Abstract
Urea cycle disorders (UCDs) are inborn errors of metabolism of the nitrogen detoxification pathway and encompass six principal enzymatic deficiencies. The aging of UCD patients leads to a better knowledge of the long-term natural history of the condition and to the reporting of previously unnoticed manifestations. Despite historical evidence of liver involvement in UCDs, little attention has been paid to this organ until recently. Hence, we reviewed the available scientific evidence on acute and chronic liver dysfunction and liver carcinogenesis in UCDs and discuss their pathophysiology. Overall, liver involvement, such as acute liver failure or steatotic-like disease, which may evolve toward cirrhosis, has been reported in all six main UCDs. Excessive glycogen storage is also a prominent histologic feature, and hypoglycemia has been reported in citrin deficiency. Hepatocarcinomas seem frequent in some UCDs, such as in citrin deficiency, and can sometimes occur in non-cirrhotic patients. UCDs may differ in liver involvement according to the enzymatic deficiency. Ornithine transcarbamylase deficiency may be associated more with acute liver failure and argininosuccinic aciduria with chronic liver failure and cirrhosis. Direct toxicity of metabolites, downstream metabolic deficiencies, impaired tricarboxylic acid cycle, oxidative stress, mitochondrial dysfunction, energy deficit, and putative toxicity of therapies combine in various ways to cause the different liver diseases reported.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY et al (2008) Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. J Neurol Sci 264:187–194. https://doi.org/10.1016/j.jns.2007.08.003
Aronson PL, Mistry RD (2011) Ornithine transcarbamylase deficiency presenting as hepatitis. Pediatr Emerg Care 27:527–529. https://doi.org/10.1097/PEC.0b013e31821d86c1
Atiq M, Holt AF, Safdar K et al (2008) Adult onset urea cycle disorder in a patient with presumed hepatic encephalopathy. J Clin Gastroenterol 42:213–214. https://doi.org/10.1097/01.mcg.0000225628.84168.25
Badizadegan K, Perez-Atayde AR (1997) Focal glycogenosis of the liver in disorders of ureagenesis: its occurrence and diagnostic significance. Hepatol Baltim Md 26:365–373. https://doi.org/10.1002/hep.510260217
Batshaw ML, Tuchman M, Summar M et al (2014) A longitudinal study of urea cycle disorders. Mol Genet Metab 113:127–130. https://doi.org/10.1016/j.ymgme.2014.08.001
Ben-Shalom E, Kobayashi K, Shaag A et al (2002) Infantile citrullinemia caused by citrin deficiency with increased dibasic amino acids. Mol Genet Metab 77:202–208
Berger C, Dimant P, Hermida L et al (2012) Hyperammonemic encephalopathy and fibrolamellar hepatocellular carcinoma. Med (Mex) 72:425–427
Billmeier GJ, Molinary SV, Wilroy RS et al (1974) Argininosuccinic aciduria: investigation of an affected family. J Pediatr 84:85–89
Bindi V, Eiroa H (2017) Citrullinemia type I with recurrent liver failure in a child. Arch Argent Pediatr 115:e39–e42. https://doi.org/10.5546/aap.2017.e34
Braga AC, Vilarinho L, Ferreira E, Rocha H (1997) Hyperargininemia presenting as persistent neonatal jaundice and hepatic cirrhosis. J Pediatr Gastroenterol Nutr 24:218–221
Braissant O, McLin VA, Cudalbu C (2013) Ammonia toxicity to the brain. J Inherit Metab Dis 36:595–612. https://doi.org/10.1007/s10545-012-9546-2
Broere D, van Gemert WG, Kneepkens CM et al (2000) A 6-year-old boy with hyperammonaemia: partial N-acetylglutamate synthase deficiency or portosystemic encephalopathy? Eur J Pediatr 159:905–907
Burgard P, Kölker S, Haege G et al (2015) Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders—review and meta-analysis of observational studies published over more than 35 years. J Inherit Metab Dis 39:219–229. https://doi.org/10.1007/s10545-015-9901-1
Capistrano-Estrada S, Marsden DL, Nyhan WL et al (1994) Histopathological findings in a male with late-onset ornithine transcarbamylase deficiency. Pediatr Pathol Affil Int Paediatr Pathol Assoc 14:235–243
Cederbaum SD, Shaw KN, Spector EB et al (1979) Hyperargininemia with arginase deficiency. Pediatr Res 13:827–833. https://doi.org/10.1203/00006450-197907000-00007
Chang K-W, Chen H-L, Chien Y-H et al (2011) SLC25A13 gene mutations in Taiwanese patients with non-viral hepatocellular carcinoma. Mol Genet Metab 103:293–296. https://doi.org/10.1016/j.ymgme.2011.03.013
Chapuy CI, Sahai I, Sharma R et al (2016) Hyperammonemic encephalopathy associated with fibrolamellar hepatocellular carcinoma: case report, literature review, and proposed treatment algorithm. Oncologist 21:514–520. https://doi.org/10.1634/theoncologist.2015-0267
Crombez EA, Cederbaum SD (2005) Hyperargininemia due to liver arginase deficiency. Mol Genet Metab 84:243–251. https://doi.org/10.1016/j.ymgme.2004.11.004
Dasarathy S, Mookerjee RP, Rackayova V et al (2017) Ammonia toxicity: from head to toe? Metab Brain Dis 32:529–538. https://doi.org/10.1007/s11011-016-9938-3
Debray F-G, Lambert M, Lemieux B et al (2008) Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15. J Med Genet 45:759–764. https://doi.org/10.1136/jmg.2008.059097
Dionisi Vici C, Bachmann C, Gambarara M et al (1987) Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement. Pediatr Res 22:364–367. https://doi.org/10.1203/00006450-198709000-00025
Edwards RL, Moseley K, Watanabe Y et al (2009) Long-term neurodevelopmental effects of early detection and treatment in a 6-year-old patient with argininaemia diagnosed by newborn screening. J Inherit Metab Dis 32(Suppl 1):S197–S200. https://doi.org/10.1007/s10545-009-1148-2
Erez A, Shchelochkov OA, Plon SE et al (2011) Insights into the pathogenesis and treatment of cancer from inborn errors of metabolism. Am J Hum Genet 88:402–421. https://doi.org/10.1016/j.ajhg.2011.03.005
Faghfoury H, Baruteau J, de Baulny HO et al (2011) Transient fulminant liver failure as an initial presentation in citrullinemia type I. Mol Genet Metab 102:413–417. https://doi.org/10.1016/j.ymgme.2010.12.007
Fecarotta S, Parenti G, Vajro P et al (2006) HHH syndrome (hyperornithinaemia, hyperammonaemia, homocitrullinuria), with fulminant hepatitis-like presentation. J Inherit Metab Dis 29:186–189. https://doi.org/10.1007/s10545-006-0120-7
Ficicioglu C, Mandell R, Shih VE (2009) Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening. Mol Genet Metab 98:273–277. https://doi.org/10.1016/j.ymgme.2009.06.011
Forget PP, van Oosterhout M, Bakker J et al (1999) Partial N-acetyl-glutamate synthetase deficiency masquerading as a valproic acid-induced Reye-like syndrome. Acta PaediatrActa Pædiatrica 88:1409–1411. https://doi.org/10.1111/j.1651-2227.1999.tb01062.x
Freeman JM, Nicholson JF, Schimke RT et al (1970) Congenital hyperammonemia. Association with hyperglycinemia and decreased levels of carbamyl phosphate synthetase. Arch Neurol 23:430–437
Fukumoto K, Sumida Y, Yoshida N et al (2008) A case of adult-onset type II citrullinemia having a liver histology of nonalcoholic steatohepatitis (NASH). Nihon Shokakibyo Gakkai Zasshi Jpn J Gastro-Enterol 105:244–251
Gallagher RC, Lam C, Wong D et al (2014) Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. J Pediatr 164:720–725.e6. https://doi.org/10.1016/j.jpeds.2013.12.024
Gao J, Gao F, Hong F et al (2015) Hyperammonemic encephalopathy in a child with ornithine transcarbamylase deficiency due to a novel combined heterozygous mutations. Am J Emerg Med 33:474.e1–3. https://doi.org/10.1016/j.ajem.2014.08.038
Gatfield PD, Taller E, Wolfe DM, Haust MD (1975) Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamyl phosphate synthetase I activity. Pediatr Res 9:488–497
Gjessing LR, Lunde HA, Undrum T et al (1986) A new patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria treated early with low protein diet. J Inherit Metab Dis 9:186–192
Glick NR, Snodgrass PJ, Schafer IA (1976) Neonatal argininosuccinic aciduria with normal brain and kidney but absent liver argininosuccinate lyase activity. Am J Hum Genet 28:22–30
Gomes Martins E, Santos Silva E, Vilarinho S et al (2010) Neonatal cholestasis: an uncommon presentation of hyperargininemia. J Inherit Metab Dis 33(Suppl 3):S503–S506. https://doi.org/10.1007/s10545-010-9263-7
Grody WW, Argyle C, Kern RM et al (1989) Differential expression of the two human arginase genes in hyperargininemia. Enzymatic, pathologic, and molecular analysis. J Clin Invest 83:602–609. https://doi.org/10.1172/JCI113923
de Groot MJ, Cuppen M, Eling M et al (2010) Metabolic investigations prevent liver transplantation in two young children with citrullinemia type I. J Inherit Metab Dis 33(Suppl 3):S413–S416. https://doi.org/10.1007/s10545-010-9207-2
Grosfeld JC, Mighorst JA, Moolhuysen TM (1964) Argininosuccinic aciduria in monilethrix. Lancet 2:789–791
Güçer S, Aşan E, Atilla P et al (2004) Early cirrhosis in a patient with type I citrullinaemia (CTLN1). J Inherit Metab Dis 27:541–542
Haberle J, Boddaert N, Burlina A et al (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 7:32. https://doi.org/10.1186/1750-1172-7-32
Hachisu M, Oda Y, Goto M et al (2005) Citrin deficiency presenting with ketotic hypoglycaemia and hepatomegaly in childhood. Eur J Pediatr 164:109–110. https://doi.org/10.1007/s00431-004-1549-z
Hagiwara N, Sekijima Y, Takei Y et al (2003) Hepatocellular carcinoma in a case of adult-onset type II citrullinemia. Intern Med Tokyo Jpn 42:978–982
Hashash JG, Thudi K, Malik SM (2012) An 18-year-old woman with a 15-cm liver mass and an ammonia level of 342. Gastroenterology 143(1157):1401–1402. https://doi.org/10.1053/j.gastro.2012.07.002
Haust MD, Gordon BA (1980) Ultrastructural changes in the mitochondria in disorders in ornithine metabolism. Pediatr Res 14:1411. https://doi.org/10.1203/00006450-198012000-00032
Haust MD, Gatfield PD, Gordon BA (1981) Ultrastructure of hepatic mitochondria in a child with hyperornithinemia, hyperammonemia, and homocitrullinuria. Hum Pathol 12:212–222
Heick HM, Shipman RT, Norman MG, James W (1980) Reye-like syndrome associated with use of insect repellent in a presumed heterozygote for ornithine carbamoyl transferase deficiency. J Pediatr 97:471–473
Holecek M, Vodenicarovova M (2016) Phenylbutyrate exerts adverse effects on liver regeneration and amino acid concentrations in partially hepatectomized rats. Int J Exp Pathol 97:278–284. https://doi.org/10.1111/iep.12190
Hopkins IJ, Connelly JF, Dawson AG et al (1969) Hyperammonaemia due to ornithine transcarbamylase deficiency. Arch Dis Child 44:143–148
Hutchin T, Preece MA, Hendriksz C et al (2009) Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK. J Inherit Metab Dis 32(Suppl 1):S151–S155. https://doi.org/10.1007/s10545-009-1116-x
Ikeda S, Yazaki M, Takei Y et al (2001) Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation. J Neurol Neurosurg Psychiatry 71:663–670
Inui A, Hashimoto T, Sogo T et al (2015) Chronic hepatitis without hepatic steatosis caused by citrin deficiency in a child. Hepatol Res Off J Jpn Soc Hepatol. https://doi.org/10.1111/hepr.12559
Itkonen O, Stenman U-H (2014) TATI as a biomarker. Clin Chim Acta Int J Clin Chem 431:260–269. https://doi.org/10.1016/j.cca.2014.02.014
Ito T, Shiraki K, Sekoguchi K et al (2000) Hepatocellular carcinoma associated with adult-type citrullinemia. Dig Dis Sci 45:2203–2206
Ito S, Kurasawa G, Yamamoto K et al (2004) A pregnant patient with fulminant hepatic failure was found to carry a novel missense mutation in the argininosuccinate synthetase gene. J Gastroenterol 39:1115–1117. https://doi.org/10.1007/s00535-004-1455-1
Jeffers LJ, Dubow RA, Zieve L et al (1988) Hepatic encephalopathy and orotic aciduria associated with hepatocellular carcinoma in a noncirrhotic liver. Hepatol Baltim Md 8:78–81
Jevon GP, Dimmick JE (1998) Histopathologic approach to metabolic liver disease: pPart 1. Pediatr Dev Pathol Off J Soc Pediatr Pathol Paediatr Pathol Soc 1:179–199
Jordá A, Rubio V, Portolés M et al (1986) A new case of arginase deficiency in a Spanish male. J Inherit Metab Dis 9:393–397
Keskinen P, Siitonen A, Salo M (2008) Hereditary urea cycle diseases in Finland. Acta Paediatr Oslo Nor 1992 97:1412–1419. https://doi.org/10.1111/j.1651-2227.2008.00923.x
Kimura A, Kage M, Nagata I et al (2010) Histological findings in the livers of patients with neonatal intrahepatic cholestasis caused by citrin deficiency. Hepatol Res Off J Jpn Soc Hepatol 40:295–303. https://doi.org/10.1111/j.1872-034X.2009.00594.x
Kobayashi K, Saheki T, Song Y-Z (1993) Citrin deficiency. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews. University of Washington, Seattle, Seattle (WA)
Kobayashi K, Nakata M, Terazono H et al (1995) Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult-onset type II citrullinemia. FEBS Lett 372:69–73
Kobayashi K, Horiuchi M, Saheki T (1997) Pancreatic secretory trypsin inhibitor as a diagnostic marker for adult-onset type II citrullinemia. Hepatol Baltim Md 25:1160–1165. https://doi.org/10.1002/hep.510250519
Kölker S, Cazorla AG, Valayannopoulos V et al (2015a) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 38:1041–1057. https://doi.org/10.1007/s10545-015-9839-3
Kölker S, Valayannopoulos V, Burlina AB et al (2015b) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis 38:1059–1074. https://doi.org/10.1007/s10545-015-9840-x
Komatsu M, Yazaki M, Tanaka N et al (2008) Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. J Hepatol 49:810–820. https://doi.org/10.1016/j.jhep.2008.05.016
Komatsu M, Kimura T, Yazaki M et al (2015) Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα. Biochim Biophys Acta 1852:473–481. https://doi.org/10.1016/j.bbadis.2014.12.011
Korman SH, Kanazawa N, Abu-Libdeh B et al (2004) Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family. J Neurol Sci 218:53–58. https://doi.org/10.1016/j.jns.2003.10.017
LaBrecque DR, Latham PS, Riely CA et al (1979) Heritable urea cycle enzyme deficiency-liver disease in 16 patients. J Pediatr 94:580–587
Laemmle A, Gallagher RC, Keogh A et al (2016) Frequency and pathophysiology of acute liver failure in ornithine transcarbamylase deficiency (OTCD). PLoS One. https://doi.org/10.1371/journal.pone.0153358
Landrieu P, François B, Lyon G, Van Hoof F (1982) Liver peroxisome damage during acute hepatic failure in partial ornithine transcarbamylase deficiency. Pediatr Res 16:977–981
Largillière C, Houssin D, Gottrand F et al (1989) Liver transplantation for ornithine transcarbamylase deficiency in a girl. J Pediatr 115:415–417
Latham PS, LaBrecque DR, McReynolds JW, Klatskin G (1984) Liver ultrastructure in mitochondrial urea cycle enzyme deficiencies and comparison with Reye’s syndrome. Hepatol Baltim Md 4:404–407
Lee HHC, Poon KH, Lai CK et al (2014) Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis. Hong Kong Med J 20:63–66
Levin B, Abraham JM, Oberholzer VG, Burgess EA (1969) Hyperammonaemia: a deficiency of liver ornithine transcarbamylase. Occurrence in mother and child. Arch Dis Child 44:152–161
Lien J, Nyhan WL, Barshop BA (2007) Fatal initial adult-onset presentation of urea cycle defect. Arch Neurol 64:1777–1779. https://doi.org/10.1001/archneur.64.12.1777
Martinelli D, Diodato D, Ponzi E et al (2015) The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome. Orphanet J Rare Dis. https://doi.org/10.1186/s13023-015-0242-9
Martín-Hernández E, Aldámiz-Echevarría L, Castejón-Ponce E et al (2014) Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. Orphanet J Rare Dis 9:187. https://doi.org/10.1186/s13023-014-0187-4
Mercimek-Mahmutoglu S, Moeslinger D, Häberle J et al (2010) Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria. Mol Genet Metab 100:24–28. https://doi.org/10.1016/j.ymgme.2010.01.013
Mew NA, Caldovic L (2011) N-acetylglutamate synthase deficiency: an insight into the genetics, epidemiology, pathophysiology, and treatment. Appl Clin Genet 4:127–135. https://doi.org/10.2147/TACG.S12702
Mhanni AA, Chan A, Collison M et al (2008) Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) presenting with acute fulminant hepatic failure. J Pediatr Gastroenterol Nutr 46:312–315. https://doi.org/10.1097/MPG.0b013e318145a8e5
Miles L, Heubi JE, Bove KE (2005) Hepatocyte glycogen accumulation in patients undergoing dietary management of urea cycle defects mimics storage disease. J Pediatr Gastroenterol Nutr 40:471–476
Mori T, Nagai K, Mori M et al (2002) Progressive liver fibrosis in late-onset argininosuccinate lyase deficiency. Pediatr Dev Pathol Off J Soc Pediatr Pathol Paediatr Pathol Soc 5:597–601. https://doi.org/10.1007/s10024-002-0109-7
Mustafa A, Clarke JTR (2006) Ornithine transcarbamoylase deficiency presenting with acute liver failure. J Inherit Metab Dis 29:586. https://doi.org/10.1007/s10545-006-0303-2
Myers JH, Shook JE (1996) Vomiting, ataxia, and altered mental status in an adolescent: late-onset ornithine transcarbamylase deficiency. Am J Emerg Med 14:553–557. https://doi.org/10.1016/S0735-6757(96)90097-2
Nagamani SCS, Erez A, Lee B (2012a) Argininosuccinate lyase deficiency. Genet mMed oOff J aAm Coll. Med Genet 14:501–507. https://doi.org/10.1038/gim.2011.1
Nagamani SCS, Shchelochkov OA, Mullins MA et al (2012b) A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria. Mol Genet Metab 107:315–321. https://doi.org/10.1016/j.ymgme.2012.09.016
Nagasaka H, Okano Y, Tsukahara H et al (2009) Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period. Mol Genet Metab 97:21–26. https://doi.org/10.1016/j.ymgme.2009.01.009
Nakayama M, Okamoto Y, Morita T et al (1990) Promoting effect of citrulline in hepatocarcinogenesis: possible mechanism in hypercitrullinemia. Hepatol Baltim Md 11:819–823
Navarro LA, Wree A, Povero D et al (2015) Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis. J Hepatol 62:412–420. https://doi.org/10.1016/j.jhep.2014.09.015
Nettesheim S, Kölker S, Karall D et al (2017) Incidence, disease onset and short-term outcome in urea cycle disorders -cross-border surveillance in Germany, Austria and Switzerland. Orphanet J Rare Dis 12:111. https://doi.org/10.1186/s13023-017-0661-x
Newnham T, Hardikar W, Allen K et al (2008) Liver transplantation for argininosuccinic aciduria: cClinical, biochemical, and metabolic outcome. Liver Transpl 14:41–45. https://doi.org/10.1002/lt.21297
Ohura T, Kobayashi K, Tazawa Y et al (2007) Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis 30:139–144. https://doi.org/10.1007/s10545-007-0506-1
Paju A, Stenman U-H (2006) Biochemistry and clinical role of trypsinogens and pancreatic secretory trypsin inhibitor. Crit Rev Clin Lab Sci 43:103–142. https://doi.org/10.1080/10408360500523852
Palmieri F (2008) Diseases caused by defects of mitochondrial carriers: a review. Biochim Biophys Acta 1777:564–578. https://doi.org/10.1016/j.bbabio.2008.03.008
Persico M, Masarone M, Damato A et al (2017) Non alcoholic fatty liver disease and eNOS dysfunction in humans. BMC Gastroenterol 17:35. https://doi.org/10.1186/s12876-017-0592-y
Portolés M, Jordá A, Vilas J, García-Piño J (1987) Arginase deficiency, congenital hypothyroidism and hepatic fibrosis. An Esp Pediatría 27:462–466
Rodríguez-Suárez E, Duce AM, Caballería J et al (2010) Non-alcoholic fatty liver disease proteomics. Proteomics Clin Appl 4:362–371. https://doi.org/10.1002/prca.200900119
Rüegger CM, Lindner M, Ballhausen D et al (2014) Cross-sectional observational study of 208 patients with non-classical urea cycle disorders. J Inherit Metab Dis 37:21–30. https://doi.org/10.1007/s10545-013-9624-0
Saegusa S, Sugaya H, Kobayashi T et al (1993) Laparoscopical fFindings of lLate oOnset Hypercitrullinemia. Gastroenterol Endosc 35:1616–1622_1. 10.11280/gee1973b.35.1616
Salek J, Byrne J, Box T et al (2010) Recurrent liver failure in a 25-year-old female. Liver tTransplant. Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc 16:1049–1053. https://doi.org/10.1002/lt.22118
Samuel N, Politansky AK, Hoffman R et al (2013) Coagulopathy unmasking hepatic failure in a child with ornithine transcarbamylase deficiency. Isr Med Assoc J IMAJ 15:777–779
Saudubray JM, Touati G, Delonlay P et al (1999) Liver transplantation in urea cycle disorders. Eur J Pediatr 158(Suppl 2):S55–S59
Scaglia F, Lee B (2006) Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency. Am J Med Genet C Semin Med Genet 142C:113–120. https://doi.org/10.1002/ajmg.c.30091
Scaglia F, Brunetti-Pierri N, Kleppe S et al (2004) Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr 134:2775S–2782S discussion 2796S–2797S
Schiff M, Benoist J-F, Cardoso ML et al (2009) Early-onset hyperargininaemia: a severe disorder? J Inherit Metab Dis 32(Suppl 1):S175–S178. https://doi.org/10.1007/s10545-009-1137-5
Schlune A, Vom Dahl S, Häussinger D et al (2015) Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids 47:1751–1762. https://doi.org/10.1007/s00726-015-2032-z
Sethi S, Tageja N, Singh J et al (2009) Hyperammonemic encephalopathy: a rare presentation of fibrolamellar hepatocellular carcinoma. Am J Med Sci 338:522–524. https://doi.org/10.1097/MAJ.0b013e3181bccfb4
Shapiro JM, Schaffner F, Tallan HH, Gaull GE (1980) Mitochondrial abnormalities of liver in primary ornithine transcarbamylase deficiency. Pediatr Res 14:735–739. https://doi.org/10.1203/00006450-198005000-00006
Shigeta T, Kasahara M, Kimura T et al (2010) Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor. Pediatr Transplant 14:E86–E88. https://doi.org/10.1111/j.1399-3046.2009.01172.x
Shih VE, Laframboise R, Mandell R, Pichette J (1992) Neonatal form of the hyperornithinaemia, hyperammonaemia, and homocitrullinuria (HHH) syndrome and prenatal diagnosis. Prenat Diagn 12:717–723. https://doi.org/10.1002/pd.1970120905
Simell O, Mackenzie S, Clow CL, Scriver CR (1985) Ornithine lLoading dDid nNot pPrevent iInduced hHyper ammonemia in a pPatient with Hyperornithinemia- Hyperammonemia-Homocitrullinuria sSyndrome. Pediatr Res 19:1283–1287. https://doi.org/10.1203/00006450-198512000-00016
Sinclair M, Ket S, Testro A et al (2014) Acute hepatic decompensation precipitated by pregnancy-related catabolic stress: a rare mimic of acute liver failure. Obstet Gynecol 123:480–483. https://doi.org/10.1097/AOG.000000000000005
Sloas HA 3rd, Ence TC, Mendez DR, Cruz AT (2013) At the intersection of toxicology, psychiatry, and genetics: a diagnosis of ornithine transcarbamylase deficiency. Am J Emerg Med 31:1420.e5–6. https://doi.org/10.1016/j.ajem.2013.05.010
Smith L, Lambert MA, Brochu P et al (1992) Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy. J Pediatr Gastroenterol Nutr 15:431–436
Soeda J, Yazaki M, Nakata T et al (2008) Primary liver carcinoma exhibiting dual hepatocellular-biliary epithelial differentiations associated with citrin deficiency: a case report. J Clin Gastroenterol 42:855–860. https://doi.org/10.1097/01.mcg.0000225683.29841.9c
Song F, Loke YK, Walsh T et al (2009) Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. BMJ 338:b1147
Sulaiman RA, Geberhiwot T (2014) Fibrolamellar hepatocellular carcinoma mimicking ornithine transcarbamylase deficiency. JIMD Rep 16:47–50. https://doi.org/10.1007/8904_2014_318
Summar ML, Koelker S, Freedenberg D et al (2013) The incidence of urea cycle disorders. Mol Genet Metab 110:179–180. https://doi.org/10.1016/j.ymgme.2013.07.008
Sunshine P, Lindenbaum JE, Levy HL, Freeman JM (1972) Hyperammonemia due to a defect in hepatic ornithine transcarbamylase. Pediatrics 50:100–111
Surjan RC, Dos Santos ES, Basseres T et al (2017) A proposed physiopathological pathway to hyperammonemic encephalopathy in a non-cirrhotic patient with fibrolamellar hepatocellular carcinoma without ornithine transcarbamylase (OTC) mutation. Am J Case Rep 18:234–241
Takagi H, Hagiwara S, Hashizume H et al (2006) Adult onset type II citrullinemia as a cause of non-alcoholic steatohepatitis. J Hepatol 44:236–239. https://doi.org/10.1016/j.jhep.2005.08.024
Takenaka K, Yasuda I, Araki H et al (2000) Type II citrullinemia in an elderly patient treated with living related partial liver transplantation. Intern Med Tokyo Jpn 39:553–558
Tallan HH, Schaffner F, Taffet SL et al (1983) Ornithine carbamoyltransferase deficiency in an adult male patient: significance of hepatic ultrastructure in clinical diagnosis. Pediatrics 71:224–232
Tamamori A, Okano Y, Ozaki H et al (2002) Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur J Pediatr 161:609–613. https://doi.org/10.1007/s00431-002-1045-2
Tan VP, Miyamoto S (2016) Nutrient-sensing mTORC1: iIntegration of metabolic and autophagic signals. J Mol Cell Cardiol 95:31–41. https://doi.org/10.1016/j.yjmcc.2016.01.005
Tanaka T, Nagao M, Tsutsumi H (2002) Application of mutation analysis for the previously uncertain cases of adult-onset type II citrullinemia (CTLN2) and their clinical profiles. Tohoku J Exp Med 198:89–97
Tanaka N, Yazaki M, Kobayashi K (2007) A lean man with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 5:A32. https://doi.org/10.1016/j.cgh.2006.06.014
Tanaka K, Nakamura K, atsumoto M, S et al (2016) Citrulline administration for urea cycle disorders in Japan. Pediatr Int. https://doi.org/10.1111/ped.13163
Tazawa Y, Kobayashi K, Ohura T et al (2001) Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. J Pediatr 138:735–740. https://doi.org/10.1067/mpd.2001.113264
Tessa A, Fiermonte G, Dionisi-Vici C et al (2009) Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Hum Mutat 30:741–748. https://doi.org/10.1002/humu.20930
Teufel U, Weitz J, Flechtenmacher C et al (2011) High urgency liver transplantation in ornithine transcarbamylase deficiency presenting with acute liver failure. Pediatr Transplant 15:E110–E115. https://doi.org/10.1111/j.1399-3046.2009.01171.x
Thaler MM, Hoogenraad NJ, Boswell M (1974) Reye’s syndrome due to a novel protein-tolerant variant of ornithine-transcarbamylase deficiency. Lancet Lond Engl 2:438–440
Thomsen KL, Grønbæk H, Glavind E et al (2014) Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function. Am J Physiol Gastrointest Liver Physiol 307:G295–G301. https://doi.org/10.1152/ajpgi.00036.2014
Todo S, Starzl TE, Tzakis A et al (1992) Orthotopic liver transplantation for urea cycle enzyme deficiency. Hepatol Baltim Md 15:419–422
Tomomasa T, Kobayashi K, Kaneko H et al (2001) Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy. J Pediatr 138:741–743. https://doi.org/10.1067/mpd.2001.113361
Trevisson E, Salviati L, Baldoin MC et al (2007) Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. Hum Mutat 28:694–702. https://doi.org/10.1002/humu.20498
Trivedi M, Zafar S, Spalding MJ, Jonnalagadda S (2001) Ornithine transcarbamylase deficiency unmasked because of gastrointestinal bleeding. J Clin Gastroenterol 32:340–343
Tsai C-W, Yang C-C, Chen H-L et al (2006) Homozygous SLC25A13 mutation in a Taiwanese patient with adult-onset citrullinemia complicated with steatosis and hepatocellular carcinoma. J Formos Med Assoc Taiwan Yi Zhi 105:852–856. https://doi.org/10.1016/S0929-6646(09)60274-6
Tsang JPK, Poon WL, Luk HM et al (2012) Arginase deficiency with new phenotype and a novel mutation: contemporary summary. Pediatr Neurol 47:263–269. https://doi.org/10.1016/j.pediatrneurol.2012.06.012
Tsujii T, Morita T, Matsuyama Y et al (1976) Sibling cases of chronic recurrent hepatocerebral disease with hypercitrullinemia. Gastroenterol Jpn 11:328–340
Tuchman M, Lee B, Lichter-Konecki U et al (2008) Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab 94:397–402. https://doi.org/10.1016/j.ymgme.2008.05.004
Wang L, Bell P, Morizono H et al (2017) AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice. Mol Genet Metab 120:299–305. https://doi.org/10.1016/j.ymgme.2017.02.011
Weber FL, Snodgrass PJ, Powell DE et al (1979) Abnormalities of hepatic mitochondrial urea-cycle enzyme activities and hepatic ultrastructure in acute fatty liver of pregnancy. J Lab Clin Med 94:27–41
Wen W, Yin D, Huang F et al (2016) NGS in argininosuccinic aciduria detects a mutation (D145G) which drives alternative splicing of ASL: a case report study. BMC Med Genet 17:9. https://doi.org/10.1186/s12881-016-0273-7
Wendel U, Wieland J, Bremer HJ, Bachmann C (1989) Ornithine transcarbamylase deficiency in a male: strict correlation between metabolic control and plasma arginine concentration. Eur J Pediatr 148:349–352
Wilson JM, Shchelochkov OA, Gallagher RC, Batshaw ML (2012) Hepatocellular carcinoma in a research subject with ornithine transcarbamylase deficiency. Mol Genet Metab 105:263–265. https://doi.org/10.1016/j.ymgme.2011.10.016
Winter HS, Perezatayde A, Levy HL, Shih VE (1980) Unique hepatic ultrastructural-changes in a patient with hyperammonemia (HAM), hyperornithinemia (HOR), and homocitrullinuria (HC). In: Pediatric research. Williams & Wilkins, Baltimore, MD, pp 583–583
Wu T, Li X, Ding Y et al (2015) Seven patients of argininemia with spastic tetraplegia as the first and major symptom and prenatal diagnosis of two fetuses with high risk. Zhonghua Er Ke Za Zhi Chin J Pediatr 53:425–430
Yankol Y, Mecit N, Kanmaz T et al (2016) Argininosuccinic aciduria-a rare indication for liver transplant: report of two cases. Exp Clin Transplant. https://doi.org/10.6002/ect.2015.0078
Yaplito-Lee J, Chow C-W, Boneh A (2013) Histopathological findings in livers of patients with urea cycle disorders. Mol Genet Metab 108:161–165. https://doi.org/10.1016/j.ymgme.2013.01.006
Yokoi T, Honke K, Funabashi T et al (1981) Partial ornithine transcarbamylase deficiency simulating Reye syndrome. J Pediatr 99:929–931
Zammarchi E, Donati MA, Filippi L, Resti M (1996) Cryptogenic hepatitis masking the diagnosis of ornithine transcarbamylase deficiency. J Pediatr Gastroenterol Nutr 22:380–383
Zamora SA, Pinto A, Scott RB, Parsons HG (1997) Mitochondrial abnormalities of liver in two children with citrullinaemia. J Inherit Metab Dis 20:509–516
Zhao X-J, Tang X-M, Zha Q-B et al (2011) Prenatal diagnosis of citrin deficiency in a Chinese family with a fatal proband. Tohoku J Exp Med 225:273–276
Zimmermann A, Bachmann C, Schubiger G (1985) Liver pathology in a new congenital disorder of urea synthesis: N-acetylglutamate synthetase deficiency. Virchows Arch A Pathol Anat Histopathol 408:259–268
Zimmermann A, Bachmann C, Baumgartner R (1986) Severe liver fibrosis in argininosuccinic aciduria. Arch Pathol Lab Med 110:136–140
Zimmermann A, Moll C, Bachmann C (1987) Liver fibrosis in carbamoylphosphate synthetase deficiency. Pediatr Pathol Affil Int Paediatr Pathol Assoc 7:191–200
Acknowledgements
The authors kindly thank the members of SFEIMA for their help in this study.
Funding
Dr. Adrien Bigot received the 2016 grant from the Adult group of the French Society for Inborn Errors of Metabolisms (SFEIMA) to support this research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
A. Bigot, M.C. Tchan, B. Thoreau, H. Blasco, and F. Maillot declare that they have no conflict of interest.
Ethical disclosure and informed consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Communicated by: John Christodoulou
Rights and permissions
About this article
Cite this article
Bigot, A., Tchan, M.C., Thoreau, B. et al. Liver involvement in urea cycle disorders: a review of the literature. J Inherit Metab Dis 40, 757–769 (2017). https://doi.org/10.1007/s10545-017-0088-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-017-0088-5