Inherent substance's hepatoprotective benefits have often been ascribed to their antioxidant qualities and capacity to activate the body's inherent antioxidant defences. Since almost every mechanism of liver injury involves oxidative stress, it is fair to assume that these substances' antioxidant qualities may be crucial to the mechanism underlying their hepatoprotective action. However, mounting data indicates that the therapeutic effects of natural substances may be due to pharmacological activity other than antioxidants. The largest organ in the human body, the liver, weighs over 1.5 kg in a fully developed adult and accounts for 2% of total body weight. The liver protects against harmful external chemical substances since it is the location of drug metabolism and biotransformation. This causes the liver to be exposed to various amounts of medications, chemicals, and other xenobiotics, which ultimately leads to liver damage. Hepatic disorders might have hundreds of different causes. Microbes (hepatitis virus A, B, C, cytomegalovirus, Epstein-Barr virus, and yellow fever virus); metabolic syndrome diseases (fatty liver disease brought on by obesity, hemochromatosis, and Wilson's disease); xenobiotics (alcohol, drugs, and chemicals); hereditary liver diseases; autoimmune diseases (biliary cirrhosis, hepatitis, and sclerosing cholangitis); and liver cancers are the most significant causes of hepatic disease. Hepatic illnesses ultimately lead to disruption and missed workdays, a reduction in personal life quality, a shortening of life expectancy, and a financial burden on both the individual and society, which in turn causes mortality and morbidity. Every year, around 2 million people worldwide pass away from hepatic complications; of these, 1 million are cirrhosis-related complications, and the remaining half are linked to liver cancer and viral hepatitis. Right now, liver cancer ranks 16 (788,000 deaths) and cirrhosis ranks 11 (1.16 million deaths) among the leading causes of death. Together, they are responsible for 3.5% of all deaths globally. In the global setting, the primary cause of liver disease is excessive consumption of alcoholic beverages. One of the main issues in treating several acute and chronic medical diseases is drug-induced liver damage (DILI). Studies have shown that the main medications causing DILI include antitubercular drugs (isoniazid), antipsychotics (chlorpromazine), penicillin antibiotics (amoxicillin), histamine antagonists (cimetidine), analgesics and antipyretics (acetaminophen), and HMG-CoA reductase inhibitors (statins). Antimicrobial drugs are thought to be the primary cause of idiosyncratic DILI worldwide. The most recent figures above reveal that the prevalence of liver illness has grown over time, significantly impacting public life worldwide, according to the WHO (1,2).

       
           
       
Fig.1: Liver disease stages

CLASSIFICATION

Drug-induced liver injury (DILI) is a collective term for several unpleasant side effects caused by various pharmaceutical drugs (both prescription and over-the-counter), herbal medicines, and nutritional supplements through a variety of mechanisms. DILI is a major global health concern, with estimated annual incidence rates ranging from 1.3 to 19.1 per 100,000 individuals worldwide, as well as regional differences in prevalence and aetiology. DILI typically occurs days to months after drug exposure, whereas liver damage from an overdose appears within hours to days. The symptoms of DILI or hepatotoxicity vary from person to person. Repeated episodes of acute liver injury lead to acute liver failure, however, in certain moderate or chronic cases, people may not show any signs of liver damage. Globally, the prevalence of acute and chronic liver disorders (CLDs) is rising, impacting people's quality of life and perhaps resulting in life-threatening complications. It will be difficult to completely eradicate hepatitis B-related advanced liver disease in the foreseeable future, while antivirals have lessened its burden. Very effective directly acting antiviral medications have reduced the burden of hepatitis C, however, this has been largely offset by an increase in IV drug abuse. There is no treatment to treat the recent, alarming increase in alcohol-related liver disease or the pandemic of non-alcoholic fatty liver disease, other than controlling risk factors (3–6). A major hazard to public health, chronic liver disease (CLD) has emerged as one of the world's leading causes of death. While there are other causes of CLDs, non-alcoholic fatty liver disease (NAFLD) is the primary cause in over 50% of cases. Non-alcoholic fatty liver disease (NAFLD), characterized by the intracellular buildup of lipids in hepatocytes, is commonly associated with a range of metabolic problems, including obesity, diabetes, dyslipidemia, hypertension, and insulin resistance. NAFLD is a unique spectrum of liver disease that ranges from a straightforward fatty infiltration to progressive non-alcoholic steatohepatitis (NASH), a more severe condition involving inflammation and further hepatocyte damage. Metabolic-associated fatty liver disease (MAFLD) is the new designation for nonalcoholic fatty liver disease (NAFLD). It is a typical positive diagnostic that is independent of alcohol use and based on metabolic measures. High waist circumference, hypertension, hypertriglyceridemia, hypo-HDL cholesterolemia, prediabetes, insulin resistance, and elevated high-sensitivity C-reactive protein levels are among the metabolic risk factors that are currently required for the diagnosis of NAFLD. Additionally, there must be evidence of hepatic steatosis (as demonstrated by biopsy, imaging, or validated serum biomarkers) and one of the following criteria: overweight/obesity, type 2 diabetes mellitus, or metabolic dysregulation (7,8).

EPIDEMIOLOGY

About two-thirds of all liver-related deaths occur in men, and liver disease causes two million deaths a year, or 4% of all deaths (1 out of every 25 deaths globally). Acute hepatitis is responsible for a lesser percentage of mortality, with cirrhosis and hepatocellular carcinoma complications accounting for the majority of deaths. Alcohol, non-alcoholic fatty liver disease, and viral hepatitis are the three main causes of cirrhosis in the world. The majority of acute hepatitis cases are caused by hepatotropic viruses, although a growing percentage of cases are caused by drug-induced liver damage. Updated from the 2019 edition, this version of the global burden of liver disease primarily focuses on areas with substantial new data, such as hepatocellular carcinoma, viral hepatitis, alcohol-associated liver disease, and non-alcoholic fatty liver disease. Using data from the 2019 Global Burden of Disease study, we evaluated the worldwide incidence, mortality, and disability-adjusted life years (DALYs) linked to a range of liver diseases, such as hepatitis B/C virus infections (HCV or HBV), alcohol-related liver disease (ALD), liver cancer, metabolic dysfunction-associated steatotic liver disease (MASLD), and other chronic liver diseases. We also looked at global trends in medication development and hepatology research. Prevalence rates for HBV, HCV, and liver cancer declined between 2000 and 2019, but they rose for ALD, MASLD, and other liver illnesses. The nations with the lowest mortality rates and DALYs were those with a high sociodemographic index (SDI). The prevalence of liver disorders differed by area and sex. Funding for hepatology research increased most in nine sample nations for MASLD and hepatobiliary cancer. From 2000 to 2019, the three main study areas in hepatology articles worldwide were MASLD, pathobiology, and cancer. At the forefront of hepatology study was the United States (U.S.), but China's influence grew over time. (9,10).

HISTOPATHOLOGY

Collagen is believed to originate from the stellate cells under pathological circumstances. Hepatic stellate cells, which are stimulated and change into a myofibroblast-like phenotype, are triggered by chronic liver damage. The extracellular matrix is then laid out. Stellate cells are known to be stimulated by chronic inflammation, disturbance of the extracellular matrix, and the release of cytokines by injured parenchymal cells. Liver fibrosis patterns are influenced by the aetiology. Portal expansion is brought on by a persistent hepatotropic virus infection, which is followed by cirrhosis, septal (bridging) fibrosis, and periportal fibrosis. Fibrosis is caused by alcoholic liver disease and adult non-alcoholic fatty liver disease, beginning with sinusoidal fibrosis and a centrilobular perivenular distribution. Hepatotropic virus infection with a periportal distribution is comparable to pediatric fatty liver disease. Usually, perivenular or perisinusoidal fibrosis is not visible. Feathery degeneration of periseptal hepatocytes resulting in the presence of conspicuous "halos" and irregularly shaped nodules (also known as a "jigsaw" micronodular pattern) are characteristics of cirrhosis of the biliary system disease. In venous outflow obstruction, fibrosis gradually connects the nearby central veins and portal tracts, leading to either veno-portal cirrhosis or veno-centric (also known as "reversed lobulation") cirrhosis. (11).

PATHOPHYSIOLOGY

Hepatic fibrosis, liver tissue architectural distortion, and regeneration nodule development are all ongoing and progressive processes that are indicative of chronic liver illness. Although fibrosis is typically irreversible, it may be reversible during its early stages. We still don't fully understand when reversible fibrosis turns into irreversible fibrosis. If left untreated, chronic liver disease typically results in permanent fibrosis, the creation of regeneration nodules, and the progression of liver cirrhosis. The underlying etiologies, host variables, and environmental conditions all affect how quickly fibrosis develops. In one study, 4852 patients with various underlying etiologies had their liver fibrosis evolution examined. Significant variations in the onset and progression of fibrosis were noted by the author. Patients with HIV-HCV coinfection had the fastest rate, whereas those with primary biliary cirrhosis had the slowest. Females showed a slower progression of liver fibrosis in all but alcoholic liver disease, and the rate of advancement increased with age. The development of more severe disease in certain individuals compared to others with the same underlying aetiology and differences in fibrosis rate progressions were also ascribed to genetic variation in another investigation. Extracellular matrix (ECM) buildup in response to chronic liver injury of any cause is known as hepatic fibrosis. Hepatic stellate cells (HSC), which are often quiescent cells that store vitamin A and are located between sinusoids and hepatocytes, start the common pathway. Chronic liver injury activates HSC to become proliferative fibrogenic myofibroblasts, which then release chemokines and other leukocyte chemoattractants to upregulate the expression of inflammatory receptors, including chemokine receptors, ICAM-1, and other inflammatory mediators. The liver cells' gene and phenotypic expression are altered during this pro-inflammatory or initiation phase, making them more susceptible to certain inflammatory cytokines. The proliferation of activated HSC cells leads to the buildup of extracellular matrix and the development of progressive fibrosis. Drugs that are known to cause liver damage in a dose-dependent way with a brief latency period have an intrinsic mechanism that is both predictable and reproducible. A rare adverse drug reaction known as idiosyncratic drug-induced liver damage (iDILI) can sometimes result in abrupt liver failure or even death. iDILI may rise as a result of an ageing population with more drug use, a steady stream of newly created medications, and an increasing danger from dietary and herbal supplements of questionable quality. Immune-mediated (allergic) liver damage from hypersensitivity and non-immune-mediated metabolic (non-allergic) processes from mitochondrial damage are the two categories of idiosyncratic DILI mechanisms.

 (12–14).

EVALUATION

The aetiology and consequences of chronic liver disease determine the diagnosis. Below is a summary of the diagnosis for different types of CLD. Hepatitis B and C viruses: PCR (both quantitative and qualitative) and serology with genotype. Elevated AST>ALT values along with a history of long-term alcohol consumption are indicative of alcoholic liver disease. In alcoholic liver disease, the AST: ALT ratio is typically 2 to 1.
Increased ferritin, serum iron, decreased TIBC, and liver biopsy are all signs of hemochromatosis. A mutation in the HFE gene, particularly C282Y, can be found via genetic testing. Wilson disease: liver biopsy, reduced serum ceruloplasmin, and elevated urine copper. Searching for the ATP7B gene genetically. ALT>AST and exclusion are the diagnoses for non-alcoholic fatty liver disease. Liver ultrasonography provides useful information. The high levels of these indicators in the blood are caused by inflammation and hepatocyte destruction, which releases aspartate aminotransferase (AST) and alanine aminotransferase (ALT). When cholestatic conditions like PBC are present, other LFT parameters (ALP and GGT) also seem to be raised. Cirrhosis cannot be ruled out by normal levels of AST and ALT, which are typically increased two to three times the normal range.[8] LFTs may be typical in cirrhosis, just like in compensated CLD. Jaundice is associated with increased levels of bilirubin (unconjugated > conjugated). The PT/INR and APTT are elevated as a result of decreased clotting factor production. Albumin levels fall and ammonia levels rise due to cirrhosis-induced liver insufficiency, which results in ascites and hepatic encephalopathy. Numerous factors have been suggested as the mechanism of developing hepatic encephalopathy, including elevated levels of ammonia, tryptophan metabolites, short-chain fatty acids, octopamine, mercaptans, enhanced oxidative stress, and increased intracellular osmolality. Serum AFP levels and abdominal ultrasound can be used to detect hepatocellular cancer. Creatinine levels in hepatorenal syndrome are typically higher than 1.5 g/dl. Increased portal pressure in CLD causes thrombocytopenia, an indirect indicator of splenomegaly. Abdominal ultrasonography, CT, fibroscopy, hepatic wedge pressure, endoscopy, EEG, TIPS, triphasic CT, and Doppler scan are among the radiologic investigations. In CLD, portal venous pressure is measured by wedge hepatic venous pressure. Portal vein thrombosis and Budd-Chiari can be diagnosed with the use of a Doppler scan. In cases of hepatic encephalopathy, the EEG displays delta waves.
Esophageal varices can be diagnosed and treated using an upper endoscopy. We can measure the size of varices during endoscopy. Varices that are huge are larger than 5 mm, whereas those that are small are smaller than 5mm. The diagnosis of chronic liver disease can be verified by a liver biopsy. Liver biopsies can be performed percutaneously, transjugular, or via laparoscopy. (15–20).

HEPATOPROTECTIVE AGENT/SUBSTANCES

Flavonoids are naturally occurring polyphenolic compounds that are abundant in fruits and flowers. Scientists have taken notice of phytochemicals in the flavonoid class because of their important pharmacological characteristics. The antibacterial, antioxidative, antifungal, analgesic, antiviral, anti-inflammatory, anticancer, antiparasitic, and antiallergic qualities of phytochemicals in the flavonoid class have been shown in several research. Red cherries, lentils, soybeans, and liquorice all contain the O-methylated isoflavone Prunetin. It belongs to the class of phytochemicals called phytoestrogens. Nowadays, only a few hepatoprotective agents are accessible. The liver is the body's most vital organ. Protecting the liver is crucial if it is going to be harmed in any way. Prunetin may have greater therapeutic promise as a hepatoprotective drug due to its anti-inflammatory and antioxidant properties. Pre-clinical assessment of prunetin's therapeutic potential as a hepatoprotective drug is the goal of this investigation (21–23). Natural substances can directly attach to biological molecules like DNA or proteins. It has been demonstrated that certain natural substances, like genistein, act as tyrosine-protein kinase inhibitors, which are crucial. Positive information based on what is now understood about the processes underlying the hepatoprotective activity of natural compounds may lead to therapeutic strategies that improve the bioavailability and efficacy of these substances. To ascertain these chemicals' safety for human use, however, pre-clinical and clinical tests must be performed. Natural substances often have a low risk of activating pro-carcinogens and interacting with medications. However, the coadministration of these compounds by healthcare professionals necessitates caution because the interaction between these compounds and pharmaceutical medications has not been well investigated, especially at the level of CYPs.Natural substances' antioxidant qualities and capacity to activate the body's natural antioxidant defence system have been widely credited with their hepatoprotective effects. Given that oxidative stress is involved in almost every mechanism of liver injury, it is logical to assume that these chemicals' antioxidant qualities may be crucial to the mechanism underlying their hepatoprotective action. However, mounting data points to additional pharmacological functions of natural substances other than antioxidants as the cause of their medicinal benefits. Current understanding of the molecular mechanisms behind the hepatoprotective effects of the 27 phytochemicals that have been investigated the most. By interfering with several molecular targets and signalling pathways, these substances have been demonstrated to have anti-inflammatory, antisteatotic, antiapoptotic, cell survival, and antiviral properties. Furthermore, hepatic stellate cell death and the promotion of extracellular matrix breakdown have been directly linked to phytochemicals' antifibrotic qualities. Even while these substances show clear hepatoprotective benefits in animal and cell culture models, a dearth of clinical research is still preventing doctors and medical professionals from officially accepting them. Therefore, it is essential to confirm the therapeutic effectiveness of possibly hepatoprotective drugs through controlled clinical trials. Knowing the fundamentals of phytochemicals' hepatoprotective action may assist in direct future medication development and reduce the likelihood of unsuccessful clinical trials (24).