Amino Acids

, Volume 49, Issue 2, pp 291–302 | Cite as

Recovery of pan-genotypic and genotype-specific amino acid alterations in chronic hepatitis C after viral clearance: transition at the crossroad of metabolism and immunity

Original Article


Recovery of amino acid (AA) metabolism and the associated clinical implications in chronic hepatitis C (CHC) patients with sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remains elusive. A prospective cohort study was conducted on 222 CHC patients with SVR. Eighty-two age-matched male genotype 1 (G1) and G2 patients underwent paired serum metabolomics analyses with liquid chromatography–tandem mass spectrometry to examine AAs before and 24 weeks after anti-HCV therapy. Before anti-HCV therapy, G1 patients had a higher HCV RNA level than G2 patients. Twenty-four weeks post-therapy versus pre-therapy, repeated-measures ANOVA showed that the levels of alanine aminotransferase and most AAs decreased while those of lipids, glutamine and putrescine increased in CHC patients. The methionine sulfoxide/methionine ratio decreased, while the asymmetric dimethylarginine/arginine, glutamine/glutamate, citrulline/arginine, ornithine/arginine, kynurenine/tryptophan, tyrosine/phenylalanine and Fisher’s ratios increased. Genotype-specific subgroup analyses showed that valine and serotonin/tyrosine increased in G1 and that kynurenine and tyrosine/phenylalanine increased and sarcosine decreased in G2 patients. Viral clearance in CHC patients pan-genotypically restored fuel utilization by decelerating the tricarboxylic acid cycle. Following improvement in liver function, the urea, nitric oxide, methionine, and polyamine cycles were accelerated. The cardiometabolic risk attenuated, but the augmented kynurenine pathway activity could increase the oncogenesis risk. The trends in neurotransmitter formation differed between G1 and G2 patients after SVR. Moreover, the HCV-suppressing effect of valine was evident in G1 patients; with the exception of prostate cancer, the oncogenesis risk increased, particularly in G2 patients, at least within 24 weeks post-anti-HCV therapy.


HCV Genotype Amino acids Targeted metabolomics LC–MS/MS 



The authors thank Mr. Cheng-Yu Huang from Metabolomics Core Laboratory, Health Aging Research Center, Chang Gung University and Mr. Chun-Ming Fan from the Department of Biomedical Sciences, College of Medicine, Chang Gung University for their excellent figure generations and Ms. Shu-Chun Chen from the Liver Research Center, Chang Gung Memorial Hospital, Taiwan, for her data mining assistance.

Compliance with ethical standards


This study was supported by grants from the Chang Gung Medical Research Program (CIRPG3D0121, CMRPG3F0471, CRRPG3F0011, CMRPG3B1743 and XMRPG3A0525) and from the National Science Council, Taiwan (102-2628-B-182-021-MY3, MOST 105-2314-B-182-023, and MOST 105-2629-B-182-001-).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Babudieri S, Soddu A, Nieddu P, Tanca A, Madeddu G, Addis MF, Pagnozzi D, Cossu-Rocca P, Massarelli G, Dore MP, Uzzau S, Mura MS (2013) Proteomic characterization of hepatitis C eradication: enzyme switch in the healing liver. J Clin Virol 57:274–278CrossRefPubMedGoogle Scholar
  2. Baniasadi H, Gowda GA, Gu H, Zeng A, Zhuang S, Skill N, Maluccio M, Raftery D (2013) Targeted metabolic profiling of hepatocellular carcinoma and hepatitis C using LC-MS/MS. Electrophoresis 34:2910–2917PubMedGoogle Scholar
  3. Bladowska J, Zimny A, Knysz B, Małyszczak K, Kołtowska A, Szewczyk P, Gąsiorowski J, Furdal M, Sąsiadek MJ (2013) Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: a pilot study. J Hepatol 59:651–657CrossRefPubMedGoogle Scholar
  4. Boulet MM, Chevrier G, Grenier-Larouche T, Pelletier M, Nadeau M, Scarpa J, Prehn C, Marette A, Adamski J, Tchernof A (2015) Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk. Am J Physiol Endocrinol Metab 309:E736–E746CrossRefPubMedGoogle Scholar
  5. Breuillard C, Cynober L, Moinard C (2015) Citrulline and nitrogen homeostasis: an overview. Amino Acids 47:685–691CrossRefPubMedGoogle Scholar
  6. Burgess DJ (2013) Metabolism: glutamine connections. Nat Rev Cancer 13:293CrossRefPubMedGoogle Scholar
  7. Chang ML (2016) Metabolic alterations and hepatitis C: from bench to bedside. World J Gastroenterol 22:1461–1476CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chang ML, Tsou YK, Hu TH, Lin CH, Lin WR, Sung CM, Chen TH, Cheng ML, Chang KC, Chiu CT, Yeh CT, Pang JH, Shiao MS (2014) Distinct patterns of the lipid alterations between genotype 1 and 2 chronic hepatitis C patients after viral clearance. PLoS One 9:e104783CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chang ML, Liang KH, Ku CL, Lo CC, Cheng YT, Hsu CM, Yeh CT, Chiu CT (2016) Resistin reinforces interferon λ-3 to eliminate hepatitis C virus with fine-tuning from RETN single-nucleotide polymorphisms. Sci Rep 6:30799CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cheng S, Rhee EP, Larson MG, Lewis GD, McCabe EL, Shen D, Palma MJ, Roberts LD, Dejam A, Souza AL, Deik AA, Magnusson M, Fox CS, O’Donnell CJ, Vasan RS, Melander O, Clish CB, Gerszten RE, Wang TJ (2012) Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 125:2222–2231CrossRefPubMedPubMedCentralGoogle Scholar
  11. Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, McHutchison JG, Subramanian M, Millington DM, Kelley RI, Patel K (2012) Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology 56:49–56CrossRefPubMedGoogle Scholar
  12. Dumas ME, Kinross J, Nicholson JK (2014) Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 146:46–62CrossRefPubMedGoogle Scholar
  13. Fitian AI, Nelson DR, Liu C, Xu Y, Ararat M, Cabrera R (2014) Integrated metabolomic profiling of hepatocellular carcinoma in hepatitis C cirrhosis through GC/MS and UPLC/MS-MS. Liver Int 34:1428–1444CrossRefPubMedPubMedCentralGoogle Scholar
  14. Flydal MI, Martinez A (2013) Phenylalanine hydroxylase: function, structure, and regulation. IUBMB Life 65:341–349CrossRefPubMedGoogle Scholar
  15. Fultang L, Vardon A, De Santo C, Mussai F (2016) Molecular basis and current strategies of therapeutic arginine depletion for cancer. Int J Cancer 139:501–509CrossRefPubMedGoogle Scholar
  16. Holecek M (2015) Ammonia and amino acid profiles in liver cirrhosis: effects of variables leading to hepatic encephalopathy. Nutrition 31:14–20CrossRefPubMedGoogle Scholar
  17. Holm E, Sedlaczek O, Grips E (1999) Amino acid metabolism in liver disease. Curr Opin Clin Nutr Metab Care 2:47–53CrossRefPubMedGoogle Scholar
  18. Hoyo-Becerra C, Schlaak JF, Hermann DM (2014) Insights from interferon-α-related depression for the pathogenesis of depression associated with inflammation. Brain Behav Immun 42:222–231CrossRefPubMedGoogle Scholar
  19. Hsu YC, Lin JT, Ho HJ, Kao YH, Huang YT, Hsiao NW, Wu MS, Liu YY, Wu CY (2014) Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology 59:1293–1302CrossRefPubMedGoogle Scholar
  20. Hu JH, Chen MY, Yeh CT, Lin HS, Lin MS, Huang TJ, Chang ML (2016) Sexual dimorphic metabolic alterations in hepatitis C virus-infected patients: a community-based study in a hepatitis b/hepatitis C virus hyperendemic area. Medicine (Baltimore) 95:e3546CrossRefGoogle Scholar
  21. Imae M, Asano T, Murakami S (2014) Potential role of taurine in the prevention of diabetes and metabolic syndrome. Amino Acids 46:81–88CrossRefPubMedGoogle Scholar
  22. Jung YS (2015) Metabolism of sulfur-containing amino acids in the liver: a link between hepatic injury and recovery. Biol Pharm Bull 38:971–974CrossRefPubMedGoogle Scholar
  23. Jungas RL, Halperin ML, Brosnan JT (1992) Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans. Physiol Rev 72:419–448PubMedGoogle Scholar
  24. Kawaguchi T, Izumi N, Charlton MR, Sata M (2011) Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology 54:1063–1070CrossRefPubMedGoogle Scholar
  25. Kawaguchi T, Torimura T, Takata A, Satomi S, Sata M (2012) Valine, a branched-chain amino Acid, reduced HCV viral load and led to eradication of HCV by interferon therapy in a decompensated cirrhotic patient. Case Rep Gastroenterol 6:660–667CrossRefPubMedPubMedCentralGoogle Scholar
  26. Lin IC, Hsu CN, Lo MH, Chien SJ, Tain YL (2016) Low urinary citrulline/arginine ratio associated with blood pressure abnormalities and arterial stiffness in childhood chronic kidney disease. J Am Soc Hypertens 10:115–123CrossRefPubMedGoogle Scholar
  27. Lynch CJ, Adams SH (2014) Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 10:723–736CrossRefPubMedPubMedCentralGoogle Scholar
  28. Miller-Fleming L, Olin-Sandoval V, Campbell K, Ralser M (2015) Remaining mysteries of molecular biology: the role of polyamines in the cell. J Mol Biol 427:3389–3406CrossRefPubMedGoogle Scholar
  29. O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF (2015) Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 277:32–48CrossRefPubMedGoogle Scholar
  30. Papageorgiou N, Androulakis E, Papaioannou S, Antoniades C, Tousoulis D (2015) Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease. Amino Acids 47:1741–1750CrossRefPubMedGoogle Scholar
  31. Ramière C, Rodriguez J, Enache LS, Lotteau V, André P, Diaz O (2014) Activity of hexokinase is increased by its interaction with hepatitis C virus protein NS5A. J Virol 88:3246–3254CrossRefPubMedPubMedCentralGoogle Scholar
  32. Roe B, Kensicki E, Mohney R, Hall WW (2011) Metabolomic profile of hepatitis C virus-infected hepatocytes. PLoS One 6:e23641CrossRefPubMedPubMedCentralGoogle Scholar
  33. Rooks MG, Garrett WS (2016) Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16:341–352CrossRefPubMedGoogle Scholar
  34. Saito T, Sugimoto M, Igarashi K, Saito K, Shao L, Katsumi T, Tomita K, Sato C, Okumoto K, Nishise Y, Watanabe H, Tomita M, Ueno Y, Soga T (2013) Dynamics of serum metabolites in patients with chronic hepatitis C receiving pegylated interferon plus ribavirin: a metabolomics analysis. Metabolism 62:1577–1586CrossRefPubMedGoogle Scholar
  35. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM (2009) Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457:910–914CrossRefPubMedPubMedCentralGoogle Scholar
  36. Sugiyama K, Ebinuma H, Nakamoto N, Sakasegawa N, Murakami Y, Chu PS, Usui S, Ishibashi Y, Wakayama Y, Taniki N, Murata H, Saito Y, Fukasawa M, Saito K, Yamagishi Y, Wakita T, Takaku H, Hibi T, Saito H, Kanai T (2014) Prominent steatosis with hypermetabolism of the cell line permissive for years of infection with hepatitis C virus. PLoS One 9:e94460CrossRefPubMedPubMedCentralGoogle Scholar
  37. Sun H, Zhang A, Yan G, Piao C, Li W, Sun C, Wu X, Li X, Chen Y, Wang X (2013) Metabolomic analysis of key regulatory metabolites in hepatitis C virus-infected tree shrews. Mol Cell Proteom 12:710–719CrossRefGoogle Scholar
  38. Toyoda H, Kumada T, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Ito T (2015) Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection. J Gastroenterol Hepatol 30:1183–1189CrossRefPubMedGoogle Scholar
  39. van Dyk M, Mangoni AA, McEvoy M, Attia JR, Sorich MJ, Rowland A (2015) Targeted arginine metabolomics: a rapid, simple UPLC-QToF-MS(E) based approach for assessing the involvement of arginine metabolism in human disease. Clin Chim Acta 447:59–65CrossRefPubMedGoogle Scholar
  40. Xiao D, Zeng L, Yao K, Kong X, Wu G, Yin Y (2016) The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications. Amino Acids 48:2067–2080CrossRefPubMedGoogle Scholar
  41. Zangerle R, Kurz K, Neurauter G, Kitchen M, Sarcletti M, Fuchs D (2010) Increased blood phenylalanine to tyrosine ratio in HIV-1 infection and correction following effective antiretroviral therapy. Brain Behav Immun 24:403–408CrossRefPubMedGoogle Scholar
  42. Zhang AH, Sun H, Han Y, Yan GL, Yuan Y, Song GC, Yuan XX, Xie N, Wang XJ (2013) Ultraperformance liquid chromatography-mass spectrometry based comprehensive metabolomics combined with pattern recognition and network analysis methods for characterization of metabolites and metabolic pathways from biological data sets. Anal Chem 85:7606–7612CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  1. 1.Division of Hepatology, Department of Gastroenterology and Hepatology, Liver Research CenterChang Gung Memorial HospitalTaoyuanTaiwan, ROC
  2. 2.Department of Medicine, College of MedicineChang Gung UniversityTaoyuanTaiwan, ROC
  3. 3.Department of Biomedical SciencesChang Gung UniversityTaoyuanTaiwan, ROC
  4. 4.Metabolomics Core Laboratory, Healthy Aging Research CenterChang Gung UniversityTaoyuanTaiwan, ROC
  5. 5.Clinical Phenome CenterChang Gung Memorial HospitalTaoyuanTaiwan, ROC
  6. 6.Clinical Informatics and Medical Statistics Research CenterChang Gung UniversityTaoyuanTaiwan, ROC
  7. 7.Division of Allergy, Asthma, and Rheumatology, Department of PediatricsChang Gung Memorial HospitalTaoyuanTaiwan, ROC

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