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Services of Gastroenterology & Clinical Pharmacology, Málaga Biomedical Research Institute, IBIMA, University Hospital, University of Málaga, Málaga, Spain
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.
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.
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.
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.
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.
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.
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.
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.
The change in OS markers such as catalase, superoxide dismutase (SOD), glutathione peroxidase, coenzyme Q, malondialdehyde, and nonenzymatic electron receptors such as glutathione
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.
Drug-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),.
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.
By minimizing OS, these agents meaningfully impede clinical progression and serve as hepatoprotective agents.
FigureCommon oxidative stress mechanism underlies hepatocellular damage by several exogenous and endogenous toxins. Merging clinical phenotypes of fatty liver disease (NAFLD/MAFLD, NASH, DILI, ALD) into a single basket entity, toxic liver diseases (TLDs), based on common pathomechanism will allow clinicians to evaluate the benefits of silymarin as an antioxidant and potential hepatoprotective agent.
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.
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.
Exploring the Pathogenetic Mechanism of Different Phenotypes of TLD
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 CLD
Phenotype
Clinical features
Etiology
Epidemiology/prevalence (global and China, wherever applicable)
Distinctive features
DILI
It is manifested in the form of elevated liver enzymes, hepatitis, hepatocellular necrosis, cholestasis, fatty liver, and liver cirrhosis.
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.
European 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.
The different categories of DILI are hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the site of injury.
Pharmacological agents, complementary and alternative medicines including traditional Chinese medicine, and herbal/dietary supplements are the causative agents in DILI.
Herbal medicines may also cause liver injury, although the actual composition of the herbal preparation may remain unclear, particularly in multicompound products.
The 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.
European 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.
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.
European 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.
European 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.
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.
As 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.
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.
European 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.
Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.
The distinct morphological features of NAFLD/MAFLD are large droplet steatosis, ballooning, lobular inflammation. Perisinusoidal fibrosis occurs at the end stages.
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.
The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.
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.
The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.
In 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.
Hepatic inflammation, necrosis, apoptosis, and fibrosis occur due to cytokine and oxidative stress cascade involving interactions between Kupffer’s cells, myofibroblasts, and endothelial cells.
Alcohol 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.
European 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.
The 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.
European 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.
Liver 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.
Table 2Diagnostic and Screening Criteria of Different Phenotypes of CLD
DILI
The CIOMS has laid down the guidelines for the evaluation of the (1) hepatocellular injury, ALT ≥3 ULN and R ≥ 5; (2) cholestatic injury, alkaline phosphatase (ALP) ≥2 ULN and R ≤2; (3) and hepatocellular-cholestatic mixed injury, ALT ≥3 ULN, ALP ≥2 ULN and 2 < R < 5.
Drug-induced autoimmune hepatitis diagnosis is based on serology, genetic test, and liver biopsy whenever possible whereas drug-induced secondary sclerosing cholangitis on MRCP or ERCP.
European 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.
Liver biopsy is considered the gold standard for differentiating the phenotypes of NAFLD/MAFLD (NAFL and NASH) and their progression (fibrosis and cirrhosis),
European 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.
nonetheless, noninvasive preliminary diagnostic evaluation includes imaging to determine steatosis and evaluation of conventional liver biochemistry, in addition to fasting blood glucose, total blood count, hemoglobin A1c, and OGTT.
European 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.
European 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.
In case NAFLD and NASH progress to fibrosis, NAFLD fibrosis score, fibrosis 4 calculator, AST/ALT ratio index, ELF panel, Fibrometer, Fibrotest, Hepascore, NAFLD activity score, in conjunction with imaging techniques such as TE, MRE, and shear wave elastography are used.
In the case of normal-weight individuals with hepatic steatosis and not having type II diabetes, the diagnostic criteria include the presence of at least 2 of the following metabolic conditions:
(1) risk factors identifying the metabolic syndromes (example specific cut-off points for the waist circumference, blood pressure ≥130/85 mm Hg, plasma triglycerides ≥150 mg/dL, plasma HDL-cholesterol <40 mg/dL for men and <50 mg/dL for women, prediabetes, that is, fasting glucose levels 100–125 mg/dL, or 2-h postload glucose levels 140–199 mg/dL, hemoglobin A1c 5.7%–6.4%).
(2) homeostatic assessment, that is, determine the HOMA-IR score ≥2.5;
(3) high plasma high sensitivity-C-reactive protein level >2 mg/L.
Abdominal ultrasonography is usually performed in clinical practice; however, CAP determination using VCTE and MRS, or MRI-PDFF, are also used to quantify liver fat.
The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.
The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.
Furthermore, physicians also prefer to wait for at least 5 y to perform a liver biopsy postdiagnosis of elevated liver function tests; additionally, if the body mass index of the patient is ≥25 kg/m2, there is an increased risk of progression to NASH.
Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study.
The screening procedure is either invasive, such as liver biopsy for evaluating the degree of steatosis and fibrosis; or noninvasive, such as TE or quantification of biological markers encompassing GGT, serum ALT, serum AST, MCV, and %CDT.
European 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.
In case of advanced fibrosis or cirrhosis, serum albumin, prothrombin time, INR, serum bilirubin levels, platelets, or white blood cell counts should be analyzed followed by endoscopy.
European 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.
European 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.
The accumulation of ROS, endoplasmic reticulum stress (ERS), depletion of adenosine triphosphate, and inhibition of mitochondrial respiratory chain contribute to DILI.
Such exogenous hepatic insults beyond a critical threshold may lead to activation of c-Jun N-terminal kinase pathways in hepatocytes, leading to impaired antioxidant mechanisms and cell death.
The accumulation of fat or triglycerides in hepatocytes due to increased uptake of fatty acids from abdominal adipose tissue, or increased de novo lipid synthesis, or reduced fatty acid oxidation, leads to excessive ROS generation and LPO.
which along with immune cells, endothelial cells, stellate cells, and Kupfer cells, may damage hepatocytes. Immune cells show specific receptors for such injured hepatocytes, such as damage-associated molecular patterns or pathogen-associated molecular patterns.
Activation of these receptors triggers the synthesis and release of inflammatory and profibrogenic mediators in injured hepatocytes. The cellular and molecular cross-talk between stressed or damaged hepatocytes, activated macrophages, and stellate cells drives matrix protein deposition—leading to the synthesis of scar tissue in the liver.
The 2-hit hypothesis suggests the first core hit to be peripheral insulin resistance (IR) accompanied by obesity and other metabolic syndromes. The second hit might be an imbalance between the generation of ROS and antioxidant mechanisms leading to LPO and mitochondrial dysfunction. The multiple parallel hits model suggests that many mechanisms might act simultaneously, resulting in hepatic inflammation and ERS.
The excessive oxidants produced via renin-angiotensin hyperactivity, mitochondrial dysfunction, dyslipidemia, and ERS lead to diminished glucose transport in skeletal muscles, decreased insulin secretion, and vascular dysfunction via activation of stress-activated serine kinases.
Alcohol impairs lipid metabolism and antioxidant mechanisms and promotes fat accumulation either by inhibiting mitochondrial β-oxidation or enhancing fatty acid synthesis.
This evidence suggests that alcohol acts as an external agent promoting toxic liver injury by disturbing the delicate balance between ROS generation and active antioxidant mechanisms.
Liver Fibrosis
Liver fibrosis is the intermediate, partially reversible serious sequel of pathologic change in patients with different phenotypes of CLD, including ALD, NAFLD/MAFLD, DILI, and viral infections, such as viral hepatitis.
of paired liver biopsy studies clearly indicated that progression to hepatic fibrosis is much faster in patients with NASH compared with patients with NAFLD. Therefore, early diagnosis of these phenotypes can mitigate the risk of progression to cirrhosis and reduce hepatic toxicity pre-emptively.
As the prevalence of CLD is growing, a higher burden of cirrhosis or liver failure and hepatocellular carcinoma remains imminent if no early interventions are initiated. As liver transplantation is a leading indication for MAFLD/NASH,
it causes a huge burden on health care resources. Slowing the progression of TLD can reduce the socioeconomic burden, especially if treatment with a hepatoprotective agent targeting common underlying mechanisms is initiated early on.
Consensus Statement on the Toxic Liver Disease Spectrum
The expert panel reviewed the current evidence and acknowledged the extensive liver damage caused by diverse endogenous or exogenous toxic agents that leads to DILI, NAFLD/MAFLD, and ALD. The panel reached a consensus on the justification to bring the previously listed diseases under a unifying entity called “toxic liver diseases,” based on common mechanisms driven by diverse endogenous and exogenous hepatotoxic agents.
OS as a Common Underlying Mechanism and Significant in the Management of TLD
Of note, OS is one of the early key mediators of hepatic injury driving disease progression.
Hepatocellular injury by ROS is due to obstruction of mitochondrial respiratory enzymes along with the deactivation of glyceraldehyde-3-phosphate dehydrogenase. The ROS produced lead to LPO and tissue damage, which activate cytokine generation by resident macrophages. Local soluble mediators and cytokines lead to the infiltration of more immune cells, which further enhances tissue OS and subsequent fibrosis.
Overnutrition and lack of exercise cause the expansion of adipose tissue, resulting in the secretion of proinflammatory cytokines, resulting in steatosis and fibrosis.
Macrophages/Kupffer cells secrete proinflammatory cytokines and undergo M1 or M2 activation and are implicated in the pathogenesis of steatosis and activation of fibrogenesis.
The damage-associated molecular patterns that are released from damaged hepatocytes activate the intrinsic immune response, including the release of cytokines, such as tumor necrosis factor (TNF)-alpha, and in turn activate death receptors such as TNF-R.
It has been shown that the antioxidant mechanism is compromised in DILI, leading to the development of intensified OS, which ultimately culminates in mitochondrial damage and cell death. Of note, DILI also leads to change in cell functionality, causing an augmentation in ROS levels or impeding detoxification mechanisms, paving the way for overall OS.
In the case of ALD, OS and carcinogenic metabolites of alcohol and inflammation might aggravate DNA mutations leading to neoplastic alteration of hepatocytes to hepatocellular carcinoma.
Of note, the OS in DILI, ALD, and NAFLD/MAFLD evaluated in different animal models was driven by mitochondrial dysfunction, impairment of hepatic function, and inflammation.
Alleviation of liver dysfunction, oxidative stress and inflammation underlies the protective effect of ferulic acid in methotrexate-induced hepatotoxicity.
As OS impacts the normal functioning of the liver, there is an urgent need to mitigate OS by establishing a promising therapeutic approach.
Consensus Statement on the Role of OS
The expert panel reviewed current evidence and agreed that OS is a common underlying pathophysiological mechanism driving diverse clinical phenotypes grouped under TLDs. The panel reached a consensus that during the early stages of TLDs, targeting OS in hepatocytes with a hepatoprotective agent may be clinically effective.
Current Treatment Approaches
The panel evaluated available treatment options and the extent to which they target OS. The therapeutic strategy is to treat the liver condition along with the associated metabolic syndrome.
Currently, the mainstay of treatment is intensive lifestyle modification, including diet, exercise, weight loss, and behavioral therapy in patients with TLD including NAFLD/MAFLD and ALD.
European 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.
No specific pharmacological agent has been approved to treat NAFLD/MAFLD. Orlistat, bariatric surgery, angiotensin receptor blockers, statins, fibrates, antidiabetic drugs, glucagon-like peptide-1, and thiazolidinediones might be considered personalized treatments for NAFLD/MAFLD.
The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.
The EASL guidelines have established the use of N-acetylcysteine, corticosteroids, granulocyte-colony-stimulating factor, pentoxifylline, and anti-TNF agents for ALD.
European 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.
As reversing NASH and liver fibrosis with existing treatment modalities is difficult, it becomes imperative to protect the liver from OS, inflammation, and fibrosis using a hepatoprotective agent. Vitamin E has been used as a hepatoprotective agent; however, its long-term safety is questionable.
National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical AssociationFatty Liver Expert Committee, Chinese Medical Doctor Association Guideline of prevention and treatment for nonalcoholic fatty liver disease: a 2018 update.
Exercise and diet induced weight loss improves measures of oxidative stress and insulin sensitivity in adults with characteristics of the metabolic syndrome.
Am J Physiol Endocrinol Metab.2007; 293: E500-E506
Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors.
and the use of antioxidants can target OS. Early intervention with antioxidant therapy can prevent or improve TLD.
Consensus Statement on Treatment Options
The panel, after reviewing the evidence, recognized the need for early interventions that can counter OS for delaying the onset or slowing the progression of TLD.
Silymarin as a Therapeutic
The panel evaluated the antioxidant properties of silymarin and its potential use in TLD. Silymarin derived from the dried seeds and fruits of Silybum marianum has been used as a natural herbal product for centuries because of its flavonolignan content (silybin is the most biologically active).
The hydrophobic nature of crude silymarin extract impacts oral bioavailability, which necessitates the inclusion of solubilizing agents in formulations.
Bioavailability and potential of silymarin accumulation in the liver and plasma in physiological amounts after oral administration have been demonstrated.
The phenolic group in silymarin interacts with the ROS generated during hepatic metabolism to form a stable, nontoxic compound. Silymarin acts as a free-radical scavenger, reduces OS, and works by modulating liver function enzymes. Silymarin inhibits the activation of fibrogenic stellate cells, restricts the release of proinflammatory mediators by hepatic macrophages, and provides clinical benefit to the injured liver.
Identification of novel mechanisms of silymarin on the carbon tetrachloride-induced liver fibrosis in mice by nuclear factor-kappaB bioluminescent imaging-guided transcriptomic analysis.
Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells.
In patients treated with silymarin, a statistically significant reduction in serum alanine aminotransferase and aspartate aminotransferase levels was reported in a meta-analysis conducted by Avelar et al.
reviewed studies that suggested a supportive role of silymarin in treating liver cirrhosis. The consensus formulated by Cheng Jun et al. also advocates the use of silymarin as a potential hepatoprotective agent.
In patients receiving long-term drug treatment, levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alanine phosphatase, total bilirubin, along with the quality of life, are improved after 2 months of treatment with silymarin.
with a concomitant reduction in SOD decline, suggesting a contribution of antioxidant properties driving risk reduction as evident in a double-blind randomized placebo-controlled trial on patients with DILI.
Silymarin treatment was effective in lowering elevated liver enzymes in patients with ALD and cirrhosis as established from a double-blind controlled trial
A randomized double-blinded, placebo-controlled trial on patients with NAFLD suggested significant benefits from the use of silymarin in the amelioration of liver aminotransferases without specific side effects.
In a randomized double-blind placebo-controlled multicenter Phase II trial, standardized 420 mg and 720 mg silymarin preparations were tested on patients with NASH without cirrhosis, wherein histologic improvement ≥2 points in NAFLD activity score were observed in silymarin-treated groups.
Similarly, randomized trials and double-blind trials on patients with NAFLD and chronic ALD, respectively, using silymarin-expressed restoration of SOD levels in the lymphocytes and erythrocytes
[Effect of silimarin (Legalon) therapy on the antioxidant defense mechanism and lipid peroxidation in alcoholic liver disease (double blind protocol)].
Evaluation of the effect derived from silybin with vitamin D and vitamin E administration on clinical, metabolic, endothelial dysfunction, oxidative stress parameters, and serological worsening markers in nonalcoholic fatty liver disease patients.
Higher-than-recommended doses of silymarin have also been used and demonstrated to be safe and tolerable as established in a randomized, double-blind, placebo-controlled trial. The use of 700 mg/d silymarin for 48 weeks in patients with NASH exhibited a significant reduction in fibrosis and improvement in liver biochemistry.
Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study.
Long-term (23 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients.
Efficacy of lifestyle changes in subjects with non-alcoholic liver steatosis and metabolic syndrome may be improved with an antioxidant nutraceutical: a controlled clinical study.
Overall, based on all clinical evidence, silymarin was found to be safe and well tolerated; thus, it can be considered a beneficial treatment for TLD.
Silymarin as a Treatment for TLD
The key target for TLD is OS, and because silymarin is safe, well tolerated, and has limited interactions with other drugs, its antioxidant properties can be leveraged clinically. Silymarin decreases OS and may be an effective treatment option for patients with TLD. As per accumulating clinical evidence, silymarin can be used as an adjunct or supportive therapy during the early stages of TLD. In the case of DILI, where there are limited treatment options, silymarin may be safer than corticosteroids, which have several adverse effects.
The Chinese Society of Hepatology and the Chinese guidelines for ALD also recommend the use of silymarin in mild liver inflammation, as an antioxidant, antifibrotic, and hepatoprotective agent.
National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association; Fatty Liver Disease Expert Committee, Chinese Medical Doctor Association Guidelines of prevention and treatment for alcoholic liver disease (2018, China).
It is the opinion of the panel of experts that patients with fatty liver with and without metabolic syndrome (especially younger patients with stronger OS), who have a higher risk of progressing to NASH and cirrhosis, are good candidates for early treatment with silymarin. As per current Chinese NAFLD guidelines, patients with NAFLD suspected of having NASH and progressive liver fibrosis may benefit from hepatoprotective drugs such as silymarin. Silymarin may be used as a hepatoprotective drug in NAFLD/MAFLD for at least 12 months if serum LFT has not decreased significantly after 6 months of treatment.
National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical AssociationFatty Liver Expert Committee, Chinese Medical Doctor Association Guideline of prevention and treatment for nonalcoholic fatty liver disease: a 2018 update.
Patients with chronic viral hepatitis may also benefit from improved liver function, leveraging the hepatoprotective properties of silymarin, without affecting antiviral efficacy.
A synergistic approach is usually preferred where silymarin is used along with lifestyle modification, providing a requisite motivational drive to patients to be compliant with therapy. The tailored formulation of silymarin needs to be standardized as per good manufacturing practice and herbal standards for ensuring the reliability and reproducibility of clinical outcomes. Therefore, the most common dosage for silymarin as established in the literature is 420 mg/d; however, it lies within the range of 140 mg/d (the lower level) to 1080 mg/d (the highest level), preferably twice or thrice daily.
The expert panel agreed on the safety, tolerability, and clinical benefits of silymarin as an antioxidant, when initiated as early treatment and used for prolonged durations with careful monitoring, and as a pharmacological tool in the management of TLDs either alone or concomitantly with other medications.
Conclusion
As the burden of TLD is increasing, it is critical to develop treatments that can target key pathophysiological mechanisms. OS as a common target can bring together NAFLD/MAFLD, ALD, DILI, NASH, and liver cirrhosis under the single basket entity of TLD and can be managed with an antioxidant. Silymarin as an antioxidant and hepatoprotective agent is safe and has reasonable clinical efficacy in TLD, as per the label. Hence, silymarin treatment can be initiated as early as possible, continued for at least 3–6 months or longer with periodic monitoring of liver function, alongside other pharmacological and nonpharmacological interventions, for TLD.
Authors' Contributions:
All authors contributed equally toward study conception and design, analysis, interpretation of data, drafting of article, and revising it critically for intellectual content. All authors were involved in the final approval for submission and agree to be accountable for all aspects of the work.
References
James 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.
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.
Drug-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),.
European 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.
Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.
The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.
European 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.
Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study.
Alleviation of liver dysfunction, oxidative stress and inflammation underlies the protective effect of ferulic acid in methotrexate-induced hepatotoxicity.
Exercise and diet induced weight loss improves measures of oxidative stress and insulin sensitivity in adults with characteristics of the metabolic syndrome.
Am J Physiol Endocrinol Metab.2007; 293: E500-E506
Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors.
Identification of novel mechanisms of silymarin on the carbon tetrachloride-induced liver fibrosis in mice by nuclear factor-kappaB bioluminescent imaging-guided transcriptomic analysis.
Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells.
[Effect of silimarin (Legalon) therapy on the antioxidant defense mechanism and lipid peroxidation in alcoholic liver disease (double blind protocol)].
Evaluation of the effect derived from silybin with vitamin D and vitamin E administration on clinical, metabolic, endothelial dysfunction, oxidative stress parameters, and serological worsening markers in nonalcoholic fatty liver disease patients.
Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study.
Long-term (23 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients.
Efficacy of lifestyle changes in subjects with non-alcoholic liver steatosis and metabolic syndrome may be improved with an antioxidant nutraceutical: a controlled clinical study.
National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association; Fatty Liver Disease Expert Committee, Chinese Medical Doctor Association
Guidelines of prevention and treatment for alcoholic liver disease (2018, China).
Conflicts of Interest: The authors disclose no conflicts.
Funding: No funding was received by any of the authors for the development of this publication. The medical writing and editing for this manuscript were supported by Viatris.
Ethical Statement: The study did not require the approval of an institutional review board.
Writing Assistance: The authors wish to thank Bushra Nabi and Lakshman Puli of IQVIA, India, for their writing and editing support.
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