Ademetionine in patients with liver disease: a review

Authors

  • Sanjiv Saigal Director - Transplant Hepatology, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity Hospital, Haryana, India
  • Dharmesh Kapoor Consultant Hepatologist, Gleneagles Global Hospitals, Hyderabad, India
  • Dyotona Sen Roy Head, Medical Affairs, Abbott India Limited, Mumbai, India

DOI:

https://doi.org/10.18203/2320-6012.ijrms20192550

Keywords:

Ademetionine, CLD, Cirrhosis, Glutathione

Abstract

The aim of the present review is to have an in-depth analysis of the published scientific literature relating to the clinical use of ademetionine in various etiologies of liver disease. Literature search was performed using electronic databases like Pubmed/Medline/others to identify studies on ademetionine in patients with intrahepatic cholestasis, alcoholic liver disease, non-alcoholic fatty liver disease, drug induced liver injury and viral hepatitis. Ademetionine has been studied in various etiologies of liver disease with varying dosing and durations. In patients with chronic and alcoholic liver disease, ademetionine was found to be beneficial in improving liver enzyme levels, increasing glutathione levels, improving signs and symptoms of fatigue, pruritus and jaundice. Positive effects of ademetionine therapy have also been documented in multiple studies in patients with non-alcoholic fatty liver disease, with improvements observed in triglyceride, total cholesterol, alanine transaminase and asprtate transaminase levels and ultrasound grading of fatty change. In patients with drug induced liver injury, improvements were observed in liver biochemical markers and symptoms such as pruritus, fatigue and jaundice. Ademetionine has also been studied in patients with viral hepatitis with improvement in laboratory markers and signs and symptoms. Published data suggest that there is clinical evidence to substantiate the use of ademetionine across indications. Its use has resulted in sustained improvement in biochemical markers; signs and symptoms of liver disease has been observed in both acute and chronic liver disease. Further data is warranted through clinical studies to focus on specific end points of therapy areas, in existing and new indications.

References

Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatol. 2014;60(6):2099-108.

The burden of liver disease in Europe -a review of available epidemiological data. Available at: http://www.easl.eu/medias/EASLimg/Discover/EU/54ae845caec619f_file.pdf. (Accessed on February 2018).

American liver foundation. The liver lowdown- liver disease: the big picture. Available at: http://www.liverfoundation.org/education/liverlowdown/ll1013/bigpicture. (Accessed on February 2018).

WHO. World Health Rankings. Available at: https://en.wikipedia.org/wiki/World_Health_Organization_ranking_of_health_systems_in_2000 (Accessed on Feb 2018).

Zakhari S. Bermuda triangle for the liver: alcohol, obesity, and viral hepatitis. J Gastroenterol Hepatol. 2013;28(1):18-25.

Jüngst C, Berg T, Cheng J, Green RM, Jia J, Mason AL, Lammert F. Intrahepatic cholestasis in common chronic liver diseases. Europ J Clinic Inves. 2013;43(10):1069-83.

Dooley JS, Lok AS, Burroughs AK, Heathcote EJ, ed. Sherlock’s diseases or the liver & biliary system. Wiley-Blackwell; 2011.

World health organization. Mortality and burden of disease attributable to selected major risks. Geneva, Switzerland: World health organization.2009. Global health risks. Available at: https://reliefweb.int/report/world/global-health-risks-mortality-and-burden-disease-attributable-selected-major-risks. (Accessed on Feb 2018).

World gastroenterology organization: e-WGN expert point of view articles collection, 2017: global burden of liver disease: a true burden on health sciences and economies. Available at: http://www.worldgastroenterology.org/publications/e-wgn/e-wgn-expert-point-of-view-articles-collection/global-burden-of-liver-disease-a-true-burden-on-health-sciences-and-economies. (Accessed on March 2017).

Garg V, Garg H, Khan A, Trehanpati N, Kumar A, Sharma BC, et al. Granulocyte colony-stimulating factor mobilizes CD34+cells and improves survival of patients with acute-on-chronic liver failure. Gastroenterol. 2012;142:505-12.

Sarkar AP, Sen S, Mondal S, Singh OP, Chakraborty A, Swaika B. A study on socio-demographic characteristics of alcoholics attending the de-addiction center at Burdwan medical college and hospital in West Bengal. Indian J Pub Heal. 2013;57(1):33.

Pal P, Ray S. Alcoholic liver disease: a comprehensive review. EMJ. 2016;1:85-92.

European association for the study of liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012;57(2):399-420.

Mann RE, Smart RG, Govoni R. The epidemiology of alcoholic liver disease. Alcohol Res Health. 2003;27(3):209-19.

Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol. 2013;59(1):160-8.

Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. Lancet. 1997;349:1498-504.

Bruha R, Dvorak K, Petrtyl J. Alcoholic liver disease. World J Hepatol. 2012;4(3):81-90.

Farrell GC. Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region? J Gastroenterol Hepatol. 2003;18:124-38.

Chitturi S, Farrell GC, George J. Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock? J Gastroenterol Hepatol. 2004;19:368-74.

El-Kader SM, El-Den Ashmawy EM. Non-alcoholic fatty liver disease: The diagnosis and management. World J Hepatol. 2015;7(6):846.

World gastroenterology organization global guidelines. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Available at: http://www.worldgastroenterology.org/assets/export/userfiles/2012_NASH%20and%20NAFLD_Final_long.pdf. Accessed on Feb 2018.

Kalra S, Vithalani M, Gulati G, Kulkarni CM, Kadam Y, Pallivathukkal J, et al. Study of prevalence of nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes patients in India (SPRINT). J Assoc Physic India. 2013;61(7):448-53.

Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58(3):593-608.

Weiß J, Rau M, Geier A. Non-alcoholic fatty liver disease: epidemiology, clinical course, investigation, and treatment. Deutsch Ärzteblatt Int. 2014;111(26):447-52.

Jüngst C, Berg T, Cheng J, Green RM, Jia J, Mason AL, et al. Intrahepatic cholestasis in common chronic liver diseases. European J Clinic Inv. 2013;43(10):1069-83.

Alkhouri N, Carter-Kent C, Feldstein AE. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev Gastroenterol Hepatol. 2011;5(2):201-12.

Sundaram C, Reddy CR, Ramana GV, Benerjea S, Venkataratnam G, Kumari GS, et al. Hepatitis B surface antigen, hepatocellular carcinoma and liver cirrhosis in south India - an autopsy study. Indian J Pathol Microbiol. 1990;33(4):334-8.

Huo T, Wu JC, Hwang SJ, Lai CR, Lee PC, Tsay SH, et al. Factors predictive of Liver Cirrhosis in patients with chronic hepatitis B: a multivariate analysis in a longitudinal study. Eur J Gastroenterol Hepatol. 2000;1(6):687-93.

Tsai JF, Chang WY, Jeng JE, Ho MS, Wang LY, Hsieh MY, et al. Hepatitis C virus infection as a risk factor for non-alcoholic liver cirrhosis in Taiwan. J Med Virol. 1993;41(4):296-300.

Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ. Long-term clinical and histopathological follow up of chronic post-transfusion hepatitis. Hepatol. 1991;14(6):674-969.

Alberti A, Chemello L, Benvegnu L. Natural history of hepatitis C. J Hepatol. 1999;31(1):17-24.

Blankson A, Wiredu E, Gyasi R, Adjei A, Tettey Y. Sero-prevalence of hepatitis B and C viruses in cirrhosis of the liver in Accra, Ghana. Ghana Med J. 2005;39(4):132-7.

Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterol. 2004;127(5):S35-0.

Puri P. Tackling the hepatitis B disease burden in India. J J Clin Exp Hepatol. 2014;4(4):312-9.

Puri P, Anand AC, Saraswat VA. Consensus statement of HCV task force of the Indian national association for study of the liver (INASL). Part I: Status Report of HCV Infection in India. J Clin Exp Hepatol. 2014;4(2):106-6.

Jüngst C, Berg T, Cheng J. Intrahepatic cholestasis in common chronic liver diseases. Eur J Clin Invest. 2013;43(10):1069-83.

Kosanam S, Boyina R. Drug-induced liver injury: a review. Int J Pharm Res. 2015;5(2):24-30.

Larry D. Epidemiology and individual susceptibility to adverse drug reaction affecting the liver. Semin Liver Dis. 2002;22:145.

Hann HW, Han SH, Block TM. Symptomatology and health attitudes of chronic hepatitis B patients in the USA. J Viral Hepatitis. 2008;15:42-51.

Lang CA, Conrad S, Garrett L. Symptom prevalence and clustering of symptoms in people living with chronic hepatitis C infection. J Pain Symptom Manage. 2006;3:335-44.

Sarkar S, Jiang Z, Evon DM. Fatigue before, during and after antiviral therapy of chronic hepatitis C: results from the Virahep-C study. J Hepatol. 2012;57:946-52.

Teuber G, Schafer A, Rimpel J. Deterioration of health-related quality of life and fatigue in patients with chronic hepatitis C: association with demographic factors, inflammatory activity, and degree of fibrosis. J Hepatol. 2008;49:923-9.

Swain MG. Fatigue in liver disease: Pathophysiology and clinical management. Cana J Gastroenterol. 2006;20(3):181.

Newton JL, Jones DE, Henderson E. Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance. Gut. 2008;57:807-13.

Blackburn P, Freeston M, Baker CR. The role of psychological factors in the fatigue of primary biliary cirrhosis. Liver Int. 2007;27:654-1.

Donaldson P, Veeramani S, Baragiotta A. Cytotoxic T-lymphocyte-associated antigen-4 single nucleotide polymorphisms and haplotypes in primary biliary cirrhosis. Clinic Gastroenterol Hepatol. 2007;5:755-60.

Jones DE, Bhala N, Burt J, Goldblatt J, Prince M, Newton JL. Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort. Gut. 2006;55(4):536-41.

Mells GF, Pells G, Newton JL, Bathgate AJ, Burroughs AK, Heneghan MA, et al. Impact of primary biliary cirrhosis on perceived quality of life: The UK‐PBC national study. Hepatol. 2013;58(1):273-83.

Dan AA, Kallman JB, Wheeler A, Younoszai Z, Collantes R, Bondini S, et al. Health‐related quality of life in patients with non‐alcoholic fatty liver disease. Aliment Pharm Therap. 2007;26(6):815-20.

David K, Kowdley KV, Unalp A, Kanwal F, Brunt EM, Schwimmer JB. NASH CRN research group. Quality of life in adults with nonalcoholic fatty liver disease: baseline data from the nonalcoholic steatohepatitis clinical research network. Hepatol. 2009;49(6):1904-2.

Kistler KD, Molleston J, Unalp A, Abrams SH, Behling C, Schwimmer JB et al. Symptoms and QOL in obese children and adolescents with non-alcoholic fatty liver disease. Aliment Pharm Ther. 2010;31:396-406.

Kistler KD, Molleston J, Unalp A, Abrams SH, Behling C, Schwimmer JB. Nonalcoholic steatohepatitis clinical research network (NASH CRN). Symptoms and quality of life in obese children and adolescents with non‐alcoholic fatty liver disease. Alim Pharm Therap. 2010;31(3):396-406.

Jones DE, Bhala N, Burt J, Goldblatt J, Prince M, Newton JL. Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort. Gut. 2006;55(4):536-41.

Weissenborn K, Ennen JC, Bokemeyer M, Ahl B, Wurster U, Tillmann H, et al. Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut. 2006;55(11):1624-30.

Donaldson P, Veeramani S, Baragiotta A. Cytotoxic T-lymphocyte-associated antigen-4 single nucleotide polymorphisms and haplotypes in primary biliary cirrhosis. Clin Gastroenterol. Hepatol. 2007;5:755-60.

Raszeja-Wyszomirska J, Wunsch E, Kempinska-Podhorodecka A. TRAF1-C5 affects quality of life in patients with primary biliary cirrhosis. Clin Dev Immunol. 2013;2013.

Kremer AE, Oude Elferink RP, Beuers U. Pathophysiology and current management of pruritus in liver disease. Clin Res Hepatol Gastroenterol. 2011;35(2):89-7.

Neuberger J, Jones EA. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy. Eur J Gastroenterol Hepatol. 2001;13(11):1393-4.

Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112(1):18-35.

United states patent application publication. Available at: https://www.google.ch/patents/US20120040923?hl=de. Accessed on Feb 2018.

Defective SAMe enters US Market. Life extension. Available at: http://www.lef.org/magazine/mag2004/ss2004_same_01.htm. Accessed on Feb 2018.

Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol. 2006;87:1-16.

Wortham M, He L, Gyamfi M, Copple BL, Wan YJ. The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet. Dig Dis Sci. 2008;53(10):2761-74.

Anstee QM, Day CP. S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol. 2012;57(5):1097.

Martínez-Chantar ML, García-Trevijano ER, Latasa MU, Pérez-Mato I, Sánchez del Pino MM, Corrales FJ, et al. Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury. Am J Clinic Nutrit. 2002;76(5):1177S-82S.

Lieber CS. S-Adenosyl-L-methionine: its role in the treatment of liver disorders. Am J Clin Nutr. 2002;76:1183S-7S.

Lieber CS. Role of S-adenosyl-L-methionine in the treatment of liver disorders. J Hepatol. 1999;30:1155-9.

Vendemiale G, Altomare E, Trizio T, Le Grazie C, Di Padova C, Salerno MT, et al. Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol. 1989;24(4):407-15.

Choudhuri G, Singh T. Heptral® (Ademetionine) in patients with chronic alcoholic liver disease: results of a multicenter observational study in Indian patients. Int J Res Health Sci. 2014;2(3):831-41.

Frezza M, Surrenti C, Manzillo G, Fiaccadori F, Bortolini M, Di Padova C. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis: a double-blind, placebo-controlled study. Gastroenterol. 1990;99(1):211-5.

Frezza M, Terpin M. The use of S-adenosyl-L-methionine in the treatment of cholestatic disorders. A meta-analysis of clinical trials. Drug Inv. 1992;4(4):101-8.

Manzillo G, Piccinino F, Surrenti C, Frezza M, Giudici GA, Le Grazie C. Multicentre double-blind placebo-controlled study of intravenous and oral s-adenosyl-L-methionine (SAMe) in cholestatic patients with liver disease. Drug Invest. 1992:90-100.

Perr D. Ademethionine in the treatment of chronic Hepatic Disease. Gastroenterol Int. 1999;12(2):62-8.

Podymova SD, Mlu N. Clinical trial of heptral in patients with chronic diffuse liver disease with intrahepatic cholestasis syndrome. Clinic Med. 1998;76(10):45-8.

Fiorelli G. S-adenosylmethionine in the treatment of intrahepatic cholestasis of chronic liver disease:a field trial. Curr Ther Res Clin Exp. 1999;60(6):335-48.

Kharchenko NV. Ademetionine in the treatment of intrahepatic cholestasis in routine clinical practice in Ukraine: a prospective, post marketing observational study. Contemp Gastroenterol. 2013;5(73):60-8.

Mato JM, Cámara J, de Paz JF, Caballería L, Coll S, Caballero A, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999;30(6):1081-9.

Altomare E, Vendemiale G, Marchesini G, Legrazie C, Dipadova C. Increased bioavailability of sulfurated compounds after S-adenosylmethionine (SAMe) administration to alcoholics. Biomed Soc Aspects Alcohol Alcohol. 1988;805:353-6.

Vendemiale G, Altomare E, Trizio T, Le Grazie C, Di Padova C, Salerno MT, et al. Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol. 1989;24(4):407-15.

Corrales F, Paiares M, Pliego M, Ortiz P, Moreno J, Puerta J, et al. Effect of S-adenosylmethionine treatment on methionine intolerance in alcoholic cirrhosis. J Hepatol. 1991;13:S111.

Loguercio C, Nardi G, Argenzio F, Aurilio C, Petrone E, Grella A, et al. Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. Alcohol Alcoholism. 1994;29(5):597-604.

Diaz Belmont A, Dominguez Henkel R, Uribe Ancira F. Parenteral S-adenosylmethionine compared to placebos in the treatment of alcoholic liver diseases. Ann Med Intern. 1996;13(1):9-15.

Chawla RK, Gaetke L, McClain CJ. S-adenosylmethionine (Adomet) and plasma methionine clearance in alcoholic subjects. Hepatol. 1999;30(4):397A.

Lei MA. Observation of efficacy of treating non-alcoholic steatohepatitis by S-adenosyl-methionine. Chinese Hepatol. 2011;16(5).

Baranovsky AYu, Raykhelson KL, Marchenko NV. S-adenosylmethionine (Heptral®) in treatment of patients with non-alcoholic steatohepatitis. Clin Perspect Gastroenterol Hepatol. 2010;1:3-10.

Boming L. Observation of efficacy of ademetionine for treating non-alcoholic fatty liver disease. Chinese Hepatol. 2011;16(4):350-1

Virukalpattigopalratnam MP, Singh T, Ravishankar AC. Heptral® (ademetionine) in patients with intrahepatic cholestasis in chronic liver disease due to non-alcoholic liver disease: results of a multicentre observational study in India. J Indian Med Assoc. 2013;111:856-9.

Bao-en W. Ademetionine 1, 4-butanedisulphonate vs traditional chinese medicine for the treatment of acute viral hepatitis with hepatocellular jaundice. Clinic Drug Inv. 2001;21(10):685-94.

Feld JJ, Modi AA, El-Diwany R, Rotman Y, Thomas E, Ahlenstiel G, et al. S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders. Gastroenterol. 2011;140(3):830-9.

Vincenzi B, Santini D, Frezza AM, Berti P, Vespasiani U, Picardi A, Tonini G. The role of S-adenosyl methionine in preventing FOLFOX-induced liver toxicity: a retrospective analysis in patients affected by resected colorectal cancer treated with adjuvant FOLFOX regimen. Expert opinion on drug safety. 2011 May 1;10(3):345-9.

Vincenzi B, Santini D, Frezza AM, Berti P, Vespasiani U, Picardi A, et al. The role of S-adenosyl methionine in preventing FOLFOX-induced liver toxicity: a retrospective analysis in patients affected by resected colorectal cancer treated with adjuvant FOLFOX regimen. Expert Opinion Drug Safety. 2011;10(3):345-9.

Santini D, Vincenzi B, Massacesi C, Picardi A, Gentilucci UV, Esposito V, et al. S-adenosylmethionine (AdoMet) supplementation for treatment of chemotherapy-induced liver injury. Anticanc Res. 2003;23(6D):5173-9.

Perlamutrov Y, Bakulev A, Korsunskaya I, Orlov E, Bolotnikova N. Ademetionine in treatment of drug induced liver injury: an observational study in Russian patients receiving immunosuppressive therapy for psoriasis. IJPSP. 2014;5(12):1007.

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Published

2019-05-29

How to Cite

Saigal, S., Kapoor, D., & Roy, D. S. (2019). Ademetionine in patients with liver disease: a review. International Journal of Research in Medical Sciences, 7(6), 2482–2493. https://doi.org/10.18203/2320-6012.ijrms20192550

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Review Articles