National Center for Advancing Translational Science and the National Institute of Diabetes and Digestive and Kidney Diseases.
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Arora, S., Young, S., Kodali, S. et al. Hepatic porphyria: A narrative review. Indian J Gastroenterol 35, 405–418 (2016). https://doi.org/10.1007/s12664-016-0698-0
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DOI: https://doi.org/10.1007/s12664-016-0698-0