Role of silymarin as antioxidant in clinical management of chronic liver diseases: a narrative review

Figures & data

Table 1. The clinical features, aetiology, distinctive features, region specific guidelines, diagnostic and screening criteria, and Russia-specific information on different phenotypes of CLD.

Clinical phenotype	Clinical features	Aetiology	Distinctive features	Diagnostic and screening criteria	Russia-specific information
ALD	The clinical phenotypes of ALD are steatosis (fat deposition), acute and chronic hepatitis (inflammation), and hepatic cirrhosis [8]. Chronic and excessive ethanol consumption leads to ALD, causing damage to the liver parenchyma, which manifests ultimately as cirrhosis. Women and individuals with poor nutrition, genetic polymorphisms or those with hepatotropic viral infections are at a higher risk for developing ALD [8,12,23].	Nearly 60%–100% of people who abuse alcohol develop ALD [8]. An amount of 40–80 g of ethyl alcohol for males and 20 g for females per day has been regarded as hepatotoxic [8].	The morphological spectrum of ALD encompasses macrovesicular or mixed-type steatosis, hepatocellular injury with ballooning, lobular inflammation [12,29].	The most recommended diagnostic techniques for ALD are ultrasound and TE to determine the degree of liver density and associated liver fibrosis [8]. Additionally, liver biopsy confirms the existence of liver injury and alcohol genesis [8]. Furthermore, certain indirect laboratory methods using biological markers for ALD are employed for diagnostic purposes, such as mean corpuscular volume, increased serum AST, increased De Ritis ratio (AST/ ALT ratio), increased serum direct bilirubin, increased serum GGTP, increased CDT [8,12].	According to WHO 2018 data, Russia ranks fourth globally in terms of alcohol consumption. Alcohol is the leading cause of death and disability due to liver cirrhosis and is responsible for 36.7% of liver cirrhosis-related deaths in Russia, which is higher than the global average [14]. Further, some studies have shown that ALD accounts for up to 61% of all hospitalised patients in Russian hepatology departments [8,84]. Nearly 1 in 2 Russians above 18 years of age have alcohol problems and, therefore, are at a high risk of developing alcohol-induced complications. The Russian guidelines do not specify a safe, well-defined daily limit for alcohol consumption.[8]
NAFLD	NAFLD is asymptomatic and comprises a spectrum of clinical conditions involving steatosis, steatohepatitis, fibrosis, and cirrhosis [85]. The histological categorisation of NAFLD includes NAFL and NASH. The presence of ≥5% hepatic steatosis without hepatic ballooning is defined as NAFL, while ≥5% hepatic steatosis with hepatocyte injury and inflammatory with or without fibrosis is NASH [27]. NAFL is a benign condition, while NASH is progressive, often advancing to cirrhosis and HCC [85].	It occurs primarily in individuals who do not consume excessive alcohol [5].	The main morphological criteria for NAFLD include large droplet steatosis, ballooning of hepatocytes, lobular inflammation followed by perisinusoidal fibrosis in later stages [5]. Cardiovascular comorbidities such as atrial fibrillation, ischaemic heart disease, and stroke are common with NAFLD. One-third of patients with NAFLD have a risk of developing liver cirrhosis and HCC. NAFLD also increases the risk of developing diabetes, cardiovascular diseases, chronic kidney diseases, breast and colorectal cancers [5,27,42]. The increase in the global prevalence of diabetes and obesity has also led to a proportionate increase in NAFLD [7].	Ultrasound examination, CT, and MRI are usually utilized for detecting fatty liver [5]. Additionally, non-invasive diagnostic tests such as FibroMax, FibroTest^®, NAFLD fibrosis score are used to establish the severity of inflammatory changes and stage of liver fibrosis. The existence of steatosis is validated using FLI and NFS [13]. Cytokeratin 18 fragment is used as an inflammatory marker [13]. The elasticity of liver tissue is determined using TE in patients with NAFLD. However, puncture biopsy is considered the gold standard for the diagnosis of NASH [5]. Furthermore, assessment of biochemical parameters—including ALT, AST, GGTP, ALP, total bilirubin, prothrombin, proteinogram, coagulogram—is used to determine the functional state of the liver [5]. Different questionnaires are used to measure patient-related outcomes in NAFLD, including the generic health-related quality-of-life tool, SF-36, and the disease-specific tool the Chronic Liver Disease Questionnaire [7].	The prevalence of NAFLD in Europe is estimated to be about 24% with an increasing gradient from Southern to Northern Europe, and NAFLD is the leading cause of CLD in Russia [5]. According to the 2015 Russian open multicenter prospective screening study, DIREG 2, the prevalence of NAFLD is 37.3% in Russia, depicting an increase of 10% over 7 years, compared to the DIREG 1 report. However, cases of NAFLD-associated liver cirrhosis increased by 5% in Russia during the same period [5].
MAFLD	The diagnosis of MAFLD is based on evidence of hepatic steatosis, in addition to any of 3 criteria—overweight/obesity, type 2 DM, and signs of metabolic dysregulation [86,87].	In individuals with normal body weight with hepatic steatosis, metabolic dysregulation is diagnosed by at least 2 metabolic risk factors (risk factors widely used to identify metabolic syndrome: homeostasis model assessment-estimated insulin resistance score ≥2.5 and plasma hs-CRP level >2 mg/L) [86]. The presence of MAFLD further accelerates the progression of other liver diseases such as ALD [11].	In individuals with normal body weight with hepatic steatosis, metabolic dysregulation is diagnosed by at least 2 metabolic risk factors (risk factors widely used to identify metabolic syndrome: homeostasis model assessment-estimated insulin resistance score ≥2.5 and plasma hs-CRP level >2 mg/L) [86]. The presence of MAFLD further accelerates the progression of other liver diseases such as ALD [11].	A positive diagnosis of MAFLD is based on histological examination (biopsy), imaging, and biomarkers found in fat accumulation in the liver [6]. For the determination of steatosis in MAFLD, ultrasound, FibroScan^® vibration-controlled TE-equipped with controlled attenuation parameter, CT, and MRI are used [6]. Certain non-invasive tests such as FLI, AST-to-platelet ratio index, FIB-4, and NFS are also used to determine the existence of steatosis and the severity of fibrosis [11].	–
DILI	Clinical and laboratory variants of DILI include hepatocellular, cholestatic, and mixed [9], depending on the pattern of elevation of liver enzymes [29].	Liver damage attributable to prescription or over-the-counter drugs, including herbal and dietary supplements, is termed DILI [9]. It was commonly associated with anti-TB drugs, but nowadays it is becoming more pronounced with the advent of monoclonal antibody therapies. Antibiotics, cardiovascular drugs, anticancer, nonsteroidal anti-inflammatory agents, and dietary supplements are important drugs more likely to cause DILI [9,33].	The pathogenetic classification of DILI includes direct damage causing intrinsic or idiosyncratic DILI. Intrinsic DILI depends on a specific drug causing dose-dependent hepatotoxicity. It occurs in a large proportion of individuals exposed to the drug (predictable) and within a short time span (hours to days). Idiosyncratic DILI is more frequent and occurs only very rarely among treated patients (unpredictable), and often only after several months of treatment [9].	Causality scores such as the RUCAM are used for confirmation of DILI [9,88]. The diagnosis varies from physical examination, laboratory findings, and instrumental diagnostics [9]. Serum ALT/AST, ALP, and total bilirubin levels form the primary parameters for detecting and classifying liver damage in suspected DILI [29]. Additionally, tests for hepatitis C virus RNA and anti-hepatitis E virus IgM are recommended in patients with suspected DILI, to eliminate the possibility of acute hepatitis C and/or E [29]. Ultrasound is suggested in DILI to exclude any focal changes to the liver and biliary obstruction [29], while liver biopsy determines parenchymal liver disease [29].	The incidence of DILI in Russia is 1–19 cases per million people per year. Nearly 10% of liver pathology-associated hospitalisations are drug induced [9].

ALD: Alcoholic liver disease; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CDT: Carbon-deficient transferrin; CLD: Chronic liver disease; CT: Computed tomography; DILI: Drug induced liver injury; DM: Diabetes mellitus; FIB-4: Fibrosis-4 index; FLI: Fatty liver index; GGTP: γ-Glutamyl transpeptidase; HCC: Hepatocellular carcinoma; hs-CRP: High sensitivity-C-reactive protein; MAFLD: Metabolic-associated fatty liver disease; MRI: Magnetic resonance imaging; NAFL: Non-alcoholic fatty liver; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; NFS: NAFLD liver fat score; RUCAM: Roussel-Uclaf Causality Assessment Method; TE: Transient elastography; WHO: World Health Organisation.

Table 2. Comparison of Russian Guidelines with other regional guidelines.

CLD phenotype	AASLD guidelines	EASL guidelines	APASL guidelines	Russian guidelines
ALD	The AUDIT and CAGE questionnaires are used along with alcohol biomarkers to aid in diagnosis. Relapse prevention medicines (naltrexone, acamprosate); cognitive-behavior therapy; and psychosocial therapy is recommended. Other treatment modalities are used in different forms of ALD, like alcoholic hepatitis, alcohol-associated steatosis. Liver transplant is undertaken is patients with decompensated alcohol-associated cirrhosis [10].	AUDIT questionnaire, MCV, AST/ALT, body mass index, LFT, non-invasive serum fibrosis test, and liver biopsy were used for diagnosis. Treatment modalities of different alcohol-associated liver disorder (alcoholic hepatitis, alcohol-associated fibrosis, alcoholic steatosis, alcoholic cirrhosis) have been elaborated in detail [12].	Various questionnaires are used to determine alcohol dependency, such as CAGE, MAST, and AUDIT. ALT, AST, AST/ALT, physical examination, hepatic imaging, and liver biopsy are used to establish the ALD diagnosis. Alcohol abstinence, naltrexone, or acamprosate in those who achieve abstinence, and nutritional therapy are recommended in ALD, while a separate treatment algorithm is followed for alcoholic hepatitis. Liver transplant in used in cirrhosis [89].	Ultrasound, TE, non-invasive fibrotests, direct laboratory markers (PEth, EtG, EtS, FAEE), and indirect markers (MCV, AST, AST/ALT, GGTP etc.) are used for diagnosis. Medicinal treatment for different ALD forms (alcoholic hepatitis), liver transplant, and rehabilitation is recommended. Additionally, silymarin is advised for use in ALD owing to its property to suppress lipid peroxidation [8].
NAFLD	Non-invasive assessment (NFS, FIB-4, EFL, serum biomarkers), imaging (vibration-controlled TE), and liver biopsy are used for diagnosis. Lifestyle intervention, insulin sensitisers, thiazolidinediones, vitamin E, bariatric surgery, and liver transplant are recommended [27].	Liver biopsy, ultrasound, biomarkers, scores of fibrosis, and HOMA-IR are used to diagnose NAFLD and associated metabolic syndrome. Diet and lifestyle modification, insulin sensitisers, antioxidants, cytoprotective, lipid-lowering agents, bariatric surgery, and liver transplant are recommended based on patient condition [26].	–	Imaging techniques; non-invasive diagnostic tests (Fibrotest, NAFLD fibrosis score, TE); and diagnostic liver biopsy are used as diagnostic aids. Metformin, pioglitazone, lipid-lowering agents, vitamin E, phospholipids, and UDCA along with other agents can be used as pharmacological treatment modalities. Silymarin use is also recommended [5].
DILI	Causality assessment and liver biopsy are conducted for diagnostic purposes. Discontinuation of the implicated agent, short-term administration of a bile acid resin, carnitine, N-acetylcystein, corticosteroids, along with other specific therapies according to causative agents, are used as treatment modalities [90].	Antibodies and HLA type tests are used for diagnosis of DILI and distinguish DILI and AIH. Injury from different drug categories had a different diagnostic approach. Liver biochemistry, imaging, and biopsy are recommended. Discontinuation of suspected agent and different targeted therapy for different agents are used (cholestyramine, carnitine, N-acetylcystein, UDCA, liver transplant) [29].	Laboratory testing, imaging, and biopsy are used for diagnosis. CDS and RUCAM scores are also employed. Withdrawal of suspected agent along with specific therapies (steroids, cholestyramine, carnitine, UDCA) is used as a management approach [91].	RUCAM scale is recommended for assessing risk of medication in DILI. Physical examination, laboratory and instrumental diagnostic techniques are used. Suspension of the causative agent is the primary step in the management of DILI. Medicinal agents (N-acetylcystein, L-carnitine, glycyrrhizic acid, L-ornithine L-aspartate, UDCA, ademetionine, glucocorticoids, phospholids) are used on a case-to-case basis [9].

ALD: Alcoholic liver disease; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; AUDIT: Alcohol use disorders identification test; CDS: Clinical Diagnostic Scale; DILI: Drug induced liver injury; EFL: Enhanced Liver Fibrosis; EtG: Ethyl glucuronide; EtS: Ethyl sulphate; FAEE: Fatty acid ethyl esters; FIB-4: Fibrosis-4 index; GGTP: γ-Glutamyl transpeptidase; HLA: human leukocyte antigen; HOMA-IR: Homeostatic Model Assessment of Insulin Resistance; LFT: Liver function test; MAFLD: Metabolic-associated fatty liver disease; MAST: Michigan Alcohol Screening Test; MCV: mean corpuscular volume; NAFLD: Non-alcoholic fatty liver disease; NFS: NAFLD liver fat score; PEth: Phosphatidylethanol; RUCAM: Roussel-Uclaf Causality Assessment Method; TE: Transient elastography; UDCA: Ursodeoxycholic acid.

Table

Author Name	Responsibilities
	Criteria 1			Criteria 2		Criteria 3	Criteria 4
	Conception and design	Acquisition of data	Analysis and interpretation of data	Drafting of the manuscript	Critical revision of the manuscript for important intellectual content	Final approval	Agreement to be accountable for all aspects of the work
Aghemo Alessio	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Alekseeva Olga P			Yes		Yes	Yes	Yes
Angelico Francesco	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Bakulin Igor G	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Bakulina Natalia V			Yes		Yes	Yes	Yes
Dmitry Bordin			Yes		Yes	Yes	Yes
Bueverov Alexey O			Yes		Yes	Yes	Yes
Drapkina Oxana M			Yes		Yes	Yes	Yes
Gillessen Anton	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Kagarmanova Elvira M			Yes		Yes	Yes	Yes
Korochanskaya Natalia V			Yes		Yes	Yes	Yes
Kucheryvii UA			Yes		Yes	Yes	Yes
Lazebnik Leonid S	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Livzan Maria A			Yes		Yes	Yes	Yes
Maev Igor V			Yes		Yes	Yes	Yes
Martynov Anatolii I	Yes	Yes	Yes		Yes	Yes	Yes
Osipenko Marina F			Yes		Yes	Yes	Yes
Sas Evgenii I			Yes		Yes	Yes	Yes
Starodubova Antonina			Yes		Yes	Yes	Yes
Uspensky Yurii P			Yes		Yes	Yes	Yes
Vinnitskaya Elena V	Yes	Yes	Yes		Yes	Yes	Yes
Yakovenko Emilia P			Yes		Yes	Yes	Yes
Yakovlev Alexey A			Yes		Yes	Yes	Yes

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Data availability statement

Data sharing is not applicable to this article, as no new data were created or analysed in this study.