Silymarin for Treating Toxic Liver Disease: International Consensus Recommendations

Abstract

Chronic liver disease (CLD) is a leading health problem impacting the quality of life globally. China shares a major global burden of CLD—including alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, and drug-induced liver injury, except for chronic viral hepatitis. Several exogenous toxins or endogenous metabolic insults trigger hepatic pathology toward steatosis, inflammation, and fibrosis, which, if left untreated, may culminate in liver cirrhosis. Oxidative stress is a common pathomechanism underlying all phenotypes of toxic liver injury; thus, these may be brought under a unified entity, viz. toxic liver disease (TLD). Therefore, a common strategy to treat TLD is to use antioxidants as hepatoprotective agents. The cornerstone for treating fatty liver disease is lifestyle modification, diet, exercise, and behavioral therapy, along with the limited use of pharmacological agents. Available preclinical and clinical evidence indicates that silymarin is a hepatoprotective agent with established antioxidant, anti-inflammatory, antifibrotic effects. An international expert panel of clinicians was convened to discuss combining alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, drug-induced liver injury, and liver cirrhosis under the single definition of TLD, based on the shared pathologic mechanism of oxidative stress. The panel highlighted the significance of silymarin as an antioxidant treatment for TLD. Chronic liver disease (CLD) is a leading health problem impacting the quality of life globally. China shares a major global burden of CLD—including alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, and drug-induced liver injury, except for chronic viral hepatitis. Several exogenous toxins or endogenous metabolic insults trigger hepatic pathology toward steatosis, inflammation, and fibrosis, which, if left untreated, may culminate in liver cirrhosis. Oxidative stress is a common pathomechanism underlying all phenotypes of toxic liver injury; thus, these may be brought under a unified entity, viz. toxic liver disease (TLD). Therefore, a common strategy to treat TLD is to use antioxidants as hepatoprotective agents. The cornerstone for treating fatty liver disease is lifestyle modification, diet, exercise, and behavioral therapy, along with the limited use of pharmacological agents. Available preclinical and clinical evidence indicates that silymarin is a hepatoprotective agent with established antioxidant, anti-inflammatory, antifibrotic effects. An international expert panel of clinicians was convened to discuss combining alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, drug-induced liver injury, and liver cirrhosis under the single definition of TLD, based on the shared pathologic mechanism of oxidative stress. The panel highlighted the significance of silymarin as an antioxidant treatment for TLD. Chronic liver disease (CLD) is one of the leading global health problems impacting the quality of life of patients. Of note, CLD affects around 1.5 billion people globally.1James S.L. Abate D. Abate K.H. et al.Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1789-1858Abstract Full Text Full Text PDF PubMed Scopus (5908) Google Scholar China has the highest burden of CLD.2Liu X. Xu J. Calling a stage-based treatment model for chronic liver diseases in China mainland.Ann Hepatol. 2020; 19: 585-589Crossref PubMed Scopus (0) Google Scholar According to the Global Burden of Disease (2017), 2.14 million deaths have occurred due to liver diseases.3Paik J.M. Golabi P. Younossi Y. et al.Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD.Hepatology. 2020; 72: 1605-1616Crossref PubMed Scopus (217) Google Scholar The disability-adjusted life-years and years of life lost due to CLD globally were 1.6% and 2.1%, respectively. However, disability-adjusted life-years and years of life lost due to CLD in the World Health Organization South East Asia region were 2.2% and 3.0%, respectively.4Asrani S.K. Devarbhavi H. Eaton J. et al.Burden of liver diseases in the world.J Hepatol. 2019; 70: 151-171Abstract Full Text Full Text PDF PubMed Scopus (1321) Google Scholar Exogenous and endogenous toxins, including alcohol, drugs, metabolic dysregulations, and industrial or environmental toxins, cause toxic liver diseases (TLDs). These toxins cause pronounced structural and functional changes in hepatocytes, leading to liver damage.5Jaeschke H. Gores G.J. Cederbaum A.I. et al.Mechanisms of hepatotoxicity.Toxicol Sci. 2002; 65: 166-176Crossref PubMed Scopus (1058) Google Scholar,6Valeeva E.T. Mukhammadiyeva G.F. Bakirov A.B. Polymorphism of glutathione S-transferase genes and the risk of toxic liver damage in petrochemical workers.Int J Occup Environ Med. 2020; 11: 53-58Crossref PubMed Scopus (2) Google Scholar Based on etiology, toxic liver damage can be associated with diverse liver diseases—including drug-induced liver injury (DILI), nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated fatty liver disease (MAFLD), alcoholic liver disease (ALD), liver fibrosis, and cirrhosis. Recently, NAFLD has been redefined as MAFLD manifesting as hepatic steatosis in addition to 1 of the 3 criteria, that is, overweight/obesity, type II diabetes mellitus, or metabolic dysregulation.7Targher G. Byrne C.D. From nonalcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease: is it time for a change of terminology?.Hepatoma Res. 2020; 6: 64Google Scholar Another relevant subtype of FLD is the toxicant-associated fatty liver disease, which is the outcome of toxicant exposure, including environmental and industrial contaminants. Toxicant-associated steatohepatitis (TASH), which is a severe form of toxicant-associated fatty liver disease, is manifested in the form of hepatic steatosis, inflammatory infiltrate, and, in some cases, fibrosis.8Wahlang B. Beier J.I. Clair H.B. et al.Toxicant-associated steatohepatitis.Toxicol Pathol. 2013; 41: 343-360Crossref PubMed Scopus (65) Google Scholar,9Armstrong L.E. Guo G.L. Understanding environmental contaminants' direct effects on non-alcoholic fatty liver disease progression.Curr Environ Health Rep. 2019; 6: 95-104Crossref PubMed Scopus (29) Google Scholar Clinically, DILI, NAFLD/MAFLD, and ALD result in inflammation and fibrosis and, if left untreated, lead to liver cirrhosis and even liver failure.10Leoni S. Tovoli F. Napoli L. et al.Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis.World J Gastroenterol. 2018; 24: 3361-3373Crossref PubMed Scopus (253) Google Scholar, 11Ye H. Nelson L.J. Gomez Del Moral M. et al.Dissecting the molecular pathophysiology of drug-induced liver injury.World J Gastroenterol. 2018; 24: 1373-1385Crossref PubMed Scopus (24) Google Scholar, 12Sepanlou S.G. Safiri S. Bisignano C. et al.The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet Gastroenterol Hepatol. 2020; 5: 245-266Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar Oxidative stress (OS) is a key mechanism for hepatotoxicity and the pathogenesis of TLD due to the accumulation of reactive oxygen species (ROS), leading to structural and functional impairment of the liver.13Cichoz-Lach H. Michalak A. Oxidative stress as a crucial factor in liver diseases.World J Gastroenterol. 2014; 20: 8082-8091Crossref PubMed Scopus (597) Google Scholar The change in OS markers such as catalase, superoxide dismutase (SOD), glutathione peroxidase, coenzyme Q, malondialdehyde, and nonenzymatic electron receptors such as glutathione14Villanueva-Paz M. Morán L. López-Alcántara N. et al.Oxidative stress in drug-induced liver injury (DILI): from mechanisms to biomarkers for use in clinical practice.Antioxidants (Basel). 2021; 10: 390Crossref PubMed Scopus (0) Google Scholar, 15Vuppalanchi R. Juluri R. Bell L.N. et al.Oxidative stress in chronic liver disease: relationship between peripheral and hepatic measurements.Am J Med Sci. 2011; 342: 314-317Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 16Li S. Tan H.Y. Wang N. et al.The role of oxidative stress and antioxidants in liver diseases.Int J Mol Sci. 2015; 16: 26087-26124Crossref PubMed Scopus (911) Google Scholar promotes an imbalance in endogenous antioxidant molecules, viz. glutathione S-transferase, heme oxygenase-1, and nicotinamide adenine dinucleotide phosphate.17Boyer-Diaz Z. Morata P. Aristu-Zabalza P. et al.Oxidative stress in chronic liver disease and portal hypertension: potential of DHA as nutraceutical.Nutrients. 2020; 12: 2627Crossref Scopus (7) Google Scholar Lipid peroxidation (LPO) causes hepatocyte damage and the release of proinflammatory cytokines.15Vuppalanchi R. Juluri R. Bell L.N. et al.Oxidative stress in chronic liver disease: relationship between peripheral and hepatic measurements.Am J Med Sci. 2011; 342: 314-317Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Covalent bonding of macromolecules (eg, protein, DNA) with metabolically activated intermediates may lead to the formation of protein adducts, which may further contribute to hepatic inflammation and disease progression.14Villanueva-Paz M. Morán L. López-Alcántara N. et al.Oxidative stress in drug-induced liver injury (DILI): from mechanisms to biomarkers for use in clinical practice.Antioxidants (Basel). 2021; 10: 390Crossref PubMed Scopus (0) Google Scholar,18Drug-induced liver injury (DILI): Current status and future directions for drug development and the post-market setting. A consensus by a CIOMS Working Group. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS),.2020Google Scholar Hence, there is a need to restore the oxidative balance by various mechanisms, such as by inhibition of CYP2E1 and attenuation of ROS generation.19Avila M.A. Dufour J.F. Gerbes A.L. et al.Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting.Gut. 2020; 69: 764-780Crossref PubMed Scopus (61) Google Scholar As different liver toxicities share OS as a common disease denominator, they can be grouped under the basket description of TLDs, creating a robust rationale for a shared treatment approach (Figure). OS can be countered with clinically safe and tolerable antioxidant molecules in addition to pharmacological and nonpharmacological interventions. Antioxidants obliterate ROS or may activate endogenous antioxidant pathways, such as the nuclear factor erythroid 2–related factor 2 pathway, and may lower the severity of liver fibrosis.15Vuppalanchi R. Juluri R. Bell L.N. et al.Oxidative stress in chronic liver disease: relationship between peripheral and hepatic measurements.Am J Med Sci. 2011; 342: 314-317Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar By minimizing OS, these agents meaningfully impede clinical progression and serve as hepatoprotective agents. The limited treatment options for TLD justify the need for safe alternatives, such as antioxidant therapy. Antioxidants started during the early stages of the disease may prevent disease progression.20Polimeni L. Del Ben M. Baratta F. et al.Oxidative stress: new insights on the association of non-alcoholic fatty liver disease and atherosclerosis.World J Hepatol. 2015; 7: 1325-1336Crossref PubMed Scopus (127) Google Scholar, 21Hashem A. Shastri Y. Al Otaibi M. et al.Expert opinion on the management of non-alcoholic fatty liver disease (NAFLD) in the Middle East with a focus on the use of silymarin.Gastroenterol Insights. 2021; 12: 155-165Crossref Google Scholar, 22Gillessen A. Schmidt H.H. Silymarin as supportive treatment in liver diseases: a narrative review.Adv Ther. 2020; 37: 1279-1301Crossref PubMed Scopus (71) Google Scholar Also, there is no international consensus on the use of antioxidants as a treatment for TLD. Regarding silymarin, although its role as an antioxidant is well recognized, there is a lack of consensus on the dose, treatment duration, and disease stage at which treatment is initiated. Thus, an international advisory panel was convened on December 5, 2020, to understand the merits of combining DILI, NAFLD/MAFLD, nonalcoholic steatohepatitis (NASH), ALD under the basket concept of TLD, and to discuss available evidence and generate consensus statements on the use of silymarin for the clinical management of TLD. The deliberations of the expert panel focused on defining TLD and its scope, understanding the role of OS in TLD, delineating the benefits of silymarin as an antioxidant, and arriving at consensus statements about silymarin as supportive treatment. The panel successfully elucidated the diseases falling under the TLD category because of the common underlying pathogenetic mechanism, that is, OS. The respective diseases, their discrete characteristics, epidemiology/prevalence, clinical manifestations (Table 1), and their diagnoses (Table 2) have been illustrated.Table 1The Clinical Features, Etiology, and Distinctive Features of Different Phenotypes of CLDPhenotypeClinical featuresEtiologyEpidemiology/prevalence (global and China, wherever applicable)Distinctive featuresDILIIt is manifested in the form of elevated liver enzymes, hepatitis, hepatocellular necrosis, cholestasis, fatty liver, and liver cirrhosis.11Ye H. Nelson L.J. Gomez Del Moral M. et al.Dissecting the molecular pathophysiology of drug-induced liver injury.World J Gastroenterol. 2018; 24: 1373-1385Crossref PubMed Scopus (24) Google Scholar DILI is categorized as intrinsic and idiosyncratic. Intrinsic DILI is dose related and occurs in patients with drug exposure within a short period. Idiosyncratic DILI is not dose related, occurs in a smaller population of drug-exposed patients, and variability in onset delays.23European Association for the Study of the Liver. Electronic address: [email protected]; Clinical Practice Guideline Panel: Chair; Panel Members. EASL clinical practice guidelines: drug-induced liver injury. J Hepatol 2019;70:1222–1261.Google Scholar The different categories of DILI are hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the site of injury.24Yu Y.C. Mao Y.M. Chen C.W. et al.CSH guidelines for the diagnosis and treatment of drug-induced liver injury.Hepatol Int. 2017; 11: 221-241Crossref PubMed Scopus (158) Google ScholarPharmacological agents, complementary and alternative medicines including traditional Chinese medicine, and herbal/dietary supplements are the causative agents in DILI.25Shen T. Liu Y. Shang J. et al.Incidence and etiology of drug-induced liver injury in mainland China.Gastroenterology. 2019; 156: 2230-2241.e11Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar,26Chen Y. Wang C. Yang H. et al.Epidemiology of drug- and herb-induced liver injury assessed for causality using the updated RUCAM in two hospitals from China.Biomed Res Int. 2021; 2021: 8894498PubMed Google Scholar,27Wai C.T. Tan B.H. Chan C.L. et al.Drug-induced liver injury at an Asian center: a prospective study.Liver Int. 2007; 27: 465-474Crossref PubMed Scopus (113) Google Scholar Drug liver toxicity is limited to antibiotics, mainly represented by antitubercular drugs.24Yu Y.C. Mao Y.M. Chen C.W. et al.CSH guidelines for the diagnosis and treatment of drug-induced liver injury.Hepatol Int. 2017; 11: 221-241Crossref PubMed Scopus (158) Google Scholar,25Shen T. Liu Y. Shang J. et al.Incidence and etiology of drug-induced liver injury in mainland China.Gastroenterology. 2019; 156: 2230-2241.e11Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar,28Liu Y. Zhan S.P. Song L. et al.Drug-induced liver injury: clinical and etiologic features at a large tertiary teaching hospital in China.Med Sci Monit. 2020; 26e919435Google Scholar,29Biswas A. Santra S. Bishnu D. et al.Isoniazid and rifampicin produce hepatic fibrosis through an oxidative stress-dependent mechanism.Int J Hepatol. 2020; 20206987295Crossref PubMed Scopus (3) Google Scholar Herbal medicines may also cause liver injury, although the actual composition of the herbal preparation may remain unclear, particularly in multicompound products.24Yu Y.C. Mao Y.M. Chen C.W. et al.CSH guidelines for the diagnosis and treatment of drug-induced liver injury.Hepatol Int. 2017; 11: 221-241Crossref PubMed Scopus (158) Google Scholar,25Shen T. Liu Y. Shang J. et al.Incidence and etiology of drug-induced liver injury in mainland China.Gastroenterology. 2019; 156: 2230-2241.e11Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar,28Liu Y. Zhan S.P. Song L. et al.Drug-induced liver injury: clinical and etiologic features at a large tertiary teaching hospital in China.Med Sci Monit. 2020; 26e919435Google Scholar,29Biswas A. Santra S. Bishnu D. et al.Isoniazid and rifampicin produce hepatic fibrosis through an oxidative stress-dependent mechanism.Int J Hepatol. 2020; 20206987295Crossref PubMed Scopus (3) Google ScholarDILI has a high incidence rate in China (23.8 per 100,000 inhabitants).25Shen T. Liu Y. Shang J. et al.Incidence and etiology of drug-induced liver injury in mainland China.Gastroenterology. 2019; 156: 2230-2241.e11Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar Large differences in the epidemiology of DILI between Western and Eastern countries have been reported.30Hayashi P.H. Fontana R.J. Clinical features, diagnosis, and natural history of drug-induced liver injury.Semin Liver Dis. 2014; 34: 134-144Crossref PubMed Scopus (53) Google ScholarThe development of jaundice or occasionally acute liver failure with coagulopathy and encephalopathy in the presence of jaundice is distinctive in DILI. Fibrosis, granulomatous hepatitis, and nodular regenerative hyperplasia are often present.23European Association for the Study of the Liver. Electronic address: [email protected]; Clinical Practice Guideline Panel: Chair; Panel Members. EASL clinical practice guidelines: drug-induced liver injury. J Hepatol 2019;70:1222–1261.Google ScholarNAFLD/MAFLDIt is primarily asymptomatic comprising several clinical conditions, including steatosis, steatohepatitis, fibrosis, and cirrhosis.31Brown G.T. Kleiner D.E. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.Metabolism. 2016; 65: 1080-1086Abstract Full Text Full Text PDF PubMed Google Scholar IR is an important parameter playing a vital role. There are 2 phenotypes of NAFLD, viz. nonalcoholic fatty liver (NAFL or simple fatty liver) and nonalcoholic steatohepatitis (NASH). Nonalcoholic fatty liver indicates the presence of steatosis only, whereas NASH represents steatosis with lobular inflammation and ballooning.32European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO)EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Abstract Full Text Full Text PDF PubMed Google ScholarNAFLD manifests as excessive liver fat in the absence of secondary causes and significant alcohol consumption.32European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO)EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Abstract Full Text Full Text PDF PubMed Google Scholar,33Cotter T.G. Rinella M. Nonalcoholic fatty liver disease 2020: the state of the disease.Gastroenterology. 2020; 158: 1851-1864Abstract Full Text Full Text PDF PubMed Google Scholar,34Chalasani N. Younossi Z. Lavine J.E. et al.The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (3244) Google Scholar The fat accumulates in the liver in the absence of alcohol consumption (alcohol intake: <20 g/d for female, <30 g/d for male) or any other secondary cause.34Chalasani N. Younossi Z. Lavine J.E. et al.The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357Crossref PubMed Scopus (3244) Google ScholarAs of 2017, there were 882 million cases of NAFLD worldwide, with a prevalence rate of 10.9%, majorly seen in the Middle East and North America. The prevalence of NAFLD in China is in the range of 6.3%–27% with a higher occurrence in males than in females and in urban areas vs rural areas. The total number of cases of NASH in China in 2016 was 32.61 million.1James S.L. Abate D. Abate K.H. et al.Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1789-1858Abstract Full Text Full Text PDF PubMed Scopus (5908) Google Scholar,32European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO)EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Abstract Full Text Full Text PDF PubMed Google Scholar,35Sarin S.K. Kumar M. 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Golovanova Е.V. et al.Non-alcoholic fatty liver disease: clinic, diagnostics, treatment.Exp Clin Gastroenterol. 2017; 2: 22-37Google Scholar Hepatic steatosis is accompanied by metabolic dysfunctions.42Eslam M. Newsome P.N. Sarin S.K. et al.A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.J Hepatol. 2020; 73: 202-209Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar Delayed diagnosis and intervention may lead to accumulation of diverse exogenous and endogenous hepatotoxic entities that lead to TLD and fibrosis via multiple biochemical pathways.43Yang J. Fernandez-Galilea M. Martinez-Fernandez L. et al.Oxidative stress and non-alcoholic fatty liver disease: effects of omega-3 fatty acid supplementation.Nutrients. 2019; 11: 872Crossref PubMed Scopus (107) Google ScholarFor MAFLD, metabolic dysfunctions such as overweight/obesity, type 2 diabetes mellitus additionally take prominence.44Eslam M. Sarin S.K. Wong V.W. et al.The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.Hepatol Int. 2020; 14: 889-919Crossref PubMed Scopus (238) Google Scholar Diverse endogenous or exogenous molecular mediators can result in multiple metabolic syndromes.7Targher G. Byrne C.D. From nonalcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease: is it time for a change of terminology?.Hepatoma Res. 2020; 6: 64Google Scholar In addition, given the increased risk of cardiovascular events in the NAFLD/MAFLD population, concomitant comorbidities such as viral hepatitis or ALD might worsen the prognosis of such patients.44Eslam M. Sarin S.K. Wong V.W. et al.The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.Hepatol Int. 2020; 14: 889-919Crossref PubMed Scopus (238) Google ScholarIn a meta-analysis by Liu et al, the global prevalence of MAFLD was demonstrated to be 50.7%, 19.7%, and 57.5% in patients with obesity, patients with type II diabetes mellitus, and patients with metabolic syndrome, respectively.36Estes C. Anstee Q.M. Arias-Loste M.T. et al.Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.J Hepatol. 2018; 69: 896-904Abstract Full Text Full Text PDF PubMed Scopus (753) Google ScholarALDIt is manifested as manifesting as simple steatosis to steatohepatitis and cirrhosis.45Gao Y.G.B. Niu J. The emerging alcoholic liver disease in China.North Am J Med Sci. 2016; 9: 55-58Google Scholar,46Crabb D.W. Im G.Y. Szabo G. et al.Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2020; 71: 306-333Crossref PubMed Scopus (260) Google Scholar Hepatic inflammation, necrosis, apoptosis, and fibrosis occur due to cytokine and oxidative stress cascade involving interactions between Kupffer’s cells, myofibroblasts, and endothelial cells.46Crabb D.W. Im G.Y. Szabo G. et al.Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2020; 71: 306-333Crossref PubMed Scopus (260) Google Scholar,47Seitz H.K. Bataller R. Cortez-Pinto H. et al.Alcoholic liver disease.Nat Rev Dis Primers. 2018; 4: 16Crossref PubMed Scopus (280) Google ScholarAlcohol is the causative agent. The daily alcohol consumption of 20 g in females and 30 g in males along with clinical or biological alterations might be indicative of liver injury.48European Association for the Study of the Liver. Electronic address: [email protected]; European Association for the Study of the Liver. EASL clinical practice guidelines: management of alcohol-related liver disease. J Hepatol 2018;69:154–181.Google ScholarThe prevalence of ALD globally was 26 million as reported by global disease burden, 2018. However, an increase in prevalence was observed in China, from 2.27% in 2000 to 8.74% in 2015, with a higher occurrence noted in males.45Gao Y.G.B. Niu J. The emerging alcoholic liver disease in China.North Am J Med Sci. 2016; 9: 55-58Google Scholar The higher mortality with ALD is due to its detection at a much later stage.19Avila M.A. Dufour J.F. Gerbes A.L. et al.Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting.Gut. 2020; 69: 764-780Crossref PubMed Scopus (61) Google Scholar,49Shah N.D. Ventura-Cots M. Abraldes J.G. et al.Alcohol-related liver disease is rarely detected at early stages compared with liver diseases of other etiologies worldwide.Clin Gastroenterol Hepatol. 2019; 17: 2320-2329.e12Abstract Full Text Full Text PDF PubMed Scopus (56) Google ScholarALD occurs even in the absence of clinical or biological manifestations and thereby is often diagnosed at later stages.19Avila M.A. Dufour J.F. Gerbes A.L. et al.Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting.Gut. 2020; 69: 764-780Crossref PubMed Scopus (61) Google Scholar The features of ALD include macrovesicular or mixed-type steatosis, hepatocellular injury with ballooning, lobular inflammation.48European Association for the Study of the Liver. Electronic address: [email protected]; European Association for the Study of the Liver. EASL clinical practice guidelines: management of alcohol-related liver disease. J Hepatol 2018;69:154–181.Google ScholarLiver fibrosisLiver fibrosis is manifested in the form of excess collagen due to new fiber formation and leads to the accumulation of extracellular matrix in the liver parenchyma.50Sánchez-Valle V. C Chavez-Tapia N. Uribe M. et al.Role of oxidative stress and molecular changes in liver fibrosis: a review.Curr Med Chem. 2012; 19: 4850-4860Crossref PubMed Scopus (0) Google ScholarIt is the sequel of other phenotypes of CLD.-ALD, alcoholic liver disease; CLD, chronic liver diseases; DILI, drug-induced liver injury; MAFLD, metabolic associated fatty liver dise