Transjugular intrahepatic portosystemic shunt in cirrhosis: An exhaustive critical update

More than five decades after it was originally conceptualized as rescue therapy for patients with intractable variceal bleeding,the transjugular intrahepatic portosystemic shunt(TIPS)procedure continues to remain a focus of intense clinical and biomedical research.By the impressive reduction in portal pressure achieved by this intervention,coupled with its minimally invasive nature,TIPS has gained increasing acceptance in the treatment of complications of portal hypertension.The early years of TIPS were plagued by poor long-term patency of the stents and increased incidence of hepatic encephalopathy.Moreover,the diversion of portal flow after placement of TIPS often resulted in derangement of hepatic functions,which was occasionally severe.While the incidence of shunt dysfunction has markedly reduced with the advent of covered stents,hepatic encephalopathy and instances of early liver failure continue to remain a significant issue after TIPS.It has emerged over the years that careful selection of patients and diligent post-procedural care is of paramount importance to optimize the outcome after TIPS.The past twenty years have seen multiple studies redefining the role of TIPS in the management of variceal bleeding and refractory ascites while exploring its application in other complications of cirrhosis like hepatic hydrothorax,portal hypertensive gastropathy,ectopic varices,hepatorenal and hepatopulmonary syndromes,non-tumoral portal vein thrombosis and chylous ascites.It has also been utilized to good effect before extrahepatic abdominal surgery to reduce perioperative morbidity and mortality.The current article aims to review the updated literature on the status of TIPS in the management of patients with liver cirrhosis.

Update on diagnosis and management of sepsis in cirrhosis: Current advances

Sepsis and septic shock are catastrophic disease entities that portend high mortality in patients with cirrhosis.In cirrhosis,hemodynamic perturbations,immune dysregulation,and persistent systemic inflammation with altered gut microbiota in the background of portal hypertension enhance the risk of infections and resistance to antimicrobials.Patients with cirrhosis develop recurrent lifethreatening infections that progress to multiple organ failure.The definition,pathophysiology,and treatment options for sepsis have been ever evolving.In this exhaustive review,we discuss novel advances in the understanding of sepsis,describe current and future biomarkers and scoring systems for sepsis,and delineate newer modalities and adjuvant therapies for the treatment of sepsis from existing literature to extrapolate the same concerning the management of sepsis in cirrhosis.We also provide insights into the role of gut microbiota in initiation and progression of sepsis and finally,propose a treatment algorithm for management of sepsis in patients with cirrhosis.

One disease, many faces-typical and atypical presentations of SARS-CoV-2 infection-related COVID-19 disease

Since the appearance of the novel coronavirus(severe acute respiratory syndrome-coronavirus-2)and related coronavirus disease 2019(COVID-19)in China in December 2019,a very high number of small and large patient series have been published in literature from around the world.Even though the classical presentation of COVID-19 is one with respiratory symptoms with or without pneumonia that can be self-limiting or evolve into severe respiratory distress syndrome with multiple organ failure,and secondary bacterial sepsis,a large body of evidence suggests a plethora of other types of clinical presentation.In this exhaustive review,we reviewed all of the published literature on COVID-19 to identify different types of clinical presentations affecting various organ systems,to provide an in-depth analysis that may prove useful for clinicians and health-workers on the frontline,battling the severe pandemic.

Comprehensive review of hepatotoxicity associated with traditional Indian Ayurvedic herbs

With growing antipathy toward conventional prescription drugs due to the fear of adverse events,the general and patient populations have been increasingly using complementary and alternative medications(CAMs)for managing acute and chronic diseases.The general misconception is that natural herbal-based preparations are devoid of toxicity,and hence short-and long-term use remain justified among people as well as the CAM practitioners who prescribe these medicines.In this regard,Ayurvedic herbal medications have become one of the most utilized in the East,specifically the Indian sub-continent,with increasing use in the West.Recent well-performed observational studies have confirmed the hepatotoxic potential of Ayurvedic drugs.Toxicity stems from direct effects or from indirect effects through herbal metabolites,unknown herb-herb and herbdrug interactions,adulteration of Ayurvedic drugs with other prescription medicines,and contamination due to poor manufacturing practices.In this exhaustive review,we present details on their hepatotoxic potential,discuss the mechanisms,clinical presentation,liver histology and patient outcomes of certain commonly used Ayurvedic herbs which will serve as a knowledge bank for physicians caring for liver disease patients,to support early identification and treatment of those who present with CAM-induced liver injury.

Identification and Analysis of Gut Microbiota and Functional Metabolism in Decompensated Cirrhosis with Infection

Background and Aims:Intestinal dysbiosis play a role in the adverse outcomes of sepsis and septic shock.However,variations in bacterial diversity and microbiota-related functional metabolic alterations within the gut microbiome in decompensated cirrhosis(DC)patients with infection remain unknown.Methods:We conducted 16-srRNA sequencing on stool samples(n=51:sepsis,27/no sepsis,24)collected from consecutive DC patients upon admission.Bacterial diversity,significant taxa,and respective metabolic profiling were performed based on subgroup comparisons.Conet/Cytoscape was utilized to identify significant non-random patterns of bacterial copresence and mutual exclusion for clinical events.Results:Genera associated with pathogenicity in conditions of immune exhaustion(Corynebacterium,Lautropia)were predominant in patients with sepsis.Metabolic pathways associated with oxidative stress and endotoxemia[lipopolysaccharide(LPS)synthesis and sulfur relay]were significantly upregulated in sepsis.Specific taxa were associated with sites of infection in DC patients.Protective oxidant pathways that increase glutathione were upregulated in those without sepsis.Gammaproteobacteria family of sulfur-metabolizing bacteria,exaggeration of orally predominant pathogens(Prevotella),and pathways of severe LPS-related hyperinflammatory stress were notable in those with interleukin-6 levels>1,000 pg/dL.Pathogenic genera related to an immune deficient state was significant in DC with≥2 infection episodes.Megamonas was associated with survival during the same admission.Conclusions:Specific gut microbiota and their metabolites were associated with sepsis and related events in patients with DC.Identifying beneficial strains that reduce immune exhaustion and supplementation of favorable metabolites could improve therapeutics for DC and sepsis,for which larger prospective,well controlled population-based studies remain an unmet need.

Modulating the Intestinal Microbiota:Therapeutic Opportunities in Liver Disease

Gut microbiota has been demonstrated to have a significant impact on the initiation,progression and development of complications associated with multiple liver diseases.Notably,nonalcoholic fatty liver diseases,including nonalcoholic steato-hepatitis and cirrhosis,severe alcoholic hepatitis,primary scle-rosing cholangitis and hepatic encephalopathy,have strong links to dysbiosis–or a pathobiological change in the microbiota.In this review,we provide clear and concise discussions on the human gut microbiota,methods of identifying gut microbiota and its functionality,liver diseases that are affected by the gut microbiota,including novel associations under research,and provide current evidence on the modulation of gut microbiota and its effects on specific liver disease conditions.

Complementary and Alternative Medicine-related Drug-induced Liver Injury in Asia

The use of complementary and alternative medicines(CAMs)for treatment of acute and chronic diseases is on the rise world over,especially in Asian countries,and mostly in China and India.Drug-induced liver injury(DILI)due to CAM is increasingly reported in the literature from multiple centers all around the world and with large-number patient series published from the West,mostly based on nation-wide DILI networks and multicenter collaboration.Comprehensive DILI networks are lacking among major Asian countries with high incidence of CAM practices.Chinese medical societies dealing with drug toxicity,CAM practice and hepatobiliary disease have adopted an integrated approach to establishing identification,diagnosis and treatment of CAM-related DILI,representing a systematic approach that could be iterated by other countries for improving patient outcomes.In this exhaustive review,we provide published data on CAM-related DILI in Asia,with detail on incidences along with analysis of patient population and their clinical outcomes.Concise and clear discussion on commonly implicated CAM agents in major Asian countries and associated chemical and toxicology analyses as well as descriptions of liver biopsy findings are discussed with future directions.

Repurposing Pirfenidone for Nonalcoholic Steatohepatitis-related Cirrhosis:A Case Series

We repurposed the antifibrotic drug pirfenidone—which is approved for treatment of idiopathic lung fibrosis—in a series of patients with nonalcoholic steatohepatitis-related cirrhosis.Our report demonstrates the observed improvements in necroinflammation and regression of cirrhosis with pirfeni-done use for 12-weeks,associated with classical hepatic repair complex features on follow-up liver biopsies.This novel work could help stimulate further randomized trials of pirfe-nidone in patients with nonalcoholic steatohepatitis-related liver fibrosis or cirrhosis,for whom no recommended drug treatments exists currently.

Role of Granulocyte Colony-stimulating Factor Therapy in Cirrhosis,'Inside Any Deep Asking Is the Answering'

Liver cirrhosis progresses through multiple clinical stages which culminate in either death or liver transplantation.Availability of organs,timely listing and prompt receipt of donor-livers pose difficulties in improving transplant-listed and transplant outcomes.In this regard,regenerative therapies,particularly with granulocyte colony-stimulating factor(GCSF),has become a lucrative option for improving transplant-free survival.However,the literature is confusing with regards to patient selection and real outcomes.In this exhaustive review,we describe the basics of liver fibrosis and cirrhosis through novel insights from a therapeutic point of view,discuss preclinical studies on GCSF in advanced liver disease to improve on clinical utility,shed light on the pertinent literature of GCSF in advanced cirrhosis,and provide astute inputs on growth factor therapy in decom-pensated cirrhosis.

Clinical outcomes and gut microbiota analysis of severe alcohol-associated hepatitis patients undergoing healthy donor fecal transplant or pentoxifylline therapy:single-center experience from Kerala

Background Severe alcohol-associated hepatitis(SAH)patients with infections have a high short-term mortality rate.Gut microbiota dysbiosis plays an important role in the pathogenesis of SAH.Preliminary studies have demonstrated long-term benefits with healthy donor fecal microbiota transplantation(FMT).Data on FMT compared with pentoxifylline for SAH and relevant gut microbial changes are lacking in literature.Methods From January 2019 to February 2021,retrospective analysis of a single hospital’s records revealed 47 SAH patients undergoing FMT(100mL/day via nasoduodenal tube for 7days)and 25matched patients receiving pentoxifylline(400mg/8 h for 28days).The primary end point was a 6-month survival rate.Secondary end points included incidence of ascites,hepatic encephalopathy,infections,acute kidney injury,and gutmicrobiota changes between post-therapy groups.Biomarker discovery and network analysis were also performed to identify significant taxa of gutmicrobiota in post-treatment groups in retrospectively stored stool samples.Results All were males.The 6-month survival rate was higher in the patients undergoing FMT than in patients receiving pentoxifylline(83.0%vs 56.0%,P=0.012).At the end of 6-month follow-up,the incidences of clinically significant ascites(56.0%vs 25.5%,P=0.011),hepatic encephalopathy(40.0%vs 10.6%,P=0.003),and critical infections(52.0%vs 14.9%,P<0.001)in patients administered pentoxifylline were significantly higher than those in patients treated with FMT.At 3 months,biomarker analysis revealed a significant abundance of Bifidobacterium and Eggerthella in the FMT group and the pentoxifylline group,respectively.At 6 months,Bifidobacterium in the FMT group and pathogenic Aerococcaceae in the pentoxifylline group were notable.Network analysis showed beneficial taxa(Bifidobacterium)as a central influencer in those undergoing FMT at 6 months.Conclusions Healthy donor FMT improved survival rate and reduced liver-related complications compared with pentoxifylline.These clinical benefits were associated with favorable modulation of intestinal bacterial communities.Difficult-totreat SAH patients may be safely bridged to transplantation using FMT.Controlled trials evaluating long-term outcomes are an unmet need.

Critically Ill COVID-19 Patient with Chronic Liver Disease-Insights into a Comprehensive Liver Intensive Care

The novel coronavirus-related coronavirus disease 2019(COVID-19)pandemic has been relentless in disrupting and overwhelming healthcare the world over.Clinical outcomes of COVID-19 in patients with chronic comorbidities,especially in those with metabolic syndrome,are well documented.Chronic liver disease and cirrhosis patients are a special subgroup,among whom the management of COVID-19 is challenging.Understanding the pathophysiology of COVID-19 in patients with cirrhosis and portal hypertension improves our identification of at-risk patients for disease progression that will further help compartmentalize generalized and specialized treatment options in this special patient group.In this exhaustive review,we critically review the impact of COVID-19 on the liver and in chronic liver disease and cirrhosis patients.We further discuss common features associated with the pathophysiology of COVID-19 and cirrhosis,based on the renin-angiotensin system and deliberate current literature on guidelines for the treatment of COVID-19 and extrapolate the same to the cirrhosis population to provide a concise and stepwise,evidence-based management for cirrhosis patients with severe and critical COVID-19.There are no specific management guidelines for cirrhosis patients with COVID-19 and current recommendations for treatment are as per guidelines for general population.Nevertheless,specific issues like avoiding corticosteroids in decompensated patients with variceal bleeding,suspected sepsis,high grade hepatic encephalopathy and acute kidney injury,use of early mechanical ventilation strategies in those with severe ascites and hepatopulmonary syndrome,avoidance of remdesivir in advanced liver disease,and application of liver-specific severity scores for prognostication and identification of futility need to be highlighted.

Outcomes and Toxicology of Herbal Drugs in Alcoholic Hepatitis-A Single Center Experience from India

Background and Aims:We aimed to study clinical out-comes and liver biopsy features of alcoholic hepatitis(AH)patients on complementary and alternative medicines(CAMs)and to analyze the retrieved drugs for chemical and toxic components linked to drug-induced liver injury.Methods:We retrospectively assessed clinical,biochemical and liver bi-opsy features of AH patients on CAM with drug-induced liver injury(AH-CAM,n=27)and compared them to a control group(classical AH,n=29)on standard of care.Patients without liver biopsy evaluation and other causes for liver dis-ease were excluded.Samples of the CAMs(n=42)from pa-tients were retrieved and assessed for chemical and toxins.Results:All were males,and significantly worse clinical pre-sentation,biochemical severity,and liver disease scores were notable in patients with AH-CAM.Traditional Ayurve-dic-polyherbal formulations were the most commonly used CAM.On liver histology,varying grades of severe-necrosis,severe hepatocellular,canalicular,cholangiolar cholestasis with predominant lymphocytic-portal-inflammation and varying grades of interface-hepatitis were noted in AH-CAM.Analysis of CAMs revealed presence of heavy metals up to 100,000 times above detectable range and adulter-ants,such as antibiotics,chemotherapy agents,nonsteroi-dal anti-inflammatory drugs,alcohols,antidepressants,anxiolytics,and recreational drugs.On follow up,a signifi-cantly higher number of patients with AH on CAM died at end of 1,3-and-6-months compared to controls(37%vs.83%,29%vs.62%,18%vs.52%respectively;p<0.001).Conclusions:Patients with AH and CAM-related drug-induced liver injury have extremely poor short-term survival in the absence of liver transplantation compared to those patients with AH on evidence-based management.Early transplant referral and educating on and curbing of CAM use in severe liver disease through strict monitoring of unregulated traditional health practices can help ease the burden of liver-related death.