Alcoholic Liver Research Articles

Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function

We discuss the article by Koizumi et al published in the World Journal of Gastroenterology . Our focus is on the therapeutic targets for fibrosis associated with alcohol-related liver disease (ALD) and the mechanism of action of elafibranor (EFN), a dual agonist of peroxisome proliferator-activated receptor α (PPARα) and peroxisome PPAR δ (PPARδ). EFN is currently in phase III clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease and primary biliary cholangitis. ALD progresses from alcoholic fatty liver to alcoholic steatohepatitis (ASH), with chronic ASH eventually leading to fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. The pathogenesis of ALD is driven by hepatic steatosis, oxidative stress, and acetaldehyde toxicity. Alcohol consumption disrupts lipid metabolism by inactivating PPARα, exacerbating the progression of ALD. EFN primarily activates PPARα, promoting lipolysis and β-oxidation in ethanol-stimulated HepG2 cells, which significantly reduces hepatic steatosis, apoptosis, and fibrosis in an ALD mouse model. Additionally, alcohol disrupts the gut-liver axis at several interconnected levels, contributing to a proinflammatory environment in the liver. EFN helps alleviate intestinal hyperpermeability by restoring tight junction protein expression and autophagy, inhibiting apoptosis and inflammatory responses, and enhancing intestinal barrier function through PPARδ activation.

High-Sensitivity C-Reactive Protein Levels in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), Metabolic Alcohol-Associated Liver Disease (MetALD), and Alcoholic Liver Disease (ALD) with Metabolic Dysfunction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a recently introduced term for steatotic liver disease (SLD). Although the inflammatory process is central to the pathogenesis of SLD, research investigating the differences in systemic inflammation across various SLD subtypes as well as sex differences is limited. This population-based, cross-sectional study investigated the association between SLD subtypes and high-sensitivity C-reactive protein (hs-CRP) levels among Korean adults (N = 20,141; mean age: 50.8 ± 16.7 years). The participants were classified into five groups that included no SLD, MASLD, metabolic alcohol-associated liver disease (MetALD), alcoholic liver disease with metabolic dysfunction (ALD with MD), and other SLDs. The median (Q1, Q3) value of the hs-CRP level was 0.54 mg/L (0.33, 1.04). Among men, compared to levels in the no SLD group, the MASLD, MetALD, and ALD with MD groups were associated with 41.9% (95% confidence interval [CI]: 35.1–49.1%), 46.8% (95% CI: 35.0–59.6%), and 51.8% (95% CI: 30.0–77.2%) increases in hs-CRP levels, respectively. The association between SLD subtypes and hs-CRP levels was stronger among women, and compared to the levels in the no SLD group, the MASLD, MetALD, and ALD with MD groups were associated with 81.5% (95% CI: 73.6–89.8%), 84.3% (95% CI: 58.1–114.8%), and 98.2% (95% CI: 38.0–184.8%) increases in hs-CRP levels, respectively. In conclusion, our findings indicate a varying profile of systemic inflammation across SLD subtypes, with more pronounced increases in hs-CRP levels in women with SLDs.

ACBP/DBI neutralization for the experimental treatment of fatty liver disease.

Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl4, and (iv) a combination of CCl4 injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.

Exploring the Updated Roles of Ferroptosis in Liver Diseases: Mechanisms, Regulators, and Therapeutic Implications.

Ferroptosis, a newly discovered mode of cell death, is a type of iron-dependent regulated cell death characterized by intracellular excessive lipid peroxidation and imbalanced redox. As the liver is susceptible to oxidative damage and the abnormal iron accumulation is a major feature of most liver diseases, studies on ferroptosis in the field of liver diseases are of great interest. Studies show that targeting the key regulators of ferroptosis can effectively alleviate or even reverse the deterioration process of liver diseases. System Xc- and glutathione peroxidase 4 are the main defense regulators of ferroptosis, while acyl-CoA synthetase long chain family member 4 is a key enzyme causing peroxidation in ferroptosis. Generally speaking, ferroptosis should be suppressed in alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver injury, while it should be induced in liver fibrosis and hepatocellular carcinoma. In this review, we summarize the main regulators involved in ferroptosis and then the mechanisms of ferroptosis in different liver diseases. Treatment options of drugs targeting ferroptosis are further concluded. Determining different triggers of ferroptosis can clarify the mechanism of ferroptosis occurs at both physiological and pathological levels.

Prolonged survival in women with Hepatocellular Carcinoma: a French observational study.

Less than 25% of hepatocellular carcinoma (HCC) occurs in women, in whom prognosis could be better. Due to the lack of date in Europe, this study aims to assess survival of patients with HCC according sex in a tertiary French liver center. Every patient diagnosed with a first diagnosis of HCC presented at our weekly multidisciplinary tumor board between 2013 and 2017 were included. Baseline characteristics of patients and tumors were compared according sex using the Mann-Whitney test for Continuous variables and the Fisher or Chi-square test for dichotomous variables. Survival analyses according sex were conducted using the Kaplan-Meier method, the log-rank test, Cox models and a propensity score. 694 patients were included, of whom 130 (18.7%) were women. Among them, 587 (86%) had cirrhosis, mainly compensated (Child A 62.7%), and related to alcohol (48.7%), HCV (27.2%), and/or metabolic-associated fatty liver disease (25.8%). HCC was unifocal in 54% of cases, with a mean main nodule size of 37 mm. Curative treatment was administered in 45.4% of cases (percutaneous ablation 93%). Compared to men, women diagnosed with HCC were older (73 vs. 65 years, p < 0.001), were more frequently HCV-infected (40% vs. 24%, p = 0.0003) and presented more often with a solitary HCC (63% vs. 52%, p = 0.020). After a median follow-up of 57 months, overall survival was significantly longer in women both in multivariate analysis (aHR 1.39 (CI95%: 1.07-1.81) p=0.014) and using a propensity score (HR 1.51 (1.13-2.02, p=0.005)). Despite being diagnosed at an older age, women with HCC exhibit significant better overall survival.

Insights into the pathogenesis of gestational and hepatic diseases: the impact of ferroptosis

Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver’s susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.

Acetylcorynoline alleviates acute liver injury via inhibiting TLR4/JNK/NF-ĸB pathway Based on RNA-seq and molecular docking in vivo and in vitro

Acute liver injury is characterized by massive inflammatory cell infiltration, destruction of liver structure and abnormalities in liver function. Acetylcorynoline (AC) is one of the main chemical components of Corydalis bungeana Turcz. which has been shown to have a protective effect against acute liver injury. However, Whether AC is protective against acute liver injury remains unclear. This study aimed to explore the protective mechanism of AC against acute liver injury from in vivo as well as experiments in vitro. In experimental in vivo studies, AC pretreatment reduced the serum levels of ALT and AST and inhibited the expression of inflammatory factors in the liver of LPS/D-GalN-induced mice and alcohol liver disease mice. RNA-sequencing and molecular docking were used to predict that AC exerts its anti-inflammatory effects through the Toll-like receptor signaling pathway. Using RT-qPCR and Western blotting to detect expression levels of key genes and nodal proteins of the Toll-like receptor signaling pathway, AC was found to inhibit the phosphorylation of nuclear factor-kappaB (NF-ĸB) and c-Jun amino-terminal kinase (JNK). This finding was validated in cellular experiments. In conclusion, AC exerts its anti-hepatic injury effect by suppressing inflammation through inhibition of the TLR4/JNK/NF-ĸB pathway.

Cholate Shunt, Oral Cholate Challenge and Endoscopic Lesions of Portal Hypertension: The SHUNT-V Study.

The accuracy of current criteria for ruling out large oesophageal varices (LEV) and other endoscopic lesions of portal hypertension (PH) may be compromised by obesity and MASLD/MASH. In the US multicentre SHUNT-V study, we evaluated the disease severity index (DSI) for detecting LEV and other lesions of PH at endoscopy. Subjects were adults with compensated cirrhosis scheduled for endoscopy to screen for varices. DSI was calculated from clearances of labelled cholates after oral and intravenous administration. DSI ≤ 18.3 was evaluated as a cut-off for ruling out LEV with acceptance criteria of negative likelihood ratio < 0.52 and sensitivity > 85%. SHUNT-V enrolled 306 subjects; 275 had both DSI and endoscopy, and 238 had Child-Pugh A cirrhosis (52.1% MASLD/MASH, 25.2% chronic hepatitis C and 15.6% alcoholic liver disease; 87% were overweight, 64% were obese and 54% had diabetes). AUROCs for DSI ranged from 0.81 to 0.82 for LEV and 0.79 to 0.80 for all significant PH lesions. DSI 18.3 had sensitivity 96.3%-100% for LEV and 97.3%-100% for all significant PH lesions. If DSI ≤ 18.3 were used as the sole determinant to defer EGD, 27%-35% of EGDs could have been avoided with 0%-3.7% of LEV and 0%-2.7% of all significant PH lesions missed. HepQuant DSI predicts the likelihood of LEV and significant PH lesions across a spectrum of patient characteristics and disease aetiologies. DSI, based on liver function and portal-systemic shunting, can aid in the decision to defer endoscopy for varices in patients with Child-Pugh A cirrhosis. The SHUNT-V study was registered at ClinicalTrials.gov (NCT03583996).

Survival of Patients with Alcohol-Related Liver Disease Cirrhosis—Usefulness of the New Liver Mortality Inpatients Prognostic Score

Background/Objectives: Alcohol can directly damage the liver, causing steatosis, steatohepatitis, cirrhosis, and hepatocellular cancer. The aim of this study was to examine 28-day survival in hospitalized patients with alcohol-related liver disease (ALD) cirrhosis, as well as to develop and validate a new survival prediction model. Methods: A total of 145 patients with ALD cirrhosis were included; 107 were diagnosed with acute decompensation (AD) and 38 with acute-on-chronic liver failure (ACLF). The new liver mortality inpatients (LIV-IN) score was calculated using the following variables: hepatic encephalopathy (HE), hepatorenal syndrome (HRS), ascites, systemic inflammatory response syndrome (SIRS), community-acquired infection (CAI), and fibrinogen. The diagnostic accuracy of the LIV-IN score was tested, along with the model for end-stage liver disease (MELD), model for end-stage liver disease-sodium (MELD-Na), albumin-bilirubin (ALBI), neutrophil-to-lymphocyte ratio (NLR), chronic liver failure consortium-C acute decompensation (CLIF-C AD), and chronic liver failure consortium-acute-on-chronic liver failure (CLIF-C ACLF). Results: Lethal outcome occurred in 46 (31.7%) patients. The mortality rate was higher in the ACLF group (n = 22, 57.9%) compared to the AD group (n = 24, 22.4%) (p &lt; 0.01). The highest predictive power for short-term mortality was observed for the LIV-IN score (AUC 73.4%, p &lt; 0.01). In patients with AD, the diagnostic accuracy of the CLIF-C AD score was better than for the LIV-IN score (AUC 0.699; p = 0.004, AUC 0.686; p = 0.007, respectively). In patients with ACLF, only the LIV-IN score had statistically significant discriminative power in predicting 28-day survival. Conclusions: The liver mortality inpatients prognostic score is a new, reliable prognostic model in predicting 28-day mortality.

Deciphering the role of LncRNA in alcoholic liver disease: Mechanisms and therapeutic potential.

Alcoholic liver disease (ALD) is a spectrum of liver damage caused by chronic alcohol consumption. The disease progresses in stages, starting with simple fatty liver, progressing to alcoholic hepatitis and potentially leading to fibrosis and cirrhosis. The pathophysiology of ALD is complex and involves several cellular and molecular mechanisms. Recent research has highlighted the role of long non-coding RNAs (LncRNAs) as critical regulators in the development and progression of ALD. This article reviews the current understanding of LncRNAs in ALD, focusing on their functions in key pathological processes and their potential as diagnostic markers and therapeutic targets.

Exploring causal associations between dietary intake and liver diseases: A bidirectional Mendelian randomization study.

Previous evidence suggests that dietary intake can affect liver diseases; However, the causal relationship between dietary intake and liver diseases remains unclear. To investigate this, we conducted a bidirectional Mendelian randomization (MR) analysis to comprehensively assess the potential causal relationship between dietary intake and liver diseases. Two-sample bidirectional MR was performed based on genome-wide association studies summary data from the UK Biobank and FinnGen database. The primary analysis method for evaluating causal relationships was inverse-variance weighted. Supplementary analyses included MR-Egger and weighted median methods. Subsequently, sensitivity analyses were performed using Cochran Q test, MR-Egger intercept test, MR-PRESSO, RadialMR, and leave-one-out analysis to assess heterogeneity and horizontal pleiotropy. MR evidence indicated that genetically predicted poultry intake (adjusted odds ratio [OR] = 0.04, 95% confidence interval [CI] = 0.00-0.43, P = .007) and salad/raw vegetable intake (adjusted OR = 0.18, 95% CI = 0.04-0.83, P = .028) were directly associated with a reduced risk of cirrhosis. Conversely, there is no causal association between dietary intake and nonalcoholic fatty liver disease, alcoholic liver disease, or hepatocellular carcinoma. This study provides evidence supporting the impact of dietary intake on liver disease. Increased intake of poultry and salad/raw vegetables is associated with a reduced risk of cirrhosis. These findings can inform preventive and therapeutic strategies for cirrhosis.

MIST1 regulates endoplasmic reticulum stress-induced hepatic apoptosis as a candidate marker of fatty liver disease progression

The liver regenerates after injury; however, prolonged injury can lead to chronic inflammation, fatty liver disease, fibrosis, and cancer. The mechanism involving the complex pathogenesis of the progression of liver injury to chronic liver disease remains unclear. In this study, we investigated the dynamics of gene expression associated with the progression of liver disease. We analyzed changes in gene expression over time in a mouse model of carbon tetrachloride (CCl4)-induced fibrosis using high-throughput RNA sequencing. Prolonged CCl4-induced liver injury increased the expression levels of genes associated with the unfolded protein response (UPR), which correlated with the duration of injury, with substantial, progressive upregulation of muscle, intestine, and stomach expression 1 (Mist1, bhlha15) in the mouse fibrosis model and other liver-damaged tissues. Knockdown of MIST1 in HepG2 cells decreased tribbles pseudokinase 3 (TRIB3) levels and increased apoptosis, consistent with the patterns detected in Mist1-knockout mice. MIST1 expression was confirmed in liver tissues from patients with metabolic dysfunction-associated steatohepatitis and alcoholic steatohepatitis (MASH) and correlated with disease progression. In conclusion, MIST1 is expressed in hepatocytes in response to damage, suggesting a new indicator of liver disease progression. Our results suggest that MIST1 plays a key role in the regulation of apoptosis and TRIB3 expression contributing to progressive liver disease after injury.

Multimedia-Based Education Led to Improvement in Disease Knowledge Among Patients with Cirrhosis.

Current evidence shows limited patient understanding of liver disease, coupled with no standard guidelines or methods to offer patient education in a busy clinical environment. We developed multimedia-based education (MBE) for those with cirrhosis & tested its effectiveness in improving patient knowledge from baseline to 1 month. This prospective study enrolled cirrhotic patients who had a scheduled visit with a hepatologist at an ambulatory academic practice or were admitted to the liver inpatient service. Once consented, patients completed a baseline knowledge questionnaire, and were given a link to watch the videos (text or email). Four videos were developed by the study team with input from clinicians and patients (liver function, symptoms and complications, medical management and preventive actions & nutrition). At month 1, the study coordinator confirmed with the patient that they had watched the videos at least once, and patients completed the same knowledge questionnaire. The scores between pre- and post-intervention were compared using the Wilcoxon signed rank test. Of the 120 enrolled, 113 completed baseline and 75 completed follow-up. 48% had alcohol-related liver disease as the underlying cause of cirrhosis. Mean MELD score at enrollment was 14.7 ± 8.14. There was a statistically significant improvement in knowledge scores across all domains from baseline to month 1 (p < 0.05). The overall knowledge score improved from 65 to 83% (p < 0.001), with highest improvement by 40% in the domain of liver function and causes of cirrhosis. MBE can help improve patients' knowledge about liver function, management, and prevention and can be used in both ambulatory and inpatient hepatology practice.

Trends in number of deaths due to alcohol-related liver diseases between 2017 and 2022 in Japan

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Distinct characteristics of MetALD (metabolic dysfunction-associated steatotic liver disease with greater alcohol consumption) in the general population.

The term MetALD has been introduced to describe individuals who have metabolic dysfunction-associated steatotic liver disease (MASLD) with greater alcohol consumption, according to the new nomenclature for steatotic liver disease (SLD). This study aims to evaluate the prevalence and clinical characteristics of MetALD in the general population. This study is a retrospective, cross-sectional analysis that utilizes the population-based data from the Korea National Health and Nutrition Examination Survey (KNHANES) undertaken between 2019 and 2021. A total of 16521 participants aged over 18years were included in the analysis. The presence of hepatic steatosis was determined based on a hepatic steatosis index of 36 or higher. The prevalence of MetALD was 2.8% (95% confidence interval, 2.5-3.2). Individuals with MetALD were predominantly men (85.4%) and tended to be younger compared to those with MASLD. They showed a higher prevalence of hypertension and had significantly higher levels of fasting glucose, triglycerides, high-density lipoprotein cholesterol, and creatinine compared to individuals with MASLD. The average daily total energy intake was higher in the MetALD group. In addition, the MetALD group had a lower proportion of unemployment with higher income compared to the MASLD group. Patients with MetALD showed distinct clinical characteristics from those with MASLD. The characteristics of MetALD were similar to those with alcohol-related liver disease. Further analysis of MetALD across various regions and ethnic groups would be needed.

Liver stiffness as a dynamic predictor of decompensation and mortality in alcohol-related liver disease

Liver stiffness as a dynamic predictor of decompensation and mortality in alcohol-related liver disease

Insights of gut-liver axis in hepatic diseases: Mechanisms, clinical implications, and therapeutic potentials.

With the rising prevalence of chronic liver diseases worldwide, there exists a need to diversify our artillery to incorporate a plethora of diagnostic and therapeutic methods to combat this disease. Currently, the most common causes of liver disease are non-alcoholic fatty liver disease, hepatitis, and alcoholic liver disease. Some of these chronic diseases have the potential to transform into hepatocellular carcinoma with advancing fibrosis. In this review, we analyse the relationship between the gut and liver and their significance in liver disease. This two-way relationship has interesting effects on each other in liver diseases. The gut microbiota, through its metabolites, influences the metabolism in numerous ways. Careful manipulation of its composition can lead to the discovery of numerous therapeutic potentials that can be applied in the treatment of various liver diseases. Numerous cohort studies with a pan-omics approach are required to understand the association between the gut microbiome and hepatic disease progression through which we can identify effective ways to deal with this issue.

Ellagic Acid Protects against Alcohol-Related Liver Disease by Modulating the Hepatic Circadian Rhythm Signaling through the Gut Microbiota-NPAS2 Axis.

Alcohol-related liver disease (ALD) encompasses a spectrum of hepatic disorders resulting from alcohol abuse, which constitutes the predominant etiology of morbidity and mortality associated with hepatic pathologies globally. Excessive alcohol consumption disrupts the integrity of the intestinal barrier and perturbs the balance of gut microbiota, thereby facilitating the progression of ALD. Ellagic acid (EA) has been extensively reported to be an effective intervention for alleviating liver symptoms. However, the target molecules of EA in improving ALD and its underlying mechanism remain elusive. First, our study indicates that EA ameliorated ALD through the hepatic circadian rhythm signaling by up-regulating neuronal PAS domain protein 2 (NPAS2). Furthermore, analysis of the intestinal microbiome showed that EA significantly enhanced the abundance of beneficial bacteria, which was positively correlated with NPAS2 expression and negatively correlated with liver injury. Finally, antibiotic treatment and fecal microbiota transplantation (FMT) experiments established a causal relationship between the reshaped microbiota and NPAS2 in the amelioration of ALD. In summary, our study demonstrates novel evidence that EA attenuated ALD by modulating the hepatic circadian rhythm signaling pathway via the gut microbiota-NPAS2 axis, providing valuable insights for EA and microbiome-targeted interventions against ALD.

Aromatic Abietane-Type Diterpenoids from the Roots of Salvia prattii and their Protective Activity Against Alcoholic Liver Disease.

Eighteen aromatic abietane-type diterpenes, including three previously unreported compounds, Salkanoids A-C (1-3), were isolated from the roots of Salvia prattii. Their stuctures were extensively elucidated using 1D/2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS) data, and ECD calculation. Among these, compounds 1, 6 and 7 belong to a class of diterpenes featuring a [5, 5]-oxaspirolactones moiety, a rare structure isolated from the Salvia plants. All the isolates were assessed for their protective effects against alcoholic liver disease using ethanol-induced AML-12 cell lines. The findings revealed that compounds 2, 5, 8 and 15 demonstrated potential protective activity.

Ayurvedic management of Alcoholic Liver Disease : A Case Report

Alcoholic liver disease (ALD) is one of the most prevalent types of liver disease worldwide. According to a 2023 study, the prevalence rate of alcoholic liver disease in India is 4.8%. This case report deals with a 51-year-old male patient initially came to OPD with complaints of yellowish discoloration of eyes, skin, and urine, loss of appetite, anorexia, distention of the abdomen, bilateral pedal edema, easy fatiguability, weakness and weight loss. Liver function test shows-high bilirubin and high transaminase, USG of the abdomen shows-Moderate Hepatomegaly with signs of Hepatitis. It was diagnosed as Kostha-Shakhashrita/Bahupitta Kamala based on the etiopathology and investigations. The patient was treated with Ayurvedic interventions viz, NABB Swarasa, Arogyavardini Vati, Phalatrikadhi Kashaya with Katuki Churna, Patolakaturohinyadhi Kashaya, Laghusoothshekara Rasa and Tab Nirocil were prescribed. After 68 days of treatment protocol, there was marked relief in the symptoms and a reduction in bilirubin and transaminase levels. The above-mentioned oral medications have shown significant results in the present study.