Liver diseases and hepatocellular carcinoma in the Asia-Pacific region: burden, trends, challenges and future directions.

Globally, nearly half of deaths from cirrhosis and chronic liver diseases (CLD) and three-quarters of deaths from hepatocellular carcinoma (HCC) occur in the Asia-Pacific region. Chronic hepatitis B is responsible for the vast majority of liver-related deaths in the region. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common form of CLD, affecting an estimated 30% of the adult population. Compared with people of European descent, people from the Asia-Pacific region carry more genetic variants associated with MASLD and its progression. Alcohol is a fast-growing cause of CLD and HCC in Asia as a result of the rising per-capita consumption of alcohol. Drug-induced liver injury is under-recognized and probably has a high prevalence in this region. The epidemiological and outcome data of acute-on-chronic liver failure are heterogeneous, and non-unified definitions across regions contribute to this heterogeneity. CLDs are severely underdiagnosed, and effective treatments and vaccinations are underutilized. In this Review, we highlight trends in the burden of CLD and HCC in the Asia-Pacific region and discuss the rapidly changing aetiologies of liver disease. We examine the multiple gaps in the care cascade and propose mitigating strategies and future directions.

Systemic Therapies for Hepatocellular Carcinoma in India.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in India. This review explores the epidemiological trends and the landscape of systemic therapy for HCC in the Indian context, acknowledging the recent shift in etiology from viral hepatitis to lifestyle-associated factors. A comprehensive review of the literature was conducted, including data from the Global Cancer Observatory and the Indian Council of Medical Research, along with a critical analysis of various clinical trials. The article investigates systemic therapies in-depth, discussing their mechanisms, efficacy, and adaptation to Indian healthcare framework. Progression-free survival with a hazard ratio of ≤0.6 compared to sorafenib, overall survival of ∼16-19 months, and objective response rate of 20-30% are the defining thresholds for systemic therapy clinical trials. Systemic therapy for advanced HCC in India primarily involves the use of tyrosine kinase inhibitors such as sorafenib, lenvatinib, regorafenib, and cabozantinib, with sorafenib being the most commonly used drug for a long time. Monoclonal antibodies such as ramucirumab and bevacizumab and immune-checkpoint inhibitors, such as atezolizumab, nivolumab, and pembrolizumab, are expanding treatment horizons. Lenvatinib has emerged as a cost-effective alternative, and the combination of atezolizumab and bevacizumab has demonstrated superior outcomes in terms of overall survival and progression-free survival. Despite these advances, late-stage diagnosis and limited healthcare accessibility pose significant challenges, often relegating patients to palliative care. Addressing HCC in India demands an integrative approach that not only encompasses advancements in systemic therapy but also targets early detection and comprehensive care models. Future strategies should focus on enhancing awareness, screening for high-risk populations, and overcoming infrastructural disparities. Ensuring the judicious use of systemic therapies within the constraints of the Indian healthcare economy is crucial. Ultimately, a nuanced understanding of systemic therapeutic options and their optimal utilization will be pivotal in elevating the standard of HCC care in India.

Downstaging with Atezolizumab-Bevacizumab: A Case Series.

Background/aims: Hepatocellular carcinoma (HCC) is generally diagnosed at an advanced stage, which limits curative treatment options for these patients. Locoregional therapy (LRT) is the standard approach to bridge and downstage unresectable HCC (uHCC) for liver transplantation (LT). Atezolizumab-bevacizumab (atezo-bev) can induce objective responses in nearly one-third of patients; however, the role and outcomes of downstaging using atezobev remains unknown. Methods: In this retrospective single-center study, we included consecutive patients between November 2020 and August 2023, who received atezo-bev with or without LRT and were subsequently considered for resection/LT after downstaging. Results: Of the 115 patients who received atezo-bev, 12 patients (10.4%) achieved complete or partial response and were willing to undergo LT; they (age: 58.5 years; women-17%; Barcelona Clinic Liver Cancer Stage System B/C:5/7) had received 3-12 cycles of atezo-bev, and 4 of them had received prior LRT. Three patients died before LT, while three were awaiting LT. Six patients underwent curative therapies: four underwent living donor LT after a median of 79.5 (54-114) days following the last atezo-bev dose, one underwent deceased donor LT 38 days after the last dose, and one underwent resection. All but one patient had complete pathologic response with no viable HCC. Three patients experienced wound healing complications, and one required re-exploration and succumbed to sepsis. After a median follow-up of 10 (4-30) months, none of the alive patients developed HCC recurrence or graft rejection. Conclusions: Surgical therapy, including LT, is possible after atezo-bev therapy in wellselected patients after downstaging.

Hepatocellular Carcinoma Screening in a Contemporary Cohort of At-Risk Patients.

Importance: Cohort studies demonstrating an association of hepatocellular carcinoma (HCC) screening with reduced mortality are prone to lead-time and length-time biases. Objective: To characterize the clinical benefits of HCC screening, adjusting for lead-time and length-time biases, in a diverse, contemporary cohort of at-risk patients. Design, Setting, and Participants: This retrospective cohort study of patients with HCC was conducted between January 2008 and December 2022 at 2 large US health systems. Data analysis was performed from September to November 2023. Main Outcomes and Measures: The primary outcome was screen-detected HCC, defined by abnormal screening-intent abdominal imaging or α-fetoprotein level within 6 months before diagnosis. Cox regression analysis was used to characterize differences in overall survival between patients with screen-detected and non-screen-detected HCC; lead-time and length-time adjustments were calculated using the Duffy parametric formula. Results: Among 1313 patients with HCC (mean [SD] age, 61.7 [9.6] years; 993 male [75.6%]; 739 [56.3%] with Barcelona Clinic Liver Cancer stage 0/A disease), HCC was screen-detected in 556 (42.3%) and non-screen detected in 757 (57.7%). Patients with screen-detected HCC had higher proportions of early-stage HCC (393 patients [70.7%] vs 346 patients [45.7%]; risk ratio [RR], 1.54; 95% CI, 1.41-1.70) and curative treatment receipt (283 patients [51.1%] vs 252 patients [33.5%]; RR, 1.52; 95% CI, 1.34-1.74) compared with patients with non-screen-detected HCC. The screen-detected group had significantly lower mortality, which persisted after correcting for lead-time bias (hazard ratio, 0.75; 95% CI, 0.65-0.87) in fully adjusted models. Both groups had similar tumor doubling times (median [IQR], 3.8 [2.2-10.7] vs 5.6 [1.7-11.4] months) and proportions of indolent tumors (28 patients [35.4%] vs 24 patients [38.1%]; RR, 0.93; 95% CI, 0.60-1.43). Adjustment for length-time bias decreased survival estimates, although 3-year and 5-year survival for patients with screen-detected HCC remained longer than that for patients with non-screen-detected HCC. Conclusions and Relevance: The findings of this cohort study suggest that HCC screening is associated with reduced mortality even after accounting for lead-time and length-time biases. However, these biases should be considered in future studies.

Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes.

BACKGROUND & AIMS: The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. METHODS: We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010-2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. RESULTS: The median API in the 169 countries was 54 [IQR 34.9-76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03-0.60; p = 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03-0.79; p = 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02-0.40; p = 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02-0.65; p = 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02-0.41; p = 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). CONCLUSIONS: The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. IMPACT AND IMPLICATIONS: We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.

Evaluation of terlipressin-related patient outcomes in hepatorenal syndrome-acute kidney injury using point-of-care echocardiography.

BACKGROUND AND AIMS: Treatment of hepatorenal syndrome-acute kidney injury (HRS-AKI), with terlipressin and albumin, provides survival benefits, but may be associated with cardiopulmonary complications. We analyzed the predictors of terlipressin response and mortality using point-of-care echocardiography (POC-Echo) and cardiac and renal biomarkers. APPROACH: Between December 2021 and January 2023, patients with HRS-AKI were assessed with POC-Echo and lung ultrasound within 6 hours of admission, at the time of starting terlipressin (48 h), and at 72 hours. Volume expansion was done with 20% albumin, followed by terlipressin infusion. Clinical data, POC-Echo data, and serum biomarkers were prospectively collected. Cirrhotic cardiomyopathy (CCM) was defined per 2020 criteria. RESULTS: One hundred and forty patients were enrolled (84% men, 59% alcohol-associated disease, mean MELD-Na 25±SD 5.6). A median daily dose of infused terlipressin was 4.3 (interquartile range: 3.9-4.6) mg/day; mean duration 6.4 ± SD 1.9 days; the complete response was in 62% and partial response in 11%. Overall mortality was 14% and 16% at 30 and 90 days, respectively. Cutoffs for prediction of terlipressin nonresponse were cardiac variables [ratio of early mitral inflow velocity and mitral annular early diastolic tissue doppler velocity > 12.5 (indicating increased left filling pressures, C-statistic: 0.774), tissue doppler mitral velocity < 7 cm/s (indicating impaired relaxation; C-statistic: 0.791), > 20.5% reduction in cardiac index at 72 hours (C-statistic: 0.885); p < 0.001] and pretreatment biomarkers (CysC > 2.2 mg/l, C-statistic: 0.640 and N-terminal proBNP > 350 pg/mL, C-statistic: 0.655; p <0.050). About 6% of all patients with HRS-AKI and 26% of patients with CCM had pulmonary edema. The presence of CCM (adjusted HR 1.9; CI: 1.8-4.5, p = 0.009) and terlipressin nonresponse (adjusted HR 5.2; CI: 2.2-12.2, p <0.001) were predictors of mortality independent of age, sex, obesity, DM-2, etiology, and baseline creatinine. CONCLUSIONS: CCM and reduction in cardiac index, reliably predict terlipressin nonresponse. CCM is independently associated with poor survival in HRS-AKI.

Comparing rare variants versus common in the pathogenesis of nonalcoholic fatty liver disease: a whole exome sequencing approach.

BACKGROUND/PURPOSE: Genome-wide association studies have reported the association of common variants with nonalcoholic fatty liver disease in genes, namely, PNPLA3/TM6SF2/MBOAT7/HSD17B13, across ethnicities. However, the approach does not identify rarer variants with a higher effect size. We therefore sequenced the complete exonic regions of patients with nonalcoholic steatohepatitis and controls to compare rare and common variants with a role in the pathogenesis. METHODS: This is a prospective study that recruited 54 individuals with/without fatty infiltration. Patients with biopsy-proven nonalcoholic steatohepatitis and persistently elevated liver enzymes were included. Controls were with normal CT/MR fat fraction. DNA was isolated from whole blood, amplified (SureSelectXT Human All Exon V5 + UTR kit) and sequenced (Illumina). Data were filtered for quality, aligned (hg19), and annotated (OpenCRAVAT). Pathogenic (Polyphen-2/SIFT/ClinVar) variants and variants reported to be associated with NAFLD based on published literature were extracted from our data and compared between patients and controls. RESULTS: The mean age of controls (N = 17) and patients (N = 37) was 46.88 ± 6.94 and 37.46 ± 13.34 years, respectively. A total of 251 missense variants out of 89 286 were classified as pathogenic. Of these, 106 (42.23%) were unique to the patients and remaining (n = 145; 57.77%) were found in both patients and controls. Majority (25/37; 67.57%) patients had a minimum of one or more rare pathogenic variant(s) related to liver pathology that was not seen in the controls. CONCLUSION: Elucidating the contribution of rare pathogenic variants would enhance our understanding of the pathogenesis. Including the rarer genes in the polygenic risk scores would enhance prediction power.

Intravenous BCAA Infusion Does Not Lead to a Sustained Recovery From Overt HE in ACLF - An Open Label Randomized Clinical Trial.

Background: Hepatic encephalopathy (HE) in acute-on-chronic liver failure (ACLF) is associated with significant morbidity and mortality. We conducted a prospective, randomized controlled clinical trial to study the efficacy of intravenous branched chain amino acids (IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24 h, day 3, and day 7. The primary outcome was an improvement in encephalopathy by ≥ 1 grade at 72 h. Patients and methods: European association for study of liver (EASL) defined ACLF patients with overt HE were assessed and randomized into the experimental arm (IV-BCAA - 500 mL/day for 3 days + Lactulose; n = 39) and the comparator arm (Lactulose alone; n = 37). Six patients developed COVID-19 after randomization and were excluded (4-experimental arm and 2-comparator arm). Results: Of 222 screened patients, 70 (35 in each arm) were included in the analysis. Baseline characteristics, including HE grade (2.9 ± 0.7 vs 2.8 ± 0.7; P = 0.86) and (chronic liver failure) CLIF-C ACLF score (54.2 ± 5.6 vs 54.8 ± 5.7; P = 0.65), were similar. Overall survival was 40% at 28 days (48.5% vs 31.4%; P = 0.14). Improvement in hepatic encephalopathy scoring algorithm (HESA) by ≥ 1 grade at 24 h occurred in 14 patients (40%) in the BCAA arm and 6 patients (17.1%) in the control group (P = 0.03) which translated to a shorter intensive care unit (ICU) stay. The median change in HESA at 24 h was greater in the BCAA arm than the control arm (P = 0.006), which was not sustained at days 3 or 7. Ammonia levels did not correlate with the grade of HE (Spearman's correlation coefficient (ρ) = - 0.0843; P = 0.29). Conclusion: Intravenous BCAA does not lead to a sustained improvement in HE grade in ACLF. Trial registration no: NCT04238416 (clinicaltrials.gov).

Liver Transplantation: Protocol for Recipient Selection, Evaluation, and Assessment.

Liver transplantation (LT) is the definitive therapy for patients with end-stage liver disease, acute liver failure, acute-on-chronic liver failure, hepatocellular carcinoma, and metabolic liver diseases. The acceptance of LT in Asia has been gradually increasing and so is the expertise to perform LT. Preparing a patient with cirrhosis for LT is the most important aspect of a successful LT. The preparation for LT begins with the first index decompensation for a patient with cirrhosis. Patients planned for LT should undergo a thorough screening for infections, and a complete cardiac, pulmonology, and psychosocial evaluation pre-LT. In this review, we discuss the indications and contraindications of LT and the evaluation and assessment of patients with liver disease planned for LT.

Effectiveness and safety of atezolizumab-bevacizumab in patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

Background: Atezolizumab-bevacizumab (atezo-bev) is recommended as first-line therapy for patients with unresectable hepatocellular carcinoma (uHCC). However, its effectiveness and safety in other populations, including those with Child-Turcotte-Pugh (CTP) class B cirrhosis, is unclear. Methods: For this systematic review and meta-analysis, electronic databases, including PubMed, Embase, and Scopus, were searched from 1st May, 2020 till 5th October, 2022; the last date of access was January 31, 2023. Pooled progression-free survival (PFS), overall survival (OS), and radiological response rate among patients receiving atezo-bev were compared between patients with CTP-A and CTP-B cirrhosis, with tyrosine kinase inhibitors (TKIs) and among those receiving the drug as first-line and later line therapy. The protocol was registered in Prospero (CRD42022364430). Findings: Among 47 studies (n = 5400 patients), pooled PFS and OS were 6.86 (95% CI, 6.31-7.41) and 13.8 months (95% CI, 11.81-15.8), respectively. Objective response rate (ORR) and disease control rate were 26.7% (24.6-29.1) and 75.3% (73.1-77.4) using RECIST criteria, and 34% (30.3-37.8) and 73.6% (68.8-78) using mRECIST criteria, respectively. Among those receiving atezo-bev, patients with CTP-B cirrhosis had similar ORRs by RECIST (odds ratio [OR], 1.42 [0.77-2.6]; P = 0.25) and mRECIST criteria (OR, 1.33 [0.52-3.39]; P = 0.53) but shorter PFS (mean difference [MD]:3.83 months [1.81-5.84]) than those with CTP-A cirrhosis. Compared to patients receiving TKIs, those receiving atezo-bev had longer PFS (MD: 2.27 months [0.94-3.5]) and higher ORR (RECIST: OR, 1.44 [1.01-2.04] and mRECIST: OR, 1.33 [1.01-1.75]). Compared to first-line therapy, later-line therapy had lower ORR (RECIST: OR, 1.82 [1.3-2.53]; P < 0.001 and mRECIST: OR, 2.02 [1.34-3.05]) but comparable PFS (MD: 0.58 months [-0.18 to 1.35]) among nine studies. The incidence of grade ≥3 adverse events among patients with CTP-A and CTP-B cirrhosis was comparable (OR, 0.89 [0.45-1.74]) as it was for patients receiving atezo-bev and TKIs (OR, 0.86 [0.61-1.2]). Interpretation: Our findings suggest that atezo-bev is safe and effective as first-line systemic therapy for patients with uHCC and CTP-A or CTP-B cirrhosis. Funding: An unsolicited grant from ROCHE Products India Pvt Ltd. was received for publication.

Safety and Efficacy of Atezolizumab-Bevacizumab in Real World: The First Indian Experience.

Background: Atezolizumab-bevacizumab (atezo/bev) combination is a recommended first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). There are no studies from India reporting the safety and efficacy of this drug in real-world settings where most patients present in an advanced stage. Methods: In this retrospective study from two centers in India, we included patients with uHCC who received atezo/bev as first-line systemic therapy. Comparison of overall survival (OS) among the different Child-Turcotte-Pugh (CTP) classes was the primary objective, while progression-free survival (PFS), radiologic response, and adverse events to the therapy were secondary objectives. Results: The median age of the 67 patients who received atezo/bev therapy was 61 (29-82) years, and 86% were males. Nonalcoholic steatohepatitis (55.2%) was the commonest cause of cirrhosis, and most patients belonged to BCLC-C (74.6%%). There were 24 patients in CTP A, 36 in CTP B, and 7 in CTP C. The median OS was 12 (95%CI, 8.16-15.83) months in the cohort. The median OS in CTP class A, B, and C was 21 (95%CI, 0-42.06) months, 9 (95%CI, 5.46-12.53) months, and 4 (95%CI, 2.14-5.85) months, respectively (P < 0.001). The median PFS in the whole cohort was 8 (95%CI, 6.03-9.96) months. The median PFS in Child A, B, and C was 18 (95%CI, 0.16-35.84) months, 8 (95%CI, 6.14-9.85) months, and 2 (95%CI, 1.77-2.23) months (P < 0.001). On mRECIST evaluation, 12.9% had achieved a complete response, 25.8% had a partial response, 27.41% had stable disease, and the rest had progressed. The objective response rate was 38.7%, and the disease control rate was 66.12%. Of the 64% who developed adverse events, 13.43% discontinued the drug. The incidence of grade ≥3 events was significantly higher in CTP C (85.7%) compared to CTP A (12.5%) and CTP B (14%) (P < 0.001). Conclusions: Atezolizumab-bevacizumab is safe and effective in uHCC in real-world settings. Candidate selection is of utmost importance in treating uHCC with atezolizumab-bevacizumab to achieve a good response. Current evidence strongly suggests limited use of atezolizumab-bevacizumab in patients with CTP C, and such individuals should not be considered for this combination therapy.

The bidirectional impacts of alcohol consumption and MAFLD for progressive fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), once considered a benign condition, has been associated with several cardiometabolic complications over the past two decades. The worldwide prevalence of NAFLD is as high as 30%. NAFLD requires the absence of a "significant alcohol intake." Conflicting reports have suggested that moderate alcohol consumption may be protective; therefore, the diagnosis of NAFLD previously relied on negative criteria. However, there has been a significant increase in alcohol consumption globally. Apart from the rise in alcohol-related liver disease (ARLD), alcohol, a major toxin, is associated with an increased risk of several cancers, including hepatocellular carcinoma. Alcohol misuse is a significant contributor to disability-adjusted life years. Recently, the term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed instead of NAFLD to include the metabolic dysfunction responsible for the major adverse outcomes in patients with fatty liver disease. MAFLD, dependent on the "positive diagnostic criteria" rather than previous exclusion criteria, may identify individuals with poor metabolic health and aid in managing patients at increased risk of all-cause and cardiovascular mortality. Although MAFLD is less stigmatizing than NAFLD, excluding alcohol intake may increase the risk of already existing underreported alcohol consumption in this subgroup of patients. Therefore, alcohol consumption may increase the prevalence of fatty liver disease and its associated complications in patients with MAFLD. This review discusses the effects of alcohol intake and MAFLD on fatty liver disease.

Early living donor liver transplantation for alcohol-associated hepatitis.

INTRODUCTION AND OBJECTIVES: Lately, there has been a steady increase in early liver transplantation for alcohol-associated hepatitis (AAH). Although several studies have reported favorable outcomes with cadaveric early liver transplantation, the experiences with early living donor liver transplantation (eLDLT) are limited. The primary objective was to assess one-year survival in patients with AAH who underwent eLDLT. The secondary objectives were to describe the donor characteristics, assess the complications following eLDLT, and the rate of alcohol relapse. MATERIALS AND METHODS: This single-center retrospective study was conducted at AIG Hospitals, Hyderabad, India, between April 1, 2020, and December 31, 2021. RESULTS: Twenty-five patients underwent eLDLT. The mean time from abstinence to eLDLT was 92.4 ± 42.94 days. The mean model for end-stage liver disease and discriminant function score at eLDLT were 28.16 ± 2.89 and 104 ± 34.56, respectively. The mean graft-to-recipient weight ratio was 0.85 ± 0.12. Survival was 72% (95%CI, 50.61-88) after a median follow-up of 551 (23-932) days post-LT. Of the 18 women donors,11 were the wives of the recipient. Six of the nine infected recipients died: three of fungal sepsis, two of bacterial sepsis, and one of COVID-19. One patient developed hepatic artery thrombosis and died of early graft dysfunction. Twenty percent had alcohol relapse. CONCLUSIONS: eLDLT is a reasonable treatment option for patients with AAH, with a survival of 72% in our experience. Infections early on post-LT accounted for mortality, and thus a high index of suspicion of infections and vigorous surveillance, in a condition prone to infections, are needed to improve outcomes.

Prophylactic Perioperative Terlipressin Therapy for Preventing Acute Kidney Injury in Living Donor Liver Transplant Recipients: A Systematic Review and Meta-Analysis.

Background: Acute kidney injury (AKI) is common in the perioperative transplant period and is associated with poor outcomes. Few studies reported a reduction in AKI incidence with terlipressin therapy by counteracting the hemodynamic alterations occurring during liver transplantation. However, the effect of terlipressin on posttransplant outcomes has not been systematically reviewed. Methods: A comprehensive search of electronic databases was performed. Studies reporting the use of terlipressin in the perioperative period of living donor liver transplantation were included. We expressed the dichotomous outcomes as risk ratio (RR, 95% confidence interval [CI]) using the random effects model. The primary aim was to assess the posttransplant risk of AKI. The secondary aims were to assess the need for renal replacement therapy (RRT), vasopressors, effect on hemodynamics, blood loss during surgery, hospital and intensive care unit (ICU) stay, and in-hospital mortality. Results: A total of nine studies reporting 711 patients (309 patients in the terlipressin group and 402 in the control group) were included for analysis. Terlipressin was administered for a mean duration of 53.44 ± 28.61 h postsurgery. The risk of AKI was lower with terlipressin (0.6 [95% CI, 0.44-0.8]; P = 0.001). However, on sensitivity analysis including only four randomized controlled trials (I2 = 0; P = 0.54), the risk of AKI was similar in both the groups (0.7 [0.43-1.09]; P = 0.11). The need for RRT was similar in both the groups (0.75 [0.35-1.56]; P = 0.44). Terlipressin therapy reduced the need for another vasopressor (0.34 [0.25-0.47]; P < 0.001) with a concomitant rise in mean arterial pressure and systemic vascular resistance by 3.2 mm Hg (1.64-4.7; P < 0.001) and 77.64 dyne cm-1.sec-5 (21.27-134; P = 0.007), respectively. Blood loss, duration of hospital/ICU stay, and mortality were similar in both groups. Conclusions: Perioperative terlipressin therapy has no clinically relevant benefit.

Tinospora Cordifolia (Giloy)-Induced Liver Injury During the COVID-19 Pandemic-Multicenter Nationwide Study From India.

Tinospora cordifolia (Giloy) is an herbal supplement commonly used in the Indian alternative medicine system Ayurveda. This herb has been promoted to the public in India as an immune booster to prevent novel coronavirus disease 2019. However, small reports have recently shown an association between Giloy use and the development of herb-induced liver injury (HILI) with autoimmune features in some patients. This large retrospective Indian multicenter study spanning 13 centers at nine locations was designed to identify features and outcomes of HILI temporally associated with Giloy use. Chemical and toxicological analyses of retrieved Giloy samples using state-of-the-art methods were also performed. We report 43 patients, of whom more than half were female, with a median time from initial Giloy consumption to symptom onset of 46 days. Patients presented with acute hepatitis, acute worsening of chronic liver disease (CLD, the most common clinical presentation), or acute liver failure. Causality assessment revealed probable liver injury in 67.4%. The most common autoantibody detected was anti-nuclear antibody. Liver biopsy in a subset revealed HILI associated with autoimmune features and hepatocyte and canalicular cholestasis and neutrophilic and eosinophilic infiltration. Conclusion: Giloy is associated with acute hepatitis with autoimmune features and can unmask autoimmune hepatitis (AIH) in people with silent AIH-related CLD. Further studies on the safety (and efficacy) of untested but heavily promoted herbals in alternative systems of medicine are an unmet need in the interests of public health and are especially important during this global health emergency.

Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail.

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic that is likely to become the most common cause of chronic liver disease in the next decade, worldwide. Though numerous drugs have been evaluated in clinical trials, most of them have returned inconclusive results and shown poorly-tolerated adverse effects. None of the drugs have been approved by the Food and Drug Administration for treating biopsy-proven non-alcoholic steatohepatitis (NASH). Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic NASH patients. Although some amelioration of inflammation has been seen, these drugs did not improve the fibrosis component of NASH. Therefore, dietary modification and weight reduction have remained the cornerstone of treatment of NASH; moreover, they have shown to improve histological activity as well as fibrosis. The search for an ideal drug or 'Holy Grail' within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for NASH which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.

Early liver transplantation after COVID-19 infection: The first report.

COVID-19 (coronavirus disease 2019) has impacted solid organ transplantation (SOT) in many ways. Transplant centers have initiated SOT despite the COVID-19 pandemic. Although it is suggested to wait for 4 weeks after COVID-19 infection, there are no data to support or refute the timing of liver transplant after COVID-19 infection. Here we describe the course and outcomes of COVID-19-infected candidates and healthy living liver donors who underwent transplantation. A total of 38 candidates and 33 potential living donors were evaluated from May 20, 2020 until October 30, 2020. Ten candidates and five donors were reverse transcriptase-polymerase chain reaction (RT-PCR) positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pretransplant. Four candidates succumbed preoperatively. Given the worsening of liver disease, four candidates underwent liver transplant after 2 weeks due to the worsening of liver disease and the other two candidates after 4 weeks. Only one recipient died due to sepsis posttransplant. Three donors underwent successful liver donation surgery after 4 weeks of COVID-19 infection without any postoperative complications, and the other two were delisted (as the candidates expired). This report is the first to demonstrate the feasibility of elective liver transplant early after COVID-19 infection.