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Molecular Medicine

, Volume 21, Issue 1, pp 487–495 | Cite as

Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver

  • Makiko Yasuda
  • Angelika L. Erwin
  • Lawrence U. Liu
  • Manisha Balwani
  • Brenden Chen
  • Senkottuvelan Kadirvel
  • Lin Gan
  • M. Isabel Fiel
  • Ronald E. Gordon
  • Chunli Yu
  • Sonia Clavero
  • Antonios Arvelakis
  • Hetanshi Naik
  • L. David Martin
  • John D. Phillips
  • Karl E. Anderson
  • Vaithamanithi M. Sadagoparamanujam
  • Sander S. Florman
  • Robert J. Desnick
Research Article

Abstract

Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient’s plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1 mRNA and activity were elevated approximately ∼3- and 5-fold, and ALA and PBG concentrations were increased ∼3- and 1,760-fold, respectively; (b) uroporphyrin III concentration was elevated; (c) microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (∼42%); (e) iron concentration was slightly elevated; and (f) heme oxygenase I mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative hyperplasia, previously not reported in AIP livers, and minimal iron deposition, despite the large number of hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks.

Notes

Acknowledgments

We thank Ethellyn Panta (Icahn School of Medicine at Mount Sinai) and Hector Bergonia (University of Utah School of Medicine) for their excellent technical assistance. This work was supported in part by Career Development Awards K01 DK087971 (to M Yasuda) and K23 DK095946 (to M Balwani) from the National Institutes of Health (NIH) and a cooperative grant (U54 DK083909) for the Porphyrias Consortium, which is a part of the NIH Rare Diseases Research Network (RDCRN) and supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Liver Tissue Cell Distribution System at the University of Minnesota provided the control human liver tissues and is funded by NIH contract HHSN276201200017C.

Supplementary material

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Supplementary material, approximately 484 KB.

References

  1. 1.
    Anderson KE, Sassa S, Bishop DF, Desnick RJ. (2001) Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. 8th edition. 8th edition. In: The Metabolic and Molecular Bases of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B (eds.) McGraw-Hill, New York, pp. 2961–3062.Google Scholar
  2. 2.
    Dar FS, et al. (2010) Liver transplantation for acute intermittent porphyria: a viable treatment? Hepatobiliary Pancreat. Dis. Int. 9:93–6.PubMedGoogle Scholar
  3. 3.
    Dowman JK, et al. (2012) Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl. 18:195–200.CrossRefGoogle Scholar
  4. 4.
    Seth AK, Badminton MN, Mirza D, Russell S, Elias E. (2007) Liver transplantation for porphyria: who, when, and how? Liver Transpl. 13:1219–27.CrossRefGoogle Scholar
  5. 5.
    Soonawalla ZF, et al. (2004) Liver transplantation as a cure for acute intermittent porphyria. Lancet. 363:705–6.CrossRefGoogle Scholar
  6. 6.
    Wahlin S, et al. (2010) Combined liver and kidney transplantation in acute intermittent porphyria. Transpl. Int. 23:e18–21.CrossRefGoogle Scholar
  7. 7.
    Harper P, Sardh E. (2014) Management of acute intermittent porphyria. Expert Opin. Orphan Drugs. 2:349–68.CrossRefGoogle Scholar
  8. 8.
    Dowman JK, Gunson BK, Bramhall S, Badminton MN, Newsome PN. (2011) Liver transplantation from donors with acute intermittent porphyria. Ann. Intern. Med. 154:571–2.CrossRefGoogle Scholar
  9. 9.
    Yasuda M, et al. (2014) 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. 111:7777–82.CrossRefGoogle Scholar
  10. 10.
    Zhang J, et al. (2011) A LC-MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen. J. Chromatogr. B Analyt. Technol Biomed. Life Sci. 879:2389–96.CrossRefGoogle Scholar
  11. 11.
    Clavero S, et al. (2010) Feline acute intermittent porphyria: a phenocopy masquerading as an erythropoietic porphyria due to dominant and recessive hydroxymethylbilane synthase mutations. Hum. Mol. Genet. 19:584–96.CrossRefGoogle Scholar
  12. 12.
    Wu D, Cederbaum AI. (2008) Development and properties of HepG2 cells that constitutively express CYP2E1. Methods Mol. Biol. 447:137–50.CrossRefGoogle Scholar
  13. 13.
    Berry EA, Trumpower BL. (1987) Simultaneous determination of hemes a, b, and c from pyridine hemochrome spectra. Anal. Biochem. 161:1–15.CrossRefGoogle Scholar
  14. 14.
    Alcock NW. (1987) A hydrogen-peroxide digestion system for tissue trace-metal analysis. Biol. Trace Elem. Res. 13:363–70.CrossRefGoogle Scholar
  15. 15.
    Barry M. (1974) Liver iron concentration, stainable iron, and total body storage iron. Gut. 15:411–5.CrossRefGoogle Scholar
  16. 16.
    Bonkovsky HL, et al. (2014) Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am. J. Med. 127:1233–41.CrossRefGoogle Scholar
  17. 17.
    von und zu Fraunberg M, Pischik E, Udd L, Kauppinen R. (2005) Clinical and biochemical characteristics and genotype-phenotype correlation in 143 Finnish and Russian patients with acute intermittent porphyria. Medicine (Baltimore). 84:35–47.CrossRefGoogle Scholar
  18. 18.
    Solis C, et al. (2004) Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch. Neurol. 61:1764–70.CrossRefGoogle Scholar
  19. 19.
    Srisook K, Kim C, Cha YN. (2005) Molecular mechanisms involved in enhancing HO-1 expression: de-repression by heme and activation by Nrf2, the “one-two” punch. Antioxid. Redox Signal. 7:1674–87.CrossRefGoogle Scholar
  20. 20.
    Gotoh S, Nakamura T, Kataoka T, Taketani S. (2011) Egr-1 regulates the transcriptional repression of mouse delta-aminolevulinic acid synthase 1 by heme. Gene. 472:28–36.CrossRefGoogle Scholar
  21. 21.
    Yamamoto M, Kure S, Engel JD, Hiraga K. (1988) Structure, turnover, and heme-mediated suppression of the level of mRNA encoding rat liver delta-aminolevulinate synthase. J. Biol. Chem. 263:15973–9.PubMedGoogle Scholar
  22. 22.
    Lathrop JT, Timko MP. (1993) Regulation by heme of mitochondrial protein transport through a conserved amino acid motif. Science. 259:522–5.CrossRefGoogle Scholar
  23. 23.
    Biempica L, Kosower N, Ma MH, Goldfischer S. (1974) Hepatic porphyrias: cytochemical and ultrastructural studies of liver in acute intermittent porphyria and porphyria cutanea tarda. Arch. Pathol. 98:336–43.PubMedGoogle Scholar
  24. 24.
    Heilmann E, Muller KM, Niedorf H, Bassewitz DB. (1976) Special clinical, light and electron microscopic aspects of acute intermittent porphyria. Ann. Clin. Res. 8Suppl 17:213–6.PubMedGoogle Scholar
  25. 25.
    Jean G, Levi L, Ranzi T. (1967) Hepatic siderosis in porphyria cutanea tarda [Clinical and pathogenetic considerations]. G. Ital. Dermatol. Minerva Dermatol. 108:507–24.PubMedGoogle Scholar
  26. 26.
    Ostrowski J, et al. (1983) Abnormalities in liver function and morphology and impaired aminopyrine metabolism in hereditary hepatic porphyrias. Gastroenterology. 85:1131–7.PubMedGoogle Scholar
  27. 27.
    Perlroth MG, et al. (1966) Acute intermittent porphyria: new morphologic and biochemical findings. Am. J. Med. 41:149–62.CrossRefGoogle Scholar
  28. 28.
    Suarez JI, et al. (1997) Acute intermittent porphyria: clinicopathologic correlation: report of a case and review of the literature. Neurology. 48:1678–83.CrossRefGoogle Scholar
  29. 29.
    Al-Mukhaizeem KA, Rosenberg A, Sherker AH. (2004) Nodular regenerative hyperplasia of the liver: an under-recognized cause of portal hypertension in hematological disorders. Am. J. Hematol. 75:225–30.CrossRefGoogle Scholar
  30. 30.
    Hartleb M, Gutkowski K, Milkiewicz P. (2011) Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension. World J. Gastroenterol. 17:1400–9.CrossRefGoogle Scholar
  31. 31.
    Schinoni MI, Andrade Z, de Freitas LA, Oliveira R, Parana R. (2004) Incomplete septal cirrhosis: an enigmatic disease. Liver Int. 24:452–6.CrossRefGoogle Scholar
  32. 32.
    Le Bail B, et al. (1997) Case report: incomplete septal cirrhosis with liver cell dysplasia. J. Gastroenterol. Hepatol. 12:267–71.CrossRefGoogle Scholar

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Authors and Affiliations

  • Makiko Yasuda
    • 1
  • Angelika L. Erwin
    • 1
  • Lawrence U. Liu
    • 2
  • Manisha Balwani
    • 1
    • 2
  • Brenden Chen
    • 1
  • Senkottuvelan Kadirvel
    • 1
  • Lin Gan
    • 1
  • M. Isabel Fiel
    • 3
  • Ronald E. Gordon
    • 3
  • Chunli Yu
    • 1
  • Sonia Clavero
    • 1
  • Antonios Arvelakis
    • 4
  • Hetanshi Naik
    • 1
  • L. David Martin
    • 5
  • John D. Phillips
    • 6
  • Karl E. Anderson
    • 7
  • Vaithamanithi M. Sadagoparamanujam
    • 7
  • Sander S. Florman
    • 2
    • 4
  • Robert J. Desnick
    • 1
  1. 1.Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of PathologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Department of SurgeryIcahn School of Medicine at Mount SinaiNew YorkUSA
  5. 5.Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  6. 6.Department of Internal MedicineUniversity of UtahSalt Lake CityUSA
  7. 7.Department of Preventive Medicine and Community HealthUniversity of Texas Medical BranchGalvestonUSA

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