Showing papers in "Journal of clinical and experimental hepatology in 2022"

A Current Understanding of Bile Acids in Chronic Liver Disease

Abstract: Chronic liver disease (CLD) is one of the leading causes of disability-adjusted life years in many countries. A recent understanding of nuclear bile acid receptor pathways has increased focus on the impact of crosstalk between the gut, bile acids, and liver on liver pathology. While conventionally used in cholestatic disorders and to dissolve gallstones, the discovery of bile acids’ influence on the gut microbiome and human metabolism offers a unique potential for their utility in early and advanced liver diseases because of diverse etiologies. Based on these findings, preclinical studies using bile acid-based molecules have shown encouraging results at addressing liver inflammation and fibrosis. Emerging data also suggest that bile acid profiles change distinctively across various causes of liver disease. We summarize the current knowledge and evidence related to bile acids in health and disease and discuss culminated and ongoing therapeutic trials of bile acid derivatives in CLD. In the near future, further evidence in this area might help clinicians better detect and manage liver diseases. Chronic liver disease (CLD) is one of the leading causes of disability-adjusted life years in many countries. A recent understanding of nuclear bile acid receptor pathways has increased focus on the impact of crosstalk between the gut, bile acids, and liver on liver pathology. While conventionally used in cholestatic disorders and to dissolve gallstones, the discovery of bile acids’ influence on the gut microbiome and human metabolism offers a unique potential for their utility in early and advanced liver diseases because of diverse etiologies. Based on these findings, preclinical studies using bile acid-based molecules have shown encouraging results at addressing liver inflammation and fibrosis. Emerging data also suggest that bile acid profiles change distinctively across various causes of liver disease. We summarize the current knowledge and evidence related to bile acids in health and disease and discuss culminated and ongoing therapeutic trials of bile acid derivatives in CLD. In the near future, further evidence in this area might help clinicians better detect and manage liver diseases. Liver cirrhosis is the 8th most common cause of death in low-middle-income countries as per the World Health Organization's official report.1The Top 10 Causes of Death. Accessed May 28, 2021. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death.Google Scholar The most common etiologies of cirrhosis are alcohol, chronic viral hepatitis, and the emerging menace of nonalcoholic fatty liver disease (NAFLD).2Wong M.C.S. Huang J.L.W. George J. et al.The changing epidemiology of liver diseases in the Asia-Pacific region.Nat Rev Gastroenterol Hepatol. 2019; 16: 57-73https://doi.org/10.1038/s41575-018-0055-0Crossref PubMed Scopus (90) Google Scholar, 3Wong R.J. Aguilar M. Cheung R. et al.Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.Gastroenterology. 2015; 148: 547-555https://doi.org/10.1053/j.gastro.2014.11.039Abstract Full Text Full Text PDF PubMed Scopus (1023) Google Scholar, 4Pimpin L. Cortez-Pinto H. Negro F. et al.Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.J Hepatol. 2018; 69: 718-735https://doi.org/10.1016/j.jhep.2018.05.011Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar Decompensated cirrhosis, in particular, has high mortality with a median survival of 2 years. In patients with cirrhosis, bacterial translocation further aggravates fluid shifts and increases mortality risk due to sepsis.5Bajaj J.S. Heuman D.M. Hylemon P.B. et al.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014; 60: 940-947https://doi.org/10.1016/j.jhep.2013.12.019Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar Recent insights about the role of bile acid (BA) composition on insulin sensitivity and their dialog with the gut microbiome, apart from their well-known digestive functions, have drawn attention to their relevance in chronic liver disease (CLD). From numerous animal and human studies, we now know that through nuclear receptors, BAs play a role in regulating the qualitative and quantitative BA pool, gut microbiome, and glucose and lipid metabolism.6Xu G. Pan L. Erickson S.K. et al.Removal of the bile acid pool upregulates cholesterol 7alpha-hydroxylase by deactivating FXR in rabbits.J Lipid Res. 2002; 43: 45-50Abstract Full Text Full Text PDF PubMed Google Scholar, 7Watanabe M. Houten S.M. Wang L. et al.Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.J Clin Invest. 2004; 113: 1408-1418https://doi.org/10.1172/JCI21025Crossref PubMed Scopus (864) Google Scholar, 8Inagaki T. Choi M. Moschetta A. et al.Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.Cell Metabol. 2005; 2: 217-225https://doi.org/10.1016/j.cmet.2005.09.001Abstract Full Text Full Text PDF PubMed Scopus (1194) Google Scholar An increase in studies characterizing the fecal and serum BA pool in cirrhosis has helped improve our understanding of the pathogenesis and enabled the development of diagnostic or prognostic markers of liver disease. As expected, many BA receptor–based therapeutics are currently in the pipeline. In this narrative review, we expand on the synthesis and metabolism of BAs, their effect on the gut microbiome, and the progression of CLD, in addition to discussing their emerging role in diagnostics and therapeutics. Primary BAs are synthesized from cholesterol in hepatocytes predominantly via the neutral/classic pathway and in small amounts by the acidic/alternate pathway. The rate-limiting and regulatory step in BA synthesis via classic pathway is enzymatically catalyzed by cholesterol 7 α hydroxylase (CYP7A1).9Chiang J.Y.L. Ferrell J.M. Bile acid biology, pathophysiology, and therapeutics.Clinical Liver Disease. 2020; 15: 91-94https://doi.org/10.1002/cld.861Crossref Scopus (16) Google Scholar This step is sensitive to negative feedback regulation via excess BAs. The primary BAs include cholic acid (CA) and chenodeoxycholic acid (CDCA) and are further conjugated to amino acids glycine and taurine (3:1) to increase their solubility. The BAs secreted by the hepatocytes are stored in the gallbladder and released postprandially into the proximal small bowel, where they carry out their well-known digestive functions such as emulsification and formation of micelles aiding in the absorption of fat- and fat-soluble vitamins. They are transported into the distal small bowel from where they are actively absorbed into the portal circulation and transported to the hepatocytes for resecretion via the enterohepatic cycle (Figure 1). The majority of the BAs are salvaged actively from the distal small bowel, and a small proportion escapes into the colon, where they are deconjugated by bacterial bile salt hydrolase and dehydroxylated to secondary BAs: deoxycholic acid and lithocholic acid. Ursodeoxycholic acid (UDCA) is a secondary BA formed from the bacterial epimerization of CDCA. These secondary BAs are also absorbed and form a minor fraction of the total BA pool in the body. Apart from their well-known digestive functions in the gut, BAs act on a myriad of nuclear receptors such as farnesoid X receptor (FXR), vitamin D receptor and pregnane X receptor, and surface receptors such as Takeda G protein–coupled receptor 5 (TGR5) (Figure 2) to bring about their signaling effects. FXR receptors are expressed widely in hepatocytes as well as enterocytes. In the hepatocytes, BAs inhibit CYP7A1 via induction of small heterodimer partner, while in the enterocytes, they induce the production of fibroblast growth factor-19 (FGF-19), which acts via FGF receptor 4 (FGFR4) to inhibit CYP7A1 and BA synthesis. BAs also act on surface receptors such as TGR5 on enteroendocrine cells, causing the release of glucagon-like peptide-1, which acts as an incretin and plays a role in adipose tissue browning.9Chiang J.Y.L. Ferrell J.M. Bile acid biology, pathophysiology, and therapeutics.Clinical Liver Disease. 2020; 15: 91-94https://doi.org/10.1002/cld.861Crossref Scopus (16) Google Scholar BA pool is depleted in patients with cirrhosis because of decreased synthesis and secretion of BAs from hepatocytes and disproportionate partitioning of BAs. Furthermore, the accumulation of BAs in the blood and within hepatocytes compounds the inhibition of CYP7A1, contributing to the BA pool depletion.10Vlahcevic Z.R. Buhac I. Farrar J.T. Bell C.C. Swell L. Bile acid metabolism in patients with cirrhosis.Gastroenterology. 1971; 60: 491-498https://doi.org/10.1016/S0016-5085(71)80053-7Abstract Full Text PDF PubMed Scopus (75) Google Scholar The decreased levels of fecal BAs promote depletion of Firmicutes, particularly Blautia and Ruminococcus species, and expansion of proinflammatory pathogenic bacteria of the phylum Proteobacteria, particularly Enterobacteriaceae (Figure 3). This is because colonic microbial groups are responsible for deconjugation and 7-alpha dehydroxylation of BAs, and it is hypothesized that the presence of microbe toxic BAs (particularly deoxycholic acid [DCA]) in the intestine is one of the factors that keep undesirable microbial populations under control.11Ridlon J.M. Kang D.J. Hylemon P.B. Bajaj J.S. Bile acids and the gut microbiome.Curr Opin Gastroenterol. 2014; 30: 332-338https://doi.org/10.1097/MOG.0000000000000057Crossref PubMed Scopus (569) Google Scholar, 12Kakiyama G. Pandak W.M. Gillevet P.M. et al.Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.J Hepatol. 2013; 58: 949-955https://doi.org/10.1016/j.jhep.2013.01.003Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 13Slocum M.M. Sittig K.M. Specian R.D. Deitch E.A. Absence of intestinal bile promotes bacterial translocation.Am Surg. 1992; 58: 305-310PubMed Google Scholar, 14Ding J.W. Andersson R. Soltesz V. Willén R. Bengmark S. The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats.Eur Surg Res. 1993; 25: 11-19https://doi.org/10.1159/000129252Crossref PubMed Scopus (109) Google Scholar, 15Fouts D.E. Torralba M. Nelson K.E. Brenner D.A. Schnabl B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease.J Hepatol. 2012; 56: 1283-1292https://doi.org/10.1016/j.jhep.2012.01.019Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar The dysbiosis is linked to loss of membrane disrupting activity of secondary BAs directly as well as indirectly via loss of secretion of receptor-mediated antimicrobial peptides via BA signaling.11Ridlon J.M. Kang D.J. Hylemon P.B. Bajaj J.S. Bile acids and the gut microbiome.Curr Opin Gastroenterol. 2014; 30: 332-338https://doi.org/10.1097/MOG.0000000000000057Crossref PubMed Scopus (569) Google Scholar The decrease in Firmicutes is possibly because BAs serve as primary fermentative electron acceptors for these bacteria.11Ridlon J.M. Kang D.J. Hylemon P.B. Bajaj J.S. Bile acids and the gut microbiome.Curr Opin Gastroenterol. 2014; 30: 332-338https://doi.org/10.1097/MOG.0000000000000057Crossref PubMed Scopus (569) Google Scholar The resulting inflammation contributes to increased translocation of bacterial products such as lipopolysaccharide and compounds the progression of cirrhosis. Apart from depleted BA pool, reduced intestinal motility decreased gastric and pancreatobiliary secretions, and portal hypertensive enteropathy can disturb the normal intestinal microbial community in patients with cirrhosis. Apart from these changes in patients with cirrhosis, the proinflammatory cytokines inhibit the classic pathway's key enzyme CYP7A1. Hence, the alternate pathway forms the major source of BA synthesis in cirrhosis.16Li Y. Lu L.-G. Therapeutic roles of bile acid signaling in chronic liver diseases.J Clin Transl Hepatol. 2018; 6: 425-430https://doi.org/10.14218/JCTH.2018.00025Crossref PubMed Scopus (7) Google Scholar Patients with cirrhosis also have a depletion of 7α dehydroxylation bacteria, which leads to decreased secondary: primary BA ratio in cirrhosis.16Li Y. Lu L.-G. Therapeutic roles of bile acid signaling in chronic liver diseases.J Clin Transl Hepatol. 2018; 6: 425-430https://doi.org/10.14218/JCTH.2018.00025Crossref PubMed Scopus (7) Google Scholar Only the emergence of new microbial groups does not foster a pathologic milieu. Even the normally prevalent microbial groups often shift toward a more toxin-producing metabolic pathway because of survival benefits in a dysbiotic environment, thereby disturbing homeostasis.17Boursier J. Mueller O. Barret M. et al.The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota.Hepatology. 2016; 63: 764-775https://doi.org/10.1002/hep.28356Crossref PubMed Scopus (562) Google Scholar Ridlon et al hypothesize that a decrease in DCA across different etiologies of cirrhosis could be beneficial as DCA could compound bacterial translocation and endotoxemia by irritating the gut mucosa, considering its membrane solubilizing potency.18Ridlon J.M. Alves J.M. Hylemon P.B. Bajaj J.S. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship.Gut Microb. 2013; 4: 382-387https://doi.org/10.4161/gmic.25723Crossref PubMed Scopus (178) Google Scholar Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients have decreased alpha/intraindividual diversity of microbes with higher proinflammatory genera levels than healthy controls, with some groups responding after 6 months of UDCA therapy.19Tang R. Wei Y. Li Y. et al.Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy.Gut. 2018; 67: 534-541https://doi.org/10.1136/gutjnl-2016-313332Crossref PubMed Scopus (164) Google Scholar Interestingly, Enterococcus was associated with an increase in TLCA (taurolithocholic acid) levels, a highly hydrophobic BA, in PSC patients.20Kummen M. Hov J.R. The gut microbial influence on cholestatic liver disease.Liver Int. 2019; 39: 1186-1196https://doi.org/10.1111/liv.14153Crossref PubMed Scopus (18) Google Scholar, 21Bajer L. Kverka M. Kostovcik M. et al.Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis.World J Gastroenterol. 2017; 23: 4548-4558https://doi.org/10.3748/wjg.v23.i25.4548Crossref PubMed Scopus (129) Google Scholar, 22Little R. Wine E. Kamath B.M. Griffiths A.M. Ricciuto A. Gut microbiome in primary sclerosing cholangitis: a review.World J Gastroenterol. 2020; 26: 2768-2780https://doi.org/10.3748/wjg.v26.i21.2768Crossref PubMed Google Scholar, 23Mattner J. Impact of microbes on the pathogenesis of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).Int J Mol Sci. 2016; 17https://doi.org/10.3390/ijms17111864Crossref PubMed Scopus (24) Google Scholar In chronic hepatitis B virus (HBV) cirrhosis, there is a decrease in the conversion of primary to secondary BAs and increase in FGF-19 (feedback inhibition of de novo BA synthesis), with advancing fibrosis.24Wang X. Chen L. Wang H. Cai W. Xie Q. Modulation of bile acid profile by gut microbiota in chronic hepatitis B.J Cell Mol Med. 2020; 24: 2573-2581https://doi.org/10.1111/jcmm.14951Crossref PubMed Scopus (9) Google Scholar In alcoholic cirrhosis, an increase in primary BAs correlated with Enterobacteriaceae populations,25Kakiyama G. Hylemon P.B. Zhou H. et al.Colonic inflammation and secondary bile acids in alcoholic cirrhosis.Am J Physiol Gastrointest Liver Physiol. 2014; 306: G929-G937https://doi.org/10.1152/ajpgi.00315.2013Crossref PubMed Scopus (109) Google Scholar whereas in NAFLD, lower levels of Ruminococcaceae were associated with higher primary BAs in both obese and lean patients with NAFLD, whereas Veillonellaceae showed a positive association with primary BAs in lean patients only.26Lee G. You H.J. Bajaj J.S. et al.Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD.Nat Commun. 2020; 11: 4982https://doi.org/10.1038/s41467-020-18754-5Crossref PubMed Scopus (42) Google Scholar Patients with autoimmune hepatitis (AIH) patients show lower alpha diversity compared with healthy controls with lower levels of commensal flora even after controlling for potential confounders, such as age, sex, and antibiotic use,27Wei Y. Li Y. Yan L. et al.Alterations of gut microbiome in autoimmune hepatitis.Gut. 2020; 69: 569-577https://doi.org/10.1136/gutjnl-2018-317836Crossref PubMed Scopus (76) Google Scholar but no correlation with BA levels has been done.28Lou J. Jiang Y. Rao B. et al.Fecal microbiomes distinguish patients with autoimmune hepatitis from healthy individuals.Front Cell Infect Microbiol. 2020; 10https://doi.org/10.3389/fcimb.2020.00342Crossref Scopus (4) Google Scholar BAs can induce cell necrosis by solubilizing the plasma membrane or by signaling programmed cell death/apoptosis. However, elevated BA concentrations, even in diseased states, rarely cause physical cellular damage.29Fickert P. Wagner M. Biliary bile acids in hepatobiliary injury - what is the link?.J Hepatol. 2017; 67: 619-631https://doi.org/10.1016/j.jhep.2017.04.026Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar BAs as signaling molecules can trigger cellular death pathways or release chemokines to recruit inflammatory cells.30Perez M.-J. Briz O. Bile-acid-induced cell injury and protection.World J Gastroenterol. 2009; 15: 1677-1689https://doi.org/10.3748/wjg.15.1677Crossref PubMed Scopus (406) Google Scholar, 31Cai S.-Y. Boyer J.L. The role of bile acids in cholestatic liver injury.Ann Transl Med. 2021; 9 (737-737)https://doi.org/10.21037/atm-20-5110Crossref Google Scholar, 32Woolbright B.L. Dorko K. Antoine D.J. et al.Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis.Toxicol Appl Pharmacol. 2015; 283: 168-177https://doi.org/10.1016/j.taap.2015.01.015Crossref PubMed Scopus (116) Google Scholar In vitro studies in hepatocytes across species have shown that intracellular accumulation of BAs can cause oligomerization of the Fas receptor and activation of TNF-related apoptosis-inducing ligand receptor or death receptor 5.33Allen K. Jaeschke H. Copple B.L. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis.Am J Pathol. 2011; 178: 175-186https://doi.org/10.1016/j.ajpath.2010.11.026Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar,34Ashby K. Navarro Almario E.E. Tong W. Borlak J. Mehta R. Chen M. Review article: therapeutic bile acids and the risks for hepatotoxicity.Aliment Pharmacol Ther. 2018; 47: 1623-1638https://doi.org/10.1111/apt.14678Crossref PubMed Scopus (24) Google Scholar This leads to activation of death-inducing signaling complex, which leads to caspase 8 activation. Caspase 8 brings about further cleavage of antiapoptotic proteins and activation of proapoptotic proteins. The downstream signaling brings about mitochondrial permeability transition, the release of cytochrome C, and mitochondrial dysfunction. Glycodeoxycholic acid (GCDCA) is primarily known to induce apoptosis of cholangiocytes and hepatocytes.13Slocum M.M. Sittig K.M. Specian R.D. Deitch E.A. Absence of intestinal bile promotes bacterial translocation.Am Surg. 1992; 58: 305-310PubMed Google Scholar In addition, reactive oxygen species generated due to excessive BAs (via phospholipase A2-induced membrane damage and interaction with nuclear receptors) overwhelm glutathione, which normally checks on repeated expected and stochastic cellular oxidative stressors. This increases the probability of cellular damage and necrosis. BAs can even increase Ca++ release from the endoplasmic reticulum (ER), triggering extracellular calcium entry into cells and activating caspases. A molecule called CHOP is involved in the ER stress pathway, and interestingly, CHOP knockout models have shown decreased liver fibrosis.33Allen K. Jaeschke H. Copple B.L. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis.Am J Pathol. 2011; 178: 175-186https://doi.org/10.1016/j.ajpath.2010.11.026Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar The cytokines released from BA-induced cellular damage activate the hepatocyte stellate cells, repeated cycles of which can lead to irreversible fibrosis. However, intrahepatocellular accumulation of BAs is key to inducing hepatocyte damage.35Jones B.A. Rao Y.P. Stravitz R.T. Gores G.J. Bile salt-induced apoptosis of hepatocytes involves activation of protein kinase C.Am J Physiol Gastrointest Liver Physiol. 1997; 272: G1109-G1115https://doi.org/10.1152/ajpgi.1997.272.5.G1109Crossref PubMed Google Scholar Exposure of hepatocytes to elevated BA concentrations as seen in obstructive cholestasis has shown to cause an increase in cytokines (interleukin [IL]-1β and IL-10), chemokines such as macrophage inflammatory protein cell adhesion molecules (ICAM-1 and VCAM-1), enzymes such as COX-2, and thereby influence immune cell levels and function.31Cai S.-Y. Boyer J.L. The role of bile acids in cholestatic liver injury.Ann Transl Med. 2021; 9 (737-737)https://doi.org/10.21037/atm-20-5110Crossref Google Scholar BA derangements are common in the diseased liver and therefore may serve as markers of derangement and potential targets to help restore normal physiology. In healthy subjects, CA:CDCA typically ranges between 0.6 and 1, while in cirrhosis, it is reduced to 0.1 to 0.5 and further decreases as the severity of cirrhosis increases. The greatest decrease in CA occurs before overt symptoms appear, i.e., in early stages of cirrhosis.36Kim M.J. Suh D.J. Profiles of serum bile acids in liver diseases.Korean J Intern Med. 1986; 1: 37-42https://doi.org/10.3904/kjim.1986.1.1.37Crossref PubMed Google Scholar The standard assay to measure BAs in serum, urine, and stool is ultraperformance liquid chromatography with tandem mass spectrometry. Other separation-based assays include gas chromatography (GC)-MS, high-performance liquid chromatography-MS, supercritical fluid chromatography, capillary electrophoresis, enzyme-linked immunosorbent assay, thin-layer chromatography, and nuclear magnetic resonance (NMR) spectroscopy–based assays. However, the more commonly used 3-α-hydroxysteroid dehydrogenase–based colorimetric assays are better suited for total BA measurements than for individual BAs, and LC/GC-MS remains the gold standard.37Porter J.L. Fordtran J.S. Santa Ana C.A. et al.Accurate enzymatic measurement of fecal bile acids in patients with malabsorption.J Lab Clin Med. 2003; 141: 411-418https://doi.org/10.1016/S0022-2143(03)00040-4Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Kim et al found the fasting serum BA concentration to be a more sensitive test of disordered hepatobiliary function than conventional liver function tests. They observed that some of their patients with cirrhosis had higher serum BA concentrations despite normal transaminases.36Kim M.J. Suh D.J. Profiles of serum bile acids in liver diseases.Korean J Intern Med. 1986; 1: 37-42https://doi.org/10.3904/kjim.1986.1.1.37Crossref PubMed Google Scholar Across various etiologies of CLD, Alamoudi et al found that total urinary BAs were maximally increased in patients with PBC and only marginally in HBV infection. The increase in total urinary CA and CDCA was highest in PSC and lowest in HBV infection. The total urinary primary/secondary BA ratio was high in most cases of CLD and low only in PBC.38Alamoudi J.A. Li W. Gautam N. et al.Bile acid indices as biomarkers for liver diseases I: diagnostic markers.World J Hepatol. 2021; 13: 433-455https://doi.org/10.4254/wjh.v13.i4.433Crossref PubMed Google Scholar In another study, including patients with alcoholic or nonalcoholic cirrhosis, serum conjugated primary BAs such as GCA, GCDCA, TCA, TCDCA, and TUDCA were higher in Child-Turcotte-Pugh (CTP) B and C than in CTP A, whereas secondary BAs showed a decreasing trend with advancing cirrhosis.39Liu N. Feng J. Lv Y. et al.Role of bile acids in the diagnosis and progression of liver cirrhosis: a prospective observational study.Exp Ther Med. 2019; 18: 4058-4066https://doi.org/10.3892/etm.2019.8011Crossref PubMed Google Scholar Higher total (but not individual) BAs were also associated with increased 6-month mortality. Prediction accuracies of BAs were slightly lower than those of the Model for End-Stage Liver Disease score; yet, BAs can still serve as prognostic indicators for cirrhotic patients. In alcoholic cirrhosis, the total fecal BA pool shrinks with a reduction in both primary and secondary BAs.25Kakiyama G. Hylemon P.B. Zhou H. et al.Colonic inflammation and secondary bile acids in alcoholic cirrhosis.Am J Physiol Gastrointest Liver Physiol. 2014; 306: G929-G937https://doi.org/10.1152/ajpgi.00315.2013Crossref PubMed Scopus (109) Google Scholar,36Kim M.J. Suh D.J. Profiles of serum bile acids in liver diseases.Korean J Intern Med. 1986; 1: 37-42https://doi.org/10.3904/kjim.1986.1.1.37Crossref PubMed Google Scholar Taurine conjugates are higher than glycine conjugates. Although the absolute CDCA pool is significantly reduced in early alcoholic cirrhosis, it is largely unchanged in advanced stages. CA synthesis progressively decreases with cirrhosis; hence CA:CDCA ratio becomes a useful index of disease severity.36Kim M.J. Suh D.J. Profiles of serum bile acids in liver diseases.Korean J Intern Med. 1986; 1: 37-42https://doi.org/10.3904/kjim.1986.1.1.37Crossref PubMed Google Scholar,40McCormick W.C. Bell C.C. Swell L. Vlahcevic Z.R. Cholic acid synthesis as an index of the severity of liver disease in man.Gut. 1973; 14: 895-902https://doi.org/10.1136/gut.14.11.895Crossref PubMed Scopus (55) Google Scholar Kakiyama et al found that alcohol intake increases stool BAs even in healthy subjects, with fecal total bile acid (TBA) levels being lowest in abstinent alcoholic cirrhotics. Second, alcoholic cirrhosis patients have higher serum BAs than nonalcoholic cirrhosis, and serum BAs were higher in both alcoholic/nonalcoholic cirrhosis in comparison to healthy subjects irrespective of alcohol intake.25Kakiyama G. Hylemon P.B. Zhou H. et al.Colonic inflammation and secondary bile acids in alcoholic cirrhosis.Am J Physiol Gastrointest Liver Physiol. 2014; 306: G929-G937https://doi.org/10.1152/ajpgi.00315.2013Crossref PubMed Scopus (109) Google Scholar NAFLD with liver fibrosis has higher total plasma BAs (with a disproportionate increase in primary BAs), which increase with advancing fibrosis. Glycine-conjugated CA and CDCA, 7-keto DCA, and GUDCA specifically show association with advancing fibrosis, whereas most secondary BAs show no significant difference.41Nimer N. Choucair I. Wang Z. et al.Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression.Metabolism. 2021; 116: 154457https://doi.org/10.1016/j.metabol.2020.154457Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The fecal BA profile in NAFLD differs in obese and nonobese/lean patients (body mass index <25 kg/m2). In Asian lean NAFLD patients, total stool BAs were higher, with an increase in both unconjugated (CA and CDCA) and conjugated BAs (GUDCA and GCDCA) and fecal TBAs among those with advanced fibrosis.26Lee G. You H.J. Bajaj J.S. et al.Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD.Nat Commun. 2020; 11: 4982https://doi.org/10.1038/s41467-020-18754-5Crossref PubMed Scopus (42) Google Scholar In obese NAFLD patients with liver fibrosis, fecal TBAs, total conjugated BAs, unconjugated BAs, and total fecal secondary BAs progressively decrease as fibrosis advances. The secondary to primary BA ratio and the unconjugated to conjugated BA ratios also show a decrease. There is no clinically relevant change in unconjugated primary BAs but conjugated primary BAs increase with advancing fibrosis.26Lee G. You H.J. Bajaj J.S. et al.Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD.Nat Commun. 2020; 11: 4982https://doi.org/10.1038/s41467-020-18754-5Crossref PubMed Scopus (42) Google Scholar Serum TBAs are also significantly increased in cirrhosis because of HBV and hepatitis C virus (HCV) infection.42Neale G. Lewis B. Weaver V. Panveliwalla D. Serum bile acids in liver disease.Gut. 1971; 12: 145-152https://doi.org/10.1136/gut.12.2.145Crossref PubMed Scopus (161) Google Scholar,43Sang C. Wang X. Zhou K. et al.Bile acid profiles are distinct among patients with different etiologies of chronic liver disease.J Proteome Res. 2021; 20: 2340-2351https://doi.org/10.1021/acs.jproteome.0c00852Crossref PubMed Scopus (6) Google Scholar Yan et al demonstrated an association of cirrhosis and serum TBAs to total cholesterol ratio in noncholestatic chronic HBV infection.44Yan L.-T. Wang L.-L. Yao J. et al.Total bile acid-to-cholesterol ratio as a novel noninvasive marker for significant liver fibrosis and cirrhosis in patients with non-cholestatic chronic hepatitis B virus infection.Medicine (Baltimore). 2020; 99https://doi.org/10.1097/MD.0000000000019248Crossref Scopus (6) Google Scholar Serum TBAs, particularly conjugated BAs, are elevated in HBV cirrhosis with a progressive increase as CTP grade advances.45Wang X. Xie G. Zhao A. et al.Serum bile acids are associated with pathological progression of hepatitis B-induced cirrhosis.J Proteome Res. 2016; 15: 1126-1134https://doi.org/10.1021/acs.jprot

Post-COVID-19 Cholestasis: A Case Series and Review of Literature

Abstract: Coronavirus disease-2019 (COVID-19) cholangiopathy is a recently known entity. There are very few reports of liver transplantation (LT) for COVID-19-induced cholangiopathy. It is well known that vaccines can prevent severe disease and improve outcomes. However, there are no reports on the impact of COVID-19 vaccines on cholestasis. Therefore, we aimed to compare the course and outcome of patients who developed cholestasis following COVID-19 infection among vaccinated and unvaccinated individuals. Methods: Patients diagnosed with post-COVID cholestasis during the pandemic were included in the study after excluding other causes of cholestasis.Eight unvaccinated and seven vaccinated individuals developed cholestasis following COVID-19 infection. Baseline demographics, presentation, severity, and management of COVID-19 were similar in both groups. However, patients in the unvaccinated group had a protracted course. The peak ALP was 312 (239-517) U/L in the vaccinated group and 571.5 (368-1058) U/L in the unvaccinated group (P = 0.02). Similarly, the peak γ-glutamyl transpeptidase values were lower in the vaccinated (325 [237-600] U/L) than in the unvaccinated group (832 [491-1640] U/L; P = 0.004). However, the peak values of total bilirubin, transaminases, and INR were similar in both groups. Five patients developed ascites gradually in the unvaccinated group whereas none in the vaccinated group developed ascites. Plasma exchange was done in five patients, and two were successfully bridged to living donor LT in the unvaccinated group. Only two patients recovered with conservative management in the unvaccinated group, whereas all recovered with conservative management in the vaccinated group. The other four patients in the unvaccinated group were planned for LT.Post-COVID-19 cholestasis is associated with high morbidity and mortality, meriting early identification and appropriate management. Vaccination can modify the course of severe COVID-19 infection and improve outcomes.

Updated Efficacy and Safety Data from IMbrave150: Atezolizumab Plus Bevacizumab vs. Sorafenib for Unresectable Hepatocellular Carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is the most common primary liver tumor and remains a significant cause of cancer-related death globally. The incidence of HCC has been on the rise along with a proportionate rising trend in mortality.1 However, since the landmark sorafenib in advanced hepatocellular carcinoma (SHARP) trial of the efficacy of sorafenib in advanced HCC, there was little progress made in the armamentarium against advanced HCC for almost a decade. The advent of combination immunotherapy opened up a whole new paradigm in the management of HCC.

Long-term Outcomes of Stool Transplant in Alcohol-associated Hepatitis-Analysis of Clinical Outcomes, Relapse, Gut Microbiota and Comparisons with Standard Care.

Abstract: Healthy donor fecal microbiota transplantation (FMT) was preliminarily shown to have clinical benefits in hepatic encephalopathy (HE), severe alcohol-associated hepatitis (SAH), and alcohol use disorder. However, the long-term outcomes of FMT and the gut microbiota (GM) changes in patients with SAH are unknown.Patients with SAH who underwent FMT (N = 35) or standard of care (SoC, N = 26) from May 2017 to June 2018 were included, and their stored stool samples were analyzed prospectively. Clinical outcomes, including infections, hospitalizations, critical illness, alcohol relapse, and survival, were evaluated. Metagenomic analysis was undertaken to identify the relative abundances (Ras) and significant taxa at baseline and post-therapy (up to three years) among survivors between the two groups.At follow-up, the incidences of ascites, HE, infections, and major hospitalizations were significantly higher in the SoC than in the FMT group (P < 0.05). Alcohol relapse was lower (28.6% versus 53.8%), and the time to relapse was higher in the FMT than in the SoC group (P = 0.04). Three-year survival was higher in the FMT than in the SoC group (65.7% versus 38.5%, P = 0.052). Death due to sepsis was significantly higher in the SoC group (N = 13/16, 81.2%; P = 0.008). GM analysis showed a significant increase in the RA of Bifidobacterium and a reduction in the RA of Acinetobacter in the FMT group. Beyond one to two years, the RA of Porphyromonas was significantly higher and that of Bifidobacterium was lower in the SoC than in the FMT group.In terms of treatment for patients with SAH, healthy donor FMT is associated with significantly lesser ascites, infections, encephalopathy, and alcohol relapse (with a trend toward higher survival rates) than SoC, associated with beneficial GM modulation. Larger controlled studies on FMT are an unmet need.

Statistical Significance Does Not Show Clinical Relevance: We Need to Go Beyond the P-value.

Abstract: I read with great appreciation the study “Comparison of Anthropometry, Bioelectrical Impedance, and Dual-energy X-ray Absorptiometry for Body Composition in Cirrhosis”.1 The authors aimed to evaluate the triceps skinfold thickness, mid-arm muscle circumference, and bioelectrical impedance analysis for assessing body composition using dual-energy X-ray absorptiometry (DEXA) (reference) and to predict fat mass and fat-free mass in patients with cirrhosis, and for that, they carried out an observational study.

Integrated Care of Alcohol-Related Liver Disease.

Abstract: Alcohol-related liver disease (ALD) is the medical manifestation of alcohol use disorder, a prevalent psychiatric condition. Acute and chronic manifestations of ALD have risen in recent years especially in young people and ALD is now a leading indication of liver transplantation (LT) worldwide. Such alarming trends raise urgent and unanswered questions about how medical and psychiatric care can be sustainably integrated to better manage ALD patients before and after LT.Critical evaluation of the interprofessional implications of broad and multifaceted ALD pathophysiology, general principles of and barriers to interprofessional teamwork and care integration, and measures that clinicians and institutions can implement for improved and integrated ALD care.The breadth of ALD pathophysiology, and its numerous medical and psychiatric comorbidities, ensures that no single medical or psychiatric discipline is adequately trained and equipped to manage the disease alone.Early models of feasible ALD care integration have emerged in recent years but much more work is needed to develop and study them. The future of ALD care is an integrated approach led jointly by interprofessional medical and psychiatric clinicians.

Diagnosis and Management of Cirrhotic Cardiomyopathy

Abstract: Cirrhotic cardiomyopathy refers to the structural and functional changes in the heart leading to either impaired systolic, diastolic, electrocardiographic, and neurohormonal changes associated with cirrhosis and portal hypertension. Cirrhotic cardiomyopathy is present in 50% of patients with cirrhosis and is clinically seen as impaired contractility, diastolic dysfunction, hyperdynamic circulation, and electromechanical desynchrony such as QT prolongation. In this review, we will discuss the cardiac physiology principles underlying cirrhotic cardiomyopathy, imaging techniques such as cardiac magnetic resonance imaging and scintigraphy, cardiac biomarkers, and newer echocardiographic techniques such as tissue Doppler imaging and speckle tracking, and emerging treatments to improve outcomes.We reviewed available literature from MEDLINE for randomized controlled trials, cohort studies, cross-sectional studies, and real-world outcomes using the search terms "cirrhotic cardiomyopathy," "left ventricular diastolic dysfunction," "heart failure in cirrhosis," "liver transplantation," and "coronary artery disease".Cirrhotic cardiomyopathy is associated with increased risk of complications such as hepatorenal syndrome, refractory ascites, impaired response to stressors including sepsis, bleeding or transplantation, poor health-related quality of life and increased morbidity and mortality. The evaluation of cirrhotic cardiomyopathy should also guide the feasibility of procedures such as transjugular intrahepatic portosystemic shunt, dose titration protocol of betablockers, and liver transplantation. The use of targeted heart rate reduction is of interest to improve cardiac filling and improve the cardiac output using repurposed heart failure drugs such as ivabradine. Liver transplantation may also reverse the cirrhotic cardiomyopathy; however, careful cardiac evaluation is necessary to rule out coronary artery disease and improve cardiac outcomes in the perioperative period.More data are needed on the new diagnostic criteria, molecular and biochemical changes, and repurposed drugs in cirrhotic cardiomyopathy. The use of advanced imaging techniques should be incorporated in clinical practice.

Pathogenesis of Alcohol-Associated Liver Disease.

Abstract: Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease. Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease. As an accessory but vital digestive organ, the liver serves crucial functions in the body’s metabolic regulation. It is the first organ exposed to blood-borne substances absorbed by the gastrointestinal (GI) tract. The liver is most prominent among other (esophagus and stomach) “first responder” organs that enzymatically oxidize imbibed alcohol/EtOH (the active ingredient in alcoholic beverages) to acetaldehyde. The latter compound is more toxic than EtOH but is relatively short-lived, as it is rapidly oxidized to acetate. Chronic, heavy alcohol (EtOH) consumption disrupts normal liver function and eventually causes hepatic structural damage, resulting in alcohol-associated liver disease (ALD). Although the liver efficiently eliminates EtOH, studies with rodents, nonhuman primates, and humans demonstrate that long-term (weeks to months in rodents; months to years in humans and primates) excessive alcohol consumption seriously damages the liver to eventually cause liver failure. This review presents updated findings on ALD development in experimental animals and humans. It will describe how EtOH metabolism initiates injury at the cellular level and how such damage initiates the spectrum of liver injury from simple fatty liver to hepatitis to decompensated cirrhosis. It will briefly describe potential new therapies and targets for ALD treatment. Throughout this review, we will use the terms “alcohol” and “EtOH” interchangeably. Excessive drinking of EtOH-containing beverages, called alcohol use disorder (AUD), is a significant global health concern. AUDs can be mild, moderate, or severe, depending on the frequency and the amount of alcohol consumed.1Leggio L. Lee M.R. Treatment of alcohol use disorder in patients with alcoholic liver disease.Am J Med. 2017; 130: 124-134Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar In 2016, heavy drinking contributed to an estimated 3 million preventable fatalities (5.3% of all deaths) worldwide.2Global Status Report on Alcohol and Health 2018. World Health Organization, Geneva2018Google Scholar For that year, the economic burden of caring for people with AUDs totaled $249 billion.3Axley P.D. Richardson C.T. Singal A.K. Epidemiology of alcohol consumption and societal burden of alcoholism and alcoholic liver disease.Clin Liver Dis. 2019; 23: 39-50Abstract Full Text Full Text PDF PubMed Google Scholar Currently, in the United States. over 20 million Americans (about six percent of the US population) have AUDs.2Global Status Report on Alcohol and Health 2018. World Health Organization, Geneva2018Google Scholar It is predicted that by 2025, per capita alcohol consumption will rise from 8 to 8.4 L of alcoholic beverages per person.2Global Status Report on Alcohol and Health 2018. World Health Organization, Geneva2018Google Scholar Heavy drinking essentially injures all organs of the body. Among these, the liver sustains the greatest degree of injury because it is the largest internal organ that receives blood-borne nutrients, toxins, and xenobiotics (foreign chemicals, both natural and artificial) from the GI tract. The liver is also the principal site of alcohol metabolism and has the highest levels of enzymes that catalyze these oxidative reactions.4Zakhari S. Li T.K. Determinants of alcohol use and abuse: impact of quantity and frequency patterns on liver disease.Hepatology. 2007; 46: 2032-2039Crossref PubMed Scopus (233) Google Scholar Inside liver cells (hepatocytes), EtOH oxidation directly (and indirectly) generates toxic intermediates and byproducts, which, if their levels are maintained by heavy drinking, cause hepatocyte damage and death. Liver cell death gives rise to hepatic inflammation (hepatitis), a lethal and acute form of ALD, which, without medical intervention, can cause significant morbidity (illness) and/or mortality (death) from liver failure, which requires a liver transplant. Recent estimates indicate that ALD causes 50% of all deaths due to liver disease.5Asrani S.K. Devarbhavi H. Eaton J. Kamath P.S. Burden of liver diseases in the world.J Hepatol. 2019; 70: 151-171Abstract Full Text Full Text PDF PubMed Scopus (1157) Google Scholar The impact of heavy drinking is clearly illustrated by historical events, including the prohibition of alcoholic beverages in the United States beginning in 1920, after which liver disease incidence significantly declined. After prohibition ended in 1933, cirrhosis incidence, began to rise again.6Stolberg V.B. A review of perspectives on alcohol and alcoholism in the history of American health and medicine.J Ethn Subst Abuse. 2006; 5: 39-106Crossref PubMed Scopus (0) Google Scholar, 7Katcher B.S. The post-repeal eclipse in knowledge about the harmful effects of alcohol.Addiction. 1993; 88: 729-744Crossref PubMed Scopus (13) Google Scholar, 8Ideology Herd D. History and changing models of liver cirrhosis epidemiology.Br J Addict. 1992; 87: 1113-1126Crossref PubMed Scopus (17) Google Scholar One hundred years later, in 2020, during the first peak of the COVID-19 pandemic in March, higher-than-normal numbers of people stayed home to avoid viral transmission. During that and subsequent months into the year 2021, retail sales of beer, wine and/or distilled spirits exceeded the January 2020 sales by 17% to 25%. According to the United Network for Organ Sharing Standard Transplant Analysis and Research, beginning in May 2020 and continuing through January 2021, the number of people with alcoholic hepatitis (AH) who registered for liver transplants rose two-to-three fold over the previous months. Comparable increases were also recorded for AH patients who received liver transplants. The latter patient numbers exceeded those who received transplants for alcohol-induced cirrhosis or for liver diseases unrelated to alcohol misuse. The latter patient numbers did not change over the eight-month time period from May to December 2020.9Anderson M.S. Valbuena V.S.M. Brown C.S. et al.Association of COVID-19 with new waiting list registrations and liver transplantation for alcoholic hepatitis in the United States.JAMA Netw Open. 2021; 4e2131132Crossref Scopus (10) Google Scholar The GI tract is the principal site of absorption of ingested alcohol and hence, plays a significant role in mediating the toxic effects of alcohol on the liver and other organs. It is also a site of metabolism of the ingested alcohol, as the major alcohol metabolizing enzymes are present in GI mucosal cells, including isozymes of alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and catalase. While GI metabolism of EtOH is quantitatively lower than the liver, it does contribute to local toxicity by generating acetaldehyde. In addition to affecting the systemic availability, the stomach lining (mucosa) is the principal site of the “first pass” metabolism of the ingested alcohol, catalyzed by various isoforms of gastric ADH. Gender, age, genetics, and gastric morphology modulate gastric ADH activity. Gastric ADH levels are significantly lower in younger women compared with age-matched men.10Baraona E. Abittan C.S. Dohmen K. et al.Gender differences in pharmacokinetics of alcohol.Alcohol Clin Exp Res. 2001; 25: 502-507Crossref PubMed Google Scholar,11Frezza M. di Padova C. Pozzato G. Terpin M. Baraona E. Lieber C.S. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism.The New England journal of medicine. 1990; 322: 95-99Crossref PubMed Google Scholar This difference likely accounts for greater alcohol-induced liver toxicity in women. When ingested with a meal, gastric absorption rates of ethanol reportedly fluctuate from 30% to 100% among healthy individuals, with only a small amount of ethanol detected in the distal small intestine. Ethanol in the small and large intestines is principally metabolized by the microbiome that inhabits this GI region. Along its GI course, EtOH becomes bioavailable through its rapid transit into the portal system through the gastric and small intestinal mucosa. GI microbial flora also anaerobically generate EtOH by fermentation in the distal intestine. Multiple factors, such as GI motility, absorption, dilution by GI secretions, and rediffusion of alcohol, all influence ethanol metabolism in the GI tract. Over 80% of ingested EtOH is oxidatively metabolized in liver parenchymal cells (hepatocytes), which comprise ∼80% of the liver’s mass and which express the major alcohol metabolizing enzymes. The EtOH oxidation pathways are presented. EtOH hepatotoxicity is mostly attributed to its conversion to acetaldehyde, which is more toxic than EtOH because acetaldehyde is highly reactive and covalently binds to proteins,12Donohue Jr., T.M. Tuma D.J. Sorrell M.F. Acetaldehyde adducts with proteins: binding of [14C]acetaldehyde to serum albumin.Arch Biochem Biophys. 1983; 220: 239-246Crossref PubMed Google Scholar,13Stevens V.J. Fantl W.J. Newman C.B. Sims R.V. Cerami A. Peterson C.M. Acetaldehyde adducts with hemoglobin.J Clin Invest. 1981; 67: 361-369Crossref PubMed Google Scholar phospholipids,14Kenney W. Acetaldehyde adducts of phospholipids.Alcohol: Clin Exp Res. 1982; 6: 412-416Crossref PubMed Google Scholar and nucleic acids.15Brooks P.J. Theruvathu J.A. DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis.Alcohol. 2005; 35: 187-193Crossref PubMed Scopus (265) Google Scholar,16Brooks P.J. Zakhari S. Acetaldehyde and the genome: beyond nuclear DNA adducts and carcinogenesis.Environ Mol Mutagen. 2014; 55: 77-91Crossref PubMed Scopus (95) Google Scholar Such binding, called adduct formation, significantly alters the biological functions of specific proteins.17Mauch T.J. Donohue Jr., T.M. Zetterman R.K. Sorrell M.F. Tuma D.J. Covalent binding of acetaldehyde selectively inhibits the catalytic activity of lysine-dependent enzymes.Hepatology. 1986; 6: 263-269Crossref PubMed Google Scholar, 18Mauch T.J. Tuma D.J. Sorrell M.F. The binding of acetaldehyde to the active site of ribonuclease: alterations in catalytic activity and effects of phosphate.Alcohol Alcohol. 1987; 22: 103-112PubMed Google Scholar, 19Smith S.L. Jennett R.B. Sorrell M.F. Tuma D.J. Acetaldehyde substoichiometrically inhibits bovine neurotubulin polymerization.J Clin Invest. 1989; 84: 337-341Crossref PubMed Google Scholar The cytosolic alcohol dehydrogenase is the primary enzyme that most efficiently catalyzes EtOH oxidation to acetaldehyde (Figure 1), while, in the same reaction, ADH catalysis reduces the cofactor NAD+, forming NADH. It is important to note that during chronic, heavy drinking, the continuous reduction of NAD+ to NADH in the reactions catalyzed by ADH and aldehyde dehydrogenase (ALDH), causes a significant decline in the ratio of intrahepatocyte NAD+/NADH, also called the cellular redox potential.4Zakhari S. Li T.K. Determinants of alcohol use and abuse: impact of quantity and frequency patterns on liver disease.Hepatology. 2007; 46: 2032-2039Crossref PubMed Scopus (233) Google Scholar The decreased redox potential causes a significant metabolic shift in hepatocytes, as EtOH metabolism generates reducing equivalents (NADH) that participate as cofactors in reductive synthesis, which shifts hepatocyte metabolism toward fatty acid synthesis (as well as increased production of lactate to cause metabolic acidosis). If the reductive fatty acid synthesis is upheld by continued drinking, hepatocytes continue to increase their fatty acid contents, which condense with glycerol to form triglycerides, stored in intracellular lipid droplets. Steatosis (fatty liver) is also maintained/augmented by significant intrahepatocyte switches in gene transcription that favor induction of transcription factors (e.g., SREBP-1c and Egr-1) to further enhance fatty acid biosynthesis.20You M. Fischer M. Deeg M.A. Crabb D.W. Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP).J Biol Chem. 2002; 277: 29342-29347Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,21McMullen M.R. Pritchard M.T. Wang Q. Millward C.A. Croniger C.M. Nagy L.E. Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice.Gastroenterology. 2005; 128: 2066-2076Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Conversely, there is a decline in the levels of the transcription factor PPAR-alpha that regulates genes of fatty acid oxidation (breakdown).22Galli A. Pinaire J. Fischer M. Dorris R. Crabb D.W. The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver.J Biol Chem. 2001; 276: 68-75Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar Enhanced production of humoral factors, including tumor necrosis factor α (TNFα) and adiponectin, further exacerbate this condition to propagate steatosis.23Donohue Jr., T.M. Alcohol-induced steatosis in liver cells.World J Gastroenterol. 2007; 13: 4974-4978Crossref PubMed Google Scholar The other major EtOH-metabolizing enzyme is cytochrome P450 2E1 (CYP2E1), a mixed-function oxidase that resides in the membranes of the smooth endoplasmic reticulum (ER). Its Km for EtOH is ∼10 mM or 50 mg per dL. Like ADH, CYP2E1 catalyzes EtOH oxidation to acetaldehyde and uses molecular oxygen (O2) and NADPH as additional substrates/cofactors. Despite having a higher substrate capacity than ADH for EtOH, CYP2E1 has a significantly lower catalytic efficiency (Kcat). However, CYP2E1 is inducible, which means its intracellular content rises in hepatocytes because EtOH, its substrate, protects CYP2E1 from being degraded by the ubiquitin-proteasome system.24Roberts B.J. Evidence of proteasome-mediated cytochrome P-450 degradation.J Biol Chem. 1997; 272: 9771-9778Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,25Roberts B.J. Song B.J. Soh Y. Park S.S. Shoaf S.E. Ethanol induces CYP2E1 by protein stabilization. Role of ubiquitin conjugation in the rapid degradation of CYP2E1.J Biol Chem. 1995; 270: 29632-29635Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar The resulting increase in hepatic CYP2E1 content escalates its Vmax, thereby boosting the rate of hepatic EtOH oxidation and clearance by both ADH and CYP2E1. While accelerated alcohol metabolism by higher levels of CYP2E1 may appear to protect an individual drinker from liver injury, the broad substrate specificity of CYP2E1 and its catalytic cycle negate any such protection. This is because faster ethanol oxidation catalyzed by higher CYP2E1 content generates not only more acetaldehyde, but the enzyme also produces higher levels of other reactive oxygen species (ROS), including free radical forms of ethanol (i.e., hydroxyethyl radicals), superoxide anions, and hydroxyl radicals. Thus, greater production of ROS in heavy drinkers causes oxidant stress. This occurs when the rate of free radical production exceeds the hepatocyte’s ability to neutralize them with natural antioxidants, including reduced glutathione and/or vitamins E, A, or C. Liver cells are also equipped with antioxidant enzymes, including the copper/zinc (Cu/Zn) and the manganese (Mn) superoxide dismutases (SODs), catalase, glutathione peroxidase (GSH Px), glutathione reductase (GSSG Rdx)), and glutathione-S-transferase (GST). Studies using rodents report that four of these six enzymes (Cu/Zn SOD, Mn SOD, GSSG Rdx, and GST) lose activity and/or content after chronic EtOH feeding, while GSH Px activity is unaffected and catalase activity rises after alcohol administration.26Chen L.H. Xi S. Cohen D.A. Liver antioxidant defenses in mice fed ethanol and the AIN-76A diet.Alcohol. 1995; 12: 453-457Crossref PubMed Scopus (0) Google Scholar, 27Dong X. Liu H. Chen F. Li D. Zhao Y. MiR-214 promotes the alcohol-induced oxidative stress via down-regulation of glutathione reductase and cytochrome P450 oxidoreductase in liver cells.Alcohol Clin Exp Res. 2014; 38: 68-77Crossref PubMed Scopus (62) Google Scholar, 28Zhao M. Matter K. Laissue J.A. Zimmermann A. Copper/zinc and manganese superoxide dismutases in alcoholic liver disease: immunohistochemical quantitation.Histol Histopathol. 1996; 11: 899-907PubMed Google Scholar Thus, the oxidant burden in hepatocytes worsens as enzymatic antioxidant defenses are weakened by EtOH administration. Recently, the importance of these antioxidant enzymes was further underscored by in vivo studies, showing that treatment of EtOH-fed rodents with nanoparticle-bound SOD-1 alleviates liver as well as adipose tissue injury.29Gopal T. Kumar N. Perriotte-Olson C. et al.Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver.Am J Physiol Gastrointest Liver Physiol. 2020; 318: G428-G438Crossref PubMed Scopus (6) Google Scholar,30Natarajan G. Perriotte-Olson C. Casey C.A. et al.Effect of nanoformulated copper/zinc superoxide dismutase on chronic ethanol-induced alterations in liver and adipose tissue.Alcohol. 2019; 79: 71-79Crossref PubMed Scopus (7) Google Scholar It is important to note that ROS spontaneously react with unsaturated lipids, forming lipid peroxides, including malondialdehyde (MDA), 4-hydroxynonenal (HNE), and acrolein that exacerbate oxidant stress. MDA can further react with acetaldehyde and then with proteins, forming larger-sized malondialdehyde-acetaldehyde (MAA)-protein adducts.31Tuma D.J. Theile G.M. Xu D. Klassen L.W. Sorrell M.F. Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long term ethanol administration.Hepatology. 1996; 23: 872-880Crossref PubMed Google Scholar Such adducts are capable of eliciting immune responses.32Thiele G.M. Tuma D.J. Willis M.S. et al.Soluble proteins modified with acetaldehyde and malondialdehyde are immunogenic in the absence of adjuvant.Alcohol Clin Exp Res. 1998; 22: 1731-1739Crossref PubMed Scopus (92) Google Scholar, 33Thiele G.M. Worrall S. Tuma D.J. Klassen L.W. Wyatt T.A. Nagata N. The chemistry and biological effects of malondialdehyde-acetaldehyde adducts.Alcohol Clin Exp Res. 2001; 25: 218S-224SCrossref PubMed Google Scholar, 34Tuma D. Klassen L. Immune responses to acetaldehyde-protein adducts: role in alcoholic liver disease.Gastroenterology. 1992; 103: 1970-1973Crossref Scopus (45) Google Scholar, 35Tuma D.J. Role of malondialdehyde-acetaldehyde adducts in liver injury(1,2).Free Radic Biol Med. 2002; 32: 303-308Crossref PubMed Scopus (0) Google Scholar Acrolein is a strong electrophile and quickly reacts with amino acids lysine, histidine, and cysteine and form adducts, which can alter the protein functions and have severe pathological consequences.36Chen W.Y. Zhang J. Ghare S. Barve S. McClain C. Joshi-Barve S. Acrolein is a pathogenic mediator of alcoholic liver disease and the scavenger hydralazine is protective in mice.Cell Mol Gastroenterol Hepatol. 2016; 2: 685-700Abstract Full Text Full Text PDF PubMed Google Scholar A recent study documented higher levels of acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA) in patients with severe acute AH, compared with controls or nonsevere acute AH suggesting that HPMA may be a novel selective, noninvasive biomarker for severe acute AH.37Vatsalya V. Kong M. Gobejishvili L. et al.Urinary acrolein metabolite levels in severe acute alcoholic hepatitis patients.Am J Physiol Gastrointest Liver Physiol. 2019; 316: G115-G122Crossref PubMed Scopus (6) Google Scholar Consistent with the multifactorial etiology of alcohol-associated liver disease, these authors also identified strong combined effects of HPMA and proinflammatory cytokines (IL-1β, IL-8, and TNFα) on the extent/pattern of liver cell death, further supporting the pathogenic role of acrolein. Finally, because CYP2E1 possesses broad substrate specificity, the enzyme metabolizes other substrates, including the analgesic acetaminophen. When CYP2E1 is induced by heavy drinking, it accelerates the conversion of acetaminophen to a hepatotoxic intermediate, which forms adducts with hepatocyte proteins to cause hepatocyte necrosis.38Schiodt F.V. Lee W.M. Bondesen S. Ott P. Christensen E. Influence of acute and chronic alcohol intake on the clinical course and outcome in acetaminophen overdose.Aliment Pharmacol Ther. 2002; 16: 707-715Crossref PubMed Scopus (0) Google Scholar Although it has an accessory role as an EtOH-metabolizing enzyme in the liver, catalase, which resides in peroxisomes and normally detoxifies hydrogen peroxide (H2O2), also catalyzes oxidation of ethanol when it is present. H2O2 participates in this oxidation, which generates acetaldehyde and H2O. While catalase is considered a minor ethanol oxidizing enzyme in the liver, it has a larger function in the brain, where the levels of ADH and CYP2E1 are significantly lower.39Aragon C.M. Rogan F. Amit Z. Ethanol metabolism in rat brain homogenates by a catalase-H2O2 system.Biochem Pharmacol. 1992; 44: 93-98Crossref PubMed Scopus (0) Google Scholar Acetaldehyde formed during catalysis by ADH, CYP2E1 and/or catalase is subsequently oxidized to acetate in a reaction catalyzed by ALDH, which also uses NAD+ as a cofactor. The reaction generates acetate and NADH. The acetate generated is believed to then enter the circulation. Major ALDH isoforms exist in the mitochondrial, microsomal, and cytosolic compartments of hepatocytes. In the mitochondrial matrix of liver cells, a low Km ALDH2 isozyme catalyzes the oxidation of the bulk of ethanol-derived acetaldehyde. Higher circulating acetaldehyde levels have been reported in problem drinkers because of enhanced acetaldehyde production and/or its slower removal, the latter owing to slower acetaldehyde clearance by the ALDH2 isozyme.40Cederbaum A.I. Alcohol metabolism.Clin Liver Dis. 2012; 16: 667-685Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar Higher acetaldehyde levels may also reflect impaired mitochondrial function that results from EtOH-induced mitochondrial depolarization, which reportedly results in the autophagic destruction of damaged mitochondria, also known as mitophagy.41Yu X. Xu Y. Zhang S. et al.Quercetin attenuates chronic ethanol-induced hepatic mitochondrial damage through enhanced mitophagy.Nutrients. 2016; 8Crossref Scopus (22) Google Scholar,42Zhong Z. Ramshesh V.K. Rehman H. et al.Acute ethanol causes hepatic mitochondrial depolarization in mice: role of ethanol metabolism.PLoS One. 2014; 9e91308Google Scholar ALD pathologies include a spectrum of hepatic lesions, including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), as shown schematically in Figure 2 . These are stages that are not mutually exclusive, as they can coexist. Most patients with ALD have hepatic steatosis, which is usually asymptomatic and is a reversible condition if drinking ceases. However, with continued EtOH misuse, 20–35% of these patients progress to steatohepatitis (ASH), which is a more severe type of injury characterized by hepatocyte ballooning and degeneration, neutrophilic infiltration, and the development of Mallory–Denk (M-D) bodies within hepatocytes. M-D bodies are partially degraded, insoluble, misfolded, aggregated proteins that accumulate and form visible inclusions. There is also hepatic infiltration by leukocytes, including T cells and natural killer (NK) cells. A relatively small number of people with a history of prolonged, heavy alcohol misuse develop the clinical syndrome known as alcoholic hepatitis (AH), which manifests by the onset of jaundice, and is frequently accompanied by other features of liver failure, including hepatic encephalopathy, coagulopathy, and ascites. AH patients exhibit fibrosis and/or its terminal or late stage, cirrhosis, which is the deposition of high amounts of extracellular matrix proteins (e.g., collagen), secreted principally by activated hepatic stellate cells (HSCs). Initially, during AH, there is active pericellular fibrosis, which may progress to cirrhosis, the late stage of hepatic scarring. Hepatic fibrosis is a transient and reversible wound-healing response that can restore the liver architecture to normal in some patients who stop drinking. However, if drinking continues, chronic inflammation and sustained fibrogenesis progresses to substitution of liver parenchyma by scar tissue. The main pathological feature of cirrhosis is the formation of regenerative nodules of hepatic parenchyma surrounded by fibrous septa. Cirrhosis development progresses from a compensated phase, when the undamaged part of the liver functionally compensates for damaged tissue, to a decompensated phase, in which scar tissue fully envelops the organ. The latter is characterized by development of portal hypertension and/or liver failure. However, some degree of hepatitis is likely always present in cirrhotic patients, while hepatic fat is usually no longer prominent in these individuals. The World Health Organization 2018 Global status report on alcohol and health estimates that 50% of all deaths due to cirrhosis are attributed to alcohol abuse.2Global Status Report on Alcohol and Health 2018. World Health Organization, Geneva2018Google Scholar Previous reports from many laboratories have demonstrated that ethanol consumption impairs several steps in methionine metabolism (reviewed in43Kharbanda K.K. Alcoholic liver disease and methionine metabolism.Sem Liver Dis. 2009; 29: 155-165Crossref PubMed Scopus (0) Google Scholar,44Kharbanda K.K. Methionine metabolic pathway in alcoholic liver injury.Current opinion in clinical nutrition and metabolic care. 2013; 16: 89-95Crossref PubMed Scopus (0) Google Scholar). Ethanol consumption predominantly inhibits the activity of a vital cellular enzyme, methionine synthase, that catalyzes the remethylation of homocysteine to methionine.43Kharbanda K.K. Alcoholic liver disease and methionine metabolism.Sem Liver Dis. 2009; 29: 155-165Crossref PubMed Scopus (0) Google Scholar, 44Kharbanda K.K. Methionine metabolic pathway in alcoholic liver injury.Current opinion in clinical nutrition and metabolic care. 2013; 16: 89-95Crossref PubMed Scopus (0) Google Scholar, 45Kharbanda K.K. Mailliard M.E. Baldwin C.R. Beckenhauer H.C. Sorrell M.F. Tuma D.J. Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway.J Hepatol. 2007; 46: 314-321Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar By way of compensation, chronic ethanol administration increases the activity of betaine homocysteine methyltransferase (BHMT) in some species.43Kharbanda K.K. Alcoholic liver disease and methionine metabolism.Sem Liver Dis. 2009; 29: 155-165Crossref PubMed Scopus (0) Google Scholar, 44Kharbanda K.K. Methionine metabolic pathway in alcoholic liver injury.Current opinion in clinical nutrition and metabolic care. 2013; 16: 89-95Crossref PubMed Scopus (0) Google Scholar, 45Kharbanda K.K. Mailliard M.E. Baldwin C.R. Beckenhauer H.C. Sorrell M.F. Tuma D.J. Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway.J Hepatol. 2007; 46: 314-321Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar This enzyme catalyzes an alternate pathway in methionine synthesis by utilizing hepatic betaine (trimethylglycine, a methyl group donor) to remethylate homocysteine46Finkelstein J.D. Martin J.J. Methionine metabolism in mammals. Distribution of homocysteine between competing pathways.J Biol Chem. 1984; 259: 9508-9513Abstract Full Text PDF PubMed Google Scholar forming methionine, thereby maintaining adequate levels of S-adenosylmethionine (SAM), the key intracellular methylating age

Is Fatty Liver Associated with Increased Mortality and Morbidity in Coronavirus Disease 2019 (COVID-19) Pneumonia?

Abstract: Fatty liver has been shown to be associated with severe COVID-19 disease without any impact on mortality. This is based on heterogenous criteria for defining both fatty liver as well as the severity parameters. This study aimed to study the impact of fatty liver on the mortality and severity of disease in patients with COVID-19 pneumonia.In a case control study design, patients with COVID-19 pneumonia (COVID-19 computed tomography severity index [CTSI] on high-resolution computed tomography chest of ≥1) with fatty liver (defined as liver to spleen attenuation index ≤5 on noncontrast computed tomography cuts of upper abdomen) were compared with those without fatty liver. The primary outcome measure was in-hospital mortality, and the secondary outcome measures were CTSI score, need for intensive care unit (ICU) care, need for ventilatory support, duration of ICU stay, and duration of hospital stay.Of 446 patients with COVID-19 pneumonia, 289 (64.7%)admitted to Max Hospital, Saket, India, between January 1, 2021, and October 30, 2021, had fatty liver. Fifty-nine of 446 patients died during the index admission. In-hospital mortality was not different between patients with fatty liver (38 [13.24%]) or without fatty liver (21 [13.81%]). COVID-19 CTSI score was found to be significantly higher among patients who had fatty liver (13.40 [5.16] vs 11.81 [5.50]; P = 0.003). There was no difference in the requirement of ICU (94 [32%] vs 62 [39.49%]; P = 0.752), requirement of ventilatory support (27 [9.34%] vs 14 [8.91%]; P = 0.385), duration of ICU stay (8.29 [6.87] vs 7.07 [5.71] days; P = 0.208), and duration of hospital stay (10.10 [7.14] vs 10.69 [8.13] days; P = 0.430) between the groups with fatty liver or no fatty liver. Similarly, no difference was found in primary or secondary outcomes measure between the group with severe fatty liver vs mild/moderate or no fatty liver. High total leucocyte count and Fibrosis-4 (FIB-4) index were independently associated with mortality.Fatty liver may not be associated with increased mortality or clinical morbidity in patients who have COVID-19 pneumonia.

Gut Microbiome and Alcohol-associated Liver Disease.

Abstract: Changes in gut microbiota (GM) may be associated with the causation and progression of multiple liver diseases such as metabolic-associated liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune liver disease, and most importantly, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infection, and hepatocellular carcinoma. ALD includes simple steatosis, steatohepatitis, AH, cirrhosis, and acute-on-chronic liver failure. Alcohol consumption is associated with GM changes even before ALD development, and continued alcohol intake results in progressive dysbiosis and development of clinical events such as AH, infection, and HE. The composition and function of GM, specific changes in bacterial communities, and the functional metabolism of GM are affected in the spectrum of ALD, as revealed using high-throughput sequencing. It was reported in preliminary studies that modulation of disrupted GM improves adverse clinical events and ameliorates disease progression in ALD. In this review, we exhaustively discuss the preclinical and clinical studies on GM in ALD and critically discuss GM modulation and its effects based on various human and animal models of ALD. Changes in gut microbiota (GM) may be associated with the causation and progression of multiple liver diseases such as metabolic-associated liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune liver disease, and most importantly, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infection, and hepatocellular carcinoma. ALD includes simple steatosis, steatohepatitis, AH, cirrhosis, and acute-on-chronic liver failure. Alcohol consumption is associated with GM changes even before ALD development, and continued alcohol intake results in progressive dysbiosis and development of clinical events such as AH, infection, and HE. The composition and function of GM, specific changes in bacterial communities, and the functional metabolism of GM are affected in the spectrum of ALD, as revealed using high-throughput sequencing. It was reported in preliminary studies that modulation of disrupted GM improves adverse clinical events and ameliorates disease progression in ALD. In this review, we exhaustively discuss the preclinical and clinical studies on GM in ALD and critically discuss GM modulation and its effects based on various human and animal models of ALD. The human gut microbiota (GM) comprises bacteria, viruses (including phages), fungi, and primitive prokaryotic archaea that inhabit the digestive tract, express 100 times more genes than their human host, and play key roles in human health and disease causation and progression. GM facilitates the breakdown and absorption of dietary nutrients and minerals, synthesis of antimicrobial peptides, fermentation of fibers to short-chain fatty acids (SCFAs), neutralization of toxins, and regulation of local and systemic endocrine and immunological functions.1Hartmann P. Chu H. Duan Y. Schnabl B. Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either.Am J Physiol Gastrointest Liver Physiol. 2019; 316: G563-G573https://doi.org/10.1152/ajpgi.00370.2018Crossref PubMed Scopus (31) Google Scholar Compositional and functional profiling revealed the association between human GM and multiple diseases affecting the liver. These diseases include hepatic steatosis, non-alcoholic fatty liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), chronic cholestatic conditions (e.g., primary biliary cholangitis and primary sclerosing cholangitis), autoimmune liver disease, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infections such as spontaneous bacterial peritonitis, and hepatocellular carcinoma.2Li R. Mao Z. Ye X. Zuo T. Human gut microbiome and liver diseases: from correlation to causation.Microorganisms. 2021; 9 (Published 2021 May 8. https://doi.org/10.3390/microorganisms9051017): 1017Crossref PubMed Scopus (6) Google Scholar In microbiome research, the most widely used high-throughput sequencing methods for analyzing bacterial communities include polymerase chain reaction (PCR) amplicon-based sequencing such as 16S ribosomal ribonucleic acid (rRNA) sequencing, deoxyribonucleic acid (DNA)-based shotgun metagenomic sequencing, and ribonucleic acid (RNA)-based meta-transcriptomic sequencing. The 16S rRNA sequencing method utilizes PCR to target and amplify areas of hypervariable regions (V1–V9) of bacterial rRNA subunit genes. In contrast, with the shotgun sequencing method, the entire metagenome of the sample can be randomly sequenced (with difficulty differentiating DNA from viable or dead cells) with no need for a specific primer. Metatranscriptomics is used to identify active microbial members in the biological sample and actively expressed genes in the community under specific conditions.3Philips C.A. Augustine P. Yerol P.K. et al.Modulating the intestinal microbiota: therapeutic opportunities in liver disease.J Clin Transl Hepatol. 2020; 8: 87-99https://doi.org/10.14218/JCTH.2019.00035Crossref PubMed Scopus (18) Google Scholar Thereafter, the raw sequenced data generated using these methods are entered into bioinformatics software pipelines for taxonomic assignment and microbial community analysis and visualization using operational taxonomic unit-based or amplicon sequence variant-based analysis. As soon as phylogenetic information is collected, functional gene composition of the bacterial community is then predicted using pipelines such as Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. To further identify significant and differentially abundant microbial taxa between communities in specific disease conditions, software tools optimized for statistical analysis of microbiome big-data, such as Linear Discriminant Analysis Effect Size, are used.3Philips C.A. Augustine P. Yerol P.K. et al.Modulating the intestinal microbiota: therapeutic opportunities in liver disease.J Clin Transl Hepatol. 2020; 8: 87-99https://doi.org/10.14218/JCTH.2019.00035Crossref PubMed Scopus (18) Google Scholar,4Gao B. Chi L. Zhu Y. et al.An introduction to next generation sequencing bioinformatic analysis in gut microbiome studies.Biomolecules. 2021 Apr 2; 11: 530https://doi.org/10.3390/biom11040530Crossref PubMed Scopus (12) Google Scholar ALD comprises simple steatosis, steatohepatitis, AH, cirrhosis, and the syndrome of AH-related acute-on-chronic liver failure (ACLF). Alcohol consumption is associated with GM changes even before ALD development.5Albhaisi S.A.M. Bajaj J.S. Sanyal A.J. Role of gut microbiota in liver disease.Am J Physiol Gastrointest Liver Physiol. 2020 Jan 1; 318: G84-G98https://doi.org/10.1152/ajpgi.00118.2019Crossref PubMed Google Scholar Continued alcohol intake worsens dysbiosis and is associated with disease progression and clinical events such as infection and HE. As reported in bench-to-bedside studies, GM composition and function play a role in the spectrum of ALD, and GM modulation improves adverse clinical events and disease progression.6Schwenger K.J. Clermont-Dejean N. Allard J.P. The role of the gut microbiome in chronic liver disease: the clinical evidence revised.JHEP Rep. 2019; 1: 214-226https://doi.org/10.1016/j.jhepr.2019.04.004Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar In the sections below, we exhaustively discuss relevant preclinical and clinical studies on GM in ALD and critically discuss GM modulation and its effects based on various human and animal models of ALD. As early as 1995, it was found that fecal cultures of male Wistar rats exposed to alcohol continuously for up to three weeks via intragastric feeding (after undergoing gut sterilization using polymyxin B and neomycin) had virtually no growth of gram-negative bacteria. Antibiotic therapy was reported to significantly reduce endotoxin levels and the average hepatic pathological score and to inhibit aspartate aminotransferase level elevation. The investigators reported that the benefits observed are as a result of reduction in Kupffer cell activation due to antibiotic therapy, without linking antibiotic therapy to the role of GM and GM modulatory effects.7Adachi Y. Moore L.E. Bradford B.U. Gao W. Thurman R.G. Antibiotics prevent liver injury in rats following long-term exposure to ethanol.Gastroenterology. 1995 Jan; 108: 218-224https://doi.org/10.1016/0016-5085(95)90027-6Abstract Full Text PDF PubMed Scopus (592) Google Scholar When intragastric alcohol or dextrose was administered to male Sprague–Dawley rats by gavage twice daily for up to 10 weeks, investigators observed changes in mucosa-associated microbiota composition in the colon, but not at weeks four and six. The authors concluded that daily alcohol consumption may affect colonic microbiome composition and result in dysbiosis that may trigger alcohol-induced endotoxemia. This study offered the first glimpse into alcohol-induced enteric dysbiosis using length-heterogeneity PCR fingerprinting.8Mutlu E. Keshavarzian A. Engen P. Forsyth C.B. Sikaroodi M. Gillevet P. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats.Alcohol Clin Exp Res. 2009 Oct; 33: 1836-1846https://doi.org/10.1111/j.1530-0277.2009.01022.xCrossref PubMed Scopus (244) Google Scholar In an intragastric alcohol-fed mouse model, investigators found that bacterial translocation occurred prior to GM changes. Using conventional culture techniques, bacterial overgrowth in the small and large intestine was observed after mice were fed intragastrical alcohol for at least three weeks. Pyrosequencing of 16S rRNA genes revealed the relative abundance of Bacteroidetes and Verrucomicrobia and the low abundance of Lactobacillus (phylum Firmicutes) in alcohol-fed mice associated with down-regulation of gene and protein expression of bactericidal c-type lectins Reg3b and Reg3g in the small intestine. Prebiotics were found to partially restore bactericidal lectins, ameliorate bacterial overgrowth, and reduce steatohepatitis.9Yan A.W. Fouts D.E. Brandl J. et al.Enteric dysbiosis associated with a mouse model of alcoholic liver disease.Hepatology. 2011 Jan; 53: 96-105https://doi.org/10.1002/hep.24018Crossref PubMed Scopus (507) Google Scholar In an experimental ALD model inspired by the Tsukamoto–French model that involved continuous intragastric feeding of wild-type and Muc2-deficient (−/−) mice with an isocaloric diet or alcohol, less alcohol-associated liver injury and steatosis were observed in the Muc2-deficient (−/−) mice than in the wild-type mice. The Muc2-deficient (−/−) mice were protected from alcohol-associated GM changes dependent on intestinal mucins, with lower amounts of bacterial products such as endotoxin found to translocate into the systemic circulation, thereby reducing the severity of liver disease.10Hartmann P. Chen P. Wang H.J. et al.Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice.Hepatology. 2013 Jul; 58: 108-119https://doi.org/10.1002/hep.26321Crossref PubMed Scopus (154) Google Scholar In another study, mice were fed liquid Lieber–DeCarli diet with or without alcohol (5% v/v) for six weeks. The authors reported that chronic ethanol feeding reduces the abundance of Bacteriodetes and Firmicutes and proportionally increases the abundance of gram-negative Proteobacteria and gram-positive Actinobacteria. Furthermore, a significant increase in the abundance of gram-negative alkaline-tolerant Alcaligenes and gram-positive Corynebacterium was observed following alcohol exposure. These GM changes are associated with increased plasma endotoxin, fecal pH, and liver inflammation and injury. Lactobacillus rhamnosus GG supplementation for six to eight weeks after alcohol feeding was reported to reduce GM changes and liver injury. The authors concluded that GM dysbiosis may be an important therapeutic target for the prevention or treatment of chronic alcohol-induced intestinal barrier dysfunction and liver disease.11Bull-Otterson L. Feng W. Kirpich I. et al.Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment.PLoS One. 2013; 8e53028https://doi.org/10.1371/journal.pone.0053028Crossref PubMed Scopus (339) Google Scholar In the study by Canesso et al. germ-free and conventional mice were subjected to acute alcohol intake by adding alcohol to their drinking water for seven days, with a higher dose of alcohol added on day seven. Compared to the alcohol-fed conventional mice, the germ-free mice were found to have no liver injury, low neutrophil infiltration, and low pro-inflammatory cytokine levels in the liver. After conventionalization using intestinal contents from the alcohol-fed conventional mice, injury, and inflammation were observed in the liver and intestine of the germ-free mice, suggesting that alcohol intake causes gut dysbiosis and liver injury. In their study, quantitative culturing of stool samples revealed increased abundance of Enterococcus species in the alcohol-fed mice.12Campos Canesso M. Lacerda Queiroz N. Marcantonio C. et al.Comparing the effects of acute alcohol consumption in germ-free and conventional mice: the role of the gut microbiota.BMC Microbiol. 2014; 14: 240Crossref PubMed Scopus (82) Google Scholar In a Tsukamoto–French mouse model that involved continuous intragastric feeding with an isocaloric diet or alcohol for three weeks, analysis of cecal contents revealed reduced synthesis of saturated long-chain fatty acids (LCFAs) associated with reduced abundance of LCFA-producing Lactobacilli. When intestinal levels of saturated fatty acids were maintained, GM disturbance lessened, resulting in less alcohol-induced liver injury.13Chen P. Torralba M. Tan J. et al.Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice.Gastroenterology. 2015 Jan; 148: 203-214.e16https://doi.org/10.1053/j.gastro.2014.09.014Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar These studies also show that alcohol-treated mice have high intestinal levels of phyla such as Verrucomicrobia, Actinobacteria, and Proteobacteria (and their respective taxa Akkermansia muciniphila, Corynebacterium species, and Alcaligenes species), which support the role of GM dysbiosis associated with alcohol-induced injuries in the liver and intestines due to loss of gut barrier integrity and function and promotion of local and systemic inflammation via portal circulation. In the Gao-binge mouse model (with chronic plus binge alcohol feeding), significant and reproducible differences in microbiome communities were observed between alcohol-fed mice and control mice on the same diet, excluding alcohol. In addition to reduction in alpha diversity and dispersion in beta diversity in alcohol-fed mice, it was found that the initial effect of alcohol was on gram-positive bacteria (increase in Adlercreutzia and Enterococcus), with increase in gram-negative communities (including Prevotella, Bilophila, Desulfovibrio, and Helicobacter), abundance of Clostridium, and reduction in Bifidobacterium, Lactobacillus (which mitigates alcohol injury), and Turicibacter (which is associated with anxiety-like effects, social avoidance behavior), and fatty liver disease.14LeBrun E.S. Nighot M. Dharmaprakash V. et al.The gut microbiome and alcoholic liver disease: ethanol consumption drives consistent and reproducible alteration in gut microbiota in mice.Life (Basel). 2020 Dec 24; 11: 7https://doi.org/10.3390/life11010007Crossref PubMed Scopus (5) Google Scholar In a study on mice by Kang et al. distinctive GM dysbiosis was observed in chronic alcoholic fatty liver disease (AFLD) and metabolic-associated fatty liver disease (MAFLD). Compared to controls, the AFLD group had significant abundance of Enterococcus and Streptococcus, and in the MAFLD group, Lachnospiraceae was the most abundant bacterial family, Erysipelatoclostridium, Gordonibacter, and Streptococcus were the most abundant bacterial taxa, and there was a reduction of Bifidobacterium.15Kang K. Sun Y. Pan D. et al.Distinctive gut microbial dysbiosis between chronic alcoholic fatty liver disease and metabolic-associated fatty liver disease in mice.Exp Ther Med. 2021 May; 21: 418https://doi.org/10.3892/etm.2021.9862Crossref PubMed Google Scholar Researchers from China showed that GM composition and structure significantly change with ALD progression and that the relative abundance of Streptococcus species significantly increases in alcohol-associated cirrhosis and correlates positively with aspartate aminotransferase level. They concluded that dysbiosis occurs from the early to the end stages of ALD and that Streptococcus may be a microbiological marker for the evaluation of liver injury severity in patients with ALD.16Zhong X. Cui P. Jiang J. et al.Streptococcus, the predominant bacterium to predict the severity of liver injury in alcoholic liver disease.Front Cell Infect Microbiol. 2021 Mar 17; 11: 649060https://doi.org/10.3389/fcimb.2021.649060Crossref PubMed Scopus (9) Google Scholar Thus, preclinical studies have demonstrated the distinct role played by GM in various stages of ALD which are dependent on microbial metabolism, host immune response, gut barrier integrity and systemic inflammation. A summary of pertinent preclinical study models and important outcomes in ALD is shown in Figure 1. Preliminary alcohol studies using small animal models have shown that probiotic therapy with Lactobacillus plantarum or L. rhamnosus or multi-strain Di-Simone formulation or any of its generics reduces systemic inflammation and gut dysbiosis, ameliorates hepatic steatosis, improves liver tests, and reduces oxidative stress. It was also shown that antibiotic cocktail or colistin therapy decreases liposaccharide and bacterial load, reduces hepatic, neurological, and systemic inflammation, and improves gut barrier integrity by increasing the relative abundance of mucin-secreting A. muciniphila. In animal models of ALD, increased relative abundance of Bacteroides was found to be associated with reduced oxidative stress, improved gut barrier integrity, and reduced liver inflammation due to intake of prebiotic oatmeal, pectin, and fructooligosaccharides.17Gupta H. Suk K.T. Kim D.J. Gut microbiota at the intersection of alcohol, brain, and the liver.J Clin Med. 2021 Feb 2; 10: 541https://doi.org/10.3390/jcm10030541Crossref PubMed Scopus (7) Google Scholar,18Chi X. Pan C.Q. Liu S. Cheng D. Cao Z. Xing H. Regulating intestinal microbiota in the prevention and treatment of alcohol-related liver disease.Chin J Gastroenterol Hepatol. 2020 Dec 17; 2020: 6629196https://doi.org/10.1155/2020/6629196Crossref PubMed Scopus (5) Google Scholar In a seminal paper, Llopis et al. reported that, compared to germ-free mice transplanted with GM from alcoholic subjects without AH, alcohol-fed germ-free mice developed severe liver inflammation and necrosis and increased intestinal permeability when transplanted with GM isolated from patients with severe AH (SAH). Thus, susceptibility to alcohol-induced liver injury was shown to be transmissible from patients to mice through fecal microbiota transplantation (FMT). Abundance of taxa such as Bilophila wadsworthia, Alistipes, Butyricimonas, Clostridium, Proteus, and Escherichia coli and reduced levels of Faecalibacterium prausnitzii (associated with anti-inflammatory effects and gut barrier health via butyric acid production) and A. muciniphila (associated with the mucin barrier) were found to be associated with SAH. On further assessment of the fecal metabolome, significant differences in bile acid derivative levels were observed between mice with liver injury and mice without liver injury. In mice without liver lesions, it was found that chenodeoxycholic and ursodeoxycholic acid levels are significantly higher in the fecal samples of mice that received FMT from an alcoholic patient without liver disease than in the fecal samples of mice that received intestinal microbiota from a patient with ALD.19Llopis M. Cassard A.M. Wrzosek L. et al.Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease.Gut. 2016 May; 65: 830-839https://doi.org/10.1136/gutjnl-2015-310585Crossref PubMed Scopus (291) Google Scholar Ferrere et al. fed alcohol and a Lieber–DeCarli diet to mice in two different animal facilities. FMT was performed with fresh feces from alcohol-resistant donor mice to alcohol-sensitive receiver mice three times a week. The control group received pectin during the entire alcohol consumption period. The investigators found that alcohol-induced steatohepatitis is associated with disruption of gut homeostasis in alcohol-sensitive mice, but not in alcohol-resistant mice. It was also found that abundance of Bacteroides is significantly lower in alcohol-sensitive mice than in alcohol-resistant mice and that FMT restores the GM of alcohol-sensitive recipient mice close to that of alcohol-resistant donor mice. Therefore, the investigators concluded that GM modulation may prevent alcohol-induced liver injury.20Ferrere G. Wrzosek L. Cailleux F. et al.Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice.J Hepatol. 2017 Apr; 66: 806-815https://doi.org/10.1016/j.jhep.2016.11.008Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar In a mouse model of chronic alcohol feeding, researchers found that type 3 innate lymphoid cells of the intestine produce lower-than-normal levels of interleukin (IL)-22 (due to alcohol-induced dysbiosis) and intestinal indole-3-acetic acid (IAA), a microbial metabolite that regulates IL-22 expression. Further, patients with SAH were found to have low fecal levels of IAA. It was reported that IAA supplementation or feeding mice IL-22-producing Lactobacillus reuteri restores IL-22 expression, thereby mitigating alcohol-induced liver injury. The study showed that focused targeting of microbiota and metabolism may ameliorate alcohol-induced liver injury and prevent AH.21Hendrikx T. Duan Y. Wang Y. et al.Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice.Gut. 2019 Aug; 68: 1504-1515https://doi.org/10.1136/gutjnl-2018-317232Crossref PubMed Scopus (105) Google Scholar It is evident that chronic alcohol consumption is associated with bacterial dysbiosis. Yang et al. demonstrated that, in mice, chronic alcohol administration increases mycobiota populations and fungal β-glucan translocation into the systemic circulation and that antifungal treatment reduces intestinal fungal overgrowth, decreases β-glucan translocation, and ameliorates alcohol-induced liver disease.22Yang A.M. Inamine T. Hochrath K. et al.Intestinal fungi contribute to development of alcoholic liver disease.J Clin Invest. 2017 Jun 30; 127: 2829-2841https://doi.org/10.1172/JCI90562Crossref PubMed Scopus (235) Google Scholar Duan et al. found that cytolysin, a two-subunit exotoxin secreted by Enterococcus faecalis, causes hepatocyte death and liver injury and that patients with SAH have increased fecal numbers of E. faecalis. It was also found that the abundance of cytolytic E. faecalis is significantly associated with liver disease severity and mortality in patients with SAH. Using humanized mice colonized with bacteria from the feces of patients with AH, the investigators studied bacteriophage targeting of cytolytic E. faecalis. They found that bacteriophage reduces cytolysin in the liver and ameliorates alcohol-induced liver disease in humanized mice, thereby demonstrating that cytolysin-positive E. faecalis is associated with poor clinical outcomes and high mortality rates in patients with AH. The study offered proof of concept that precision therapy using bacteriophages to target cytolytic E. faecalis is a method of intestinal microbiota editing for the improvement of clinical outcomes, pending further prospective clinical trials.23Duan Y. Llorente C. Lang S. et al.Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.Nature. 2019; 575: 505-511https://doi.org/10.1038/s41586-019-1742-xCrossref PubMed Scopus (267) Google Scholar Wrzosek et al. used the prebiotic pectin to modulate intestinal microbiota in a mouse model of ALD in which the GM of alcoholic patients was transplanted into human-associated mice. They focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR), and found that pectin treatment modifies the microbiome and metabolome of human microbiota-associated alcohol-fed mice, resulting in increased production of bacterial tryptophan metabolites that are associated with amelioration of liver injury. The investigators showed that SAH is associated with low levels of bacterial tryptophan derivatives. The use of AhR agonists that target the GM (e.g., moderate amounts of the prebiotic pectin) may positively affect the AhR pathway and ameliorate alcohol-induced liver injury.24Wrzosek L. Ciocan D. Hugot C. et al.Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury.Gut. 2021 Jul; 70: 1299-1308https://doi.org/10.1136/gutjnl-2020-321565Crossref PubMed Scopus (33) Google Scholar Gut microbiome modulation studies in the preclinical setting have underlined the role of systemic and local inflammation as well as dysregulated host immune functions in alcohol-associated liver injury. The use of prebiotic/probiotic therapy, antimicrobial agents or fecal transplantation in small animal models have demonstrated the role of dysbiosis in driving alcohol-induced liver injury and its amelioration through modification of bacterial communities and beneficial modifications via microbial metabolite generation or systemic immune modulation. Figure 2 summarizes the important preclinical GM modulation studies in ALD. In 1984, Bode et al. reported GM changes associated with chronic alcohol abuse in humans. They analyzed the types and numbers of bacteria in jejunal aspirates from chronic alcoholics and hospitalized control patients. They found that the number of anaerobic and aerobic microbes (gram-negative anaerobic bacteria and endospore-forming rods) is significantly higher and jejunal fluid cultures reveal coliform organisms more frequently in alcoholics than in controls.25Bode J.C. Bode C. Heidelbach R. Dürr H.K. Martini G.A. Jejunal microflora in patients with chronic alcohol abuse.Hepato-Gastroenterology. 1984 Feb; 31: 30-34PubMed Google Scholar A large body of evidence indicates the role of GM in patients with ALD of different stages. Studies showed that ALD without cirrhosis is associated with reduced Bacteroidetes and increased Proteobacteria that active alcohol use is associated with reduced Ruminococcaceae, which reverses after abstinence, and that dysbiosis is worse in patients with ALD and cirrhosis than in patients with non-ALD cirrhosis of comparable severity.26Mutlu E.A. Gillevet P.M. Rangwala H. et al.Colonic microbiome is altered in alcoholism.Am J Physiol Gastrointest Liver Physiol. 2012 May 1; 302: G966-G978https://doi.org/10.1152/ajpgi.00380.2011Crossref PubMed Scopus (470) Google Scholar, 27Leclercq S. Matamoros S. Cani P.D. et al.Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.Proc Natl Acad Sci U S A. 2014 Oct 21; 111: E4485-E4493https://doi.org/10.1073/pnas.1415174111Crossref PubMed Scopus (476) Google Scholar, 28Bajaj J.S. Heuman D.M. Hylemon P.B. et al.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014 May; 60: 940-947https://doi.org/10.1016/j.jhep.2013.12.019Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar Depletion of commensal bacteria and increased relative abundance of Lactobacillus and Bifidobacterium were observed in actively drinking patients with alcohol-associated cirrhosis, and oral-predominant bacteria were found to be associated with activation of alcohol metabolism and inflammatory pathways. Researchers also found that alcohol-dependence correlates inversely with the levels of butyrate-producing species from the Clostridiales order. The pro-inflammatory Enterobacteriaceae was significantly elevated in patients with alcohol-dependence, and over-representation of oral microbes in the gut was observed in patients with cirrhosis.29Dubinkina V.B. Tyakht A.V. Odintsova V.Y. et al.Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease.Microbiome. 2017 Oct 17; 5: 141https://doi.org/10.1186/s40168-017-0359-2Crossref PubMed Scopus (174) Google Scholar Bajaj et al. reported that, compared to non-drinkers and controls, actively drinking patients with cirrhosis have significant duodenal, ileal, and colonic mucosal and fecal dysbiosis with low autochthonous bacterial taxa,30Bajaj J.S. Kakiyama G. Zhao D. et al.Continued alcohol misuse in human cirrhosis is associated with an impaired gut-liver Axis.Alcohol Clin Exp Res. 2017 Nov; 41: 1857-1865https://doi.org/10.1111/acer.13498Crossref PubMed Scopus (63) Google Scholar which were linked with alterations in microbial function pertaining to bile acid levels. Studies also showed that reduced abundance of A. muciniphila is associated with increased severity of ALD (lowest in AH) and that secondary bile acid levels are higher in the serum and feces of actively drinking patients with ALD-related cirrhosis than in thos

Predictors of in-hospital Outcomes in Patients With Cirrhosis and Coronavirus Disease-2019

Abstract: Coronavirus disease-2019 (COVID-19) cases continue to increase globally. Poor outcomes in patients with COVID-19 and cirrhosis have been reported; predictors of outcome are unclear. The existing data is from the early part of the pandemic when variants of concern (VOC) were not reported.We aimed to assess the outcomes and predictors in patients with cirrhosis and COVID-19. We also compared the differences in outcomes between the first wave of pandemic and the second wave.In this retrospective analysis of a prospectively maintained database, data on consecutive cirrhosis patients (n = 221) admitted to the COVID-19 care facility of a tertiary care center in India were evaluated for presentation, the severity of liver disease, the severity of COVID-19, and outcomes.The clinical presentation included: 18 (8.1%) patients had compensated cirrhosis, 139 (62.9%) acute decompensation (AD), and 64 (29.0%) had an acute-on-chronic liver failure (ACLF). Patients with ACLF had more severe COVID-19 infection than those with compensated cirrhosis and AD (54.7% vs. 16.5% and 33.3%, P < 0.001). The overall mortality was 90 (40.7%), the highest among ACLF (72.0%). On multivariate analysis, independent predictors of mortality were high leukocyte count, alkaline phosphatase, creatinine, child class, model for end-stage liver disease (MELD) score, and COVID-19 severity. The second wave had more cases of severe COVID-19 as compared to the first wave, with a similar MELD score and Child score. The overall mortality was similar between the two waves.Patients with COVID-19 and cirrhosis have high mortality (40%), particularly those with ACLF (72%). A higher leukocyte count, creatinine, alkaline phosphatase, Child class, and MELD score are predictors of mortality.

Gut Barrier and Microbiota in Cirrhosis

Abstract: Gut microbiota and their homeostatic functions are central to the maintenance of the intestinal mucosal barrier. The gut barrier functions as a structural, biological, and immunological barrier, preventing local and systemic invasion and inflammation of pathogenic taxa, resulting in the propagation or causation of organ-specific (liver disease) or systemic diseases (sepsis) in the host. In health, commensal bacteria are involved in regulating pathogenic bacteria, sinister bacterial products, and antigens; and help control and kill pathogenic organisms by secreting antimicrobial metabolites. Gut microbiota also participates in the extraction, synthesis, and absorption of nutrient metabolites, maintains intestinal epithelial integrity and regulates the development, homeostasis, and function of innate and adaptive immune cells. Cirrhosis is associated with local and systemic immune, vascular, and inflammatory changes directly or indirectly linked to perturbations in quality and quantity of intestinal microbiota and intestinal mucosal integrity. Dysbiosis and gut barrier dysfunction are directly involved in the pathogenesis of compensated cirrhosis and the type and severity of complications in decompensated cirrhosis, such as bacterial infections, encephalopathy, extrahepatic organ failure, and progression to acute on chronic liver failure. This paper reviews the normal gut barrier, gut barrier dysfunction, and dysbiosis-associated clinical events in patients with cirrhosis. The role of dietary interventions, antibiotics, prebiotics, probiotics, synbiotics, and healthy donor fecal microbiota transplantation (FMT) to modulate the gut microbiota for improving patient outcomes is further discussed. Gut microbiota and their homeostatic functions are central to the maintenance of the intestinal mucosal barrier. The gut barrier functions as a structural, biological, and immunological barrier, preventing local and systemic invasion and inflammation of pathogenic taxa, resulting in the propagation or causation of organ-specific (liver disease) or systemic diseases (sepsis) in the host. In health, commensal bacteria are involved in regulating pathogenic bacteria, sinister bacterial products, and antigens; and help control and kill pathogenic organisms by secreting antimicrobial metabolites. Gut microbiota also participates in the extraction, synthesis, and absorption of nutrient metabolites, maintains intestinal epithelial integrity and regulates the development, homeostasis, and function of innate and adaptive immune cells. Cirrhosis is associated with local and systemic immune, vascular, and inflammatory changes directly or indirectly linked to perturbations in quality and quantity of intestinal microbiota and intestinal mucosal integrity. Dysbiosis and gut barrier dysfunction are directly involved in the pathogenesis of compensated cirrhosis and the type and severity of complications in decompensated cirrhosis, such as bacterial infections, encephalopathy, extrahepatic organ failure, and progression to acute on chronic liver failure. This paper reviews the normal gut barrier, gut barrier dysfunction, and dysbiosis-associated clinical events in patients with cirrhosis. The role of dietary interventions, antibiotics, prebiotics, probiotics, synbiotics, and healthy donor fecal microbiota transplantation (FMT) to modulate the gut microbiota for improving patient outcomes is further discussed. For understanding the role of gut barrier (GB) function and its clinical implications in cirrhosis, it is pertinent to understand normal GB, microbiota association, and the role of functional microbial metabolites. The GB provides effective mechanisms via intricate checkpoints (network of mechanical and immunological components) to combat damaging metabolites and pathogens from translocating into the host circulation. The GB consists of several component levels that separate the lamina propria and a thin layer of loose (areolar) connective tissue lying beneath the epithelium from the intestinal lumen 1Salvo Romero E. Alonso Cotoner C. Pardo Camacho C. Casado Bedmar M. Vicario M. The intestinal barrier function and its involvement in digestive disease.Rev Esp Enferm Dig. 2015 Nov; 107: 686-696Google Scholar. Epithelial cells form brush-bordered microvilli that physically prevent pathogens from coming into contact with the enterocyte body and also secrete intestinal alkaline phosphatase that dephosphorylates lipopolysaccharides and prevents bacterial growth 2Camilleri M. Madsen K. Spiller R. Greenwood-Van Meerveld B. Verne G.N. Intestinal barrier function in health and gastrointestinal disease.Neuro Gastroenterol Motil. 2012 Jun; 24: 503-512Google Scholar. A change in the composition of the gut microbiota (GM) is termed dysbiosis. It is classified into three types: the outgrowth of commensal microbiota with the potential to cause pathology (pathobionts), reduction or complete loss of normally abundant members of the microbiota (loss of commensals), and reduction in microbial diversity (loss of richness).3Camilleri M. Vakil N. Microbiome: in search of mechanistic information and relevance.Am J Gastroenterol. 2019 Jul; 114: 1014-1016Google Scholar In the intestinal lumen, degradation of pathogenic bacteria, bacterial products, and antigens; control and killing of pathogenic organisms via antimicrobial metabolites occur in the presence of commensal bacterial communities 4Turner J.R. Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application.Am J Pathol. 2006 Dec; 169: 1901-1909Google Scholar. The functions of GM in humans are manifold: (a) extraction, synthesis, and absorption of nutrient metabolites such as bile acids, vitamins, and short-chain fatty acids (SCFAs); (b) immune function against pathogenic bacteria colonization via growth inhibition through various processes such as pH modulation and nutrient competition; (c) maintenance of intestinal epithelium integrity; and (d) regulating the development, homeostasis, and function of innate and adaptive immune cells (5Wells J.M. Brummer R.J. Derrien M. et al.Homeostasis of the gut barrier and potential biomarkers.Am J Physiol Gastrointest Liver Physiol. 2017 Mar; 312: G171-G193Google Scholar). In humans, the dominant gut microbial phyla are Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia. Firmicutes and Bacteroidetes represent 90% of the GM, respectively. The Firmicutes phylum includes Lactobacillus, Bacillus, and Clostridium (representing 95% of all species). Bacteroides and Prevotella predominate Bacteroidetes, whereas the Bifidobacterium genus mainly represents the Actinobacteria phylum. The microbiota varies between individuals based on different aspects, such as the anatomical site of the gut (Lactobacillus and Enterobacteriaceae in the small intestine; Bacteroidaceae, Prevotellaceae, Lachnospiraceae, and Ruminococcaceae in the colon), age (childhood: Bifidobacterium, Bacteroides; over 70 years: Proteobacteria), and antibiotic treatments (macrolides: reduces Actinobacteria, increases Bacteroides; ciprofloxacin: reduces Bifidobacterium and Fecalibacterium; Clindamycin: reduces Lactobacillus).6Thursby E. Juge N. Introduction to the human gut microbiota.Biochem J. 2017 May; 474: 1823-1836Google Scholar,7Rinninella E. Raoul P. Cintoni M. et al.What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases.Microorganisms. 2019 Jan; 7: 14Google Scholar These bacterial communities maintain homeostatic functions of the lumen-mucosa interface by stabilizing the water, mucus, and immunoglobulin secretion and sustaining cellular processes that promote epithelial junctional barrier health 8Paone P. Cani P.D. Mucus barrier, mucins, and gut microbiota: the expected slimy partners?.Gut. 2020 Dec; 69: 2232-2243Google Scholar. Although there seems to be no controversy regarding GB dysfunction in diseases resulting in intestinal inflammation, which leads to structural abnormalities of the epithelium, the term “leaky gut” is an oversimplification of a complex event that reflects intestinal permeability, which cannot be used to generalize a pathophysiological event. In this regard, an ideal term would be intestinal barrier dysfunction 9Quigley E.M. Leaky gut - concept or clinical entity?.Curr Opin Gastroenterol. 2016 Mar; 32: 74-79Google Scholar, 10Alam A. Neish A. Role of gut microbiota in intestinal wound healing and barrier function.Tissue Barriers. 2018 Nov; 6: 1539595Google Scholar, 11Okumura R. Takeda K. Roles of intestinal epithelial cells in the maintenance of gut homeostasis.Exp Mol Med. 2017 May; 49: e338Google Scholar, 12Kurashima Y. Kiyono H. Mucosal ecological network of epithelium and immune cells for gut homeostasis and tissue healing.Annu Rev Immunol. 2017 Apr; 35: 119-147Google Scholar. Any process that directly or indirectly disrupts the GB function does so by directly modulating the GM quantity (changes in alpha diversity) and quality (metabolic functions). The secretory pathways, antimicrobial peptides (AMPs), and beneficial antimetabolites governed by healthy commensal bacteria help maintain GB integrity and function in a healthy state.13Liu S. Song P. Sun F. et al.The concept revolution of gut barrier: from epithelium to endothelium.Int Rev Immunol. 2020 Nov; : 1-8Google Scholar Various cellular components of GB have specified roles in regulating intestinal homeostasis. These include (a) enterocytes of the small intestine and colon are responsible for physical barrier function via junctional protein complexes; (b) Paneth cells of the small intestine, which promote microbial sensing, secrete AMPs, defensins, lysozyme, tumor-necrosis factor (TNF)-α, and phospholipases; (c) goblet cells that produce and release mucins and promote the development of T-regulatory cells (Tregs) for immune surveillance and defense mechanisms; (d) Tuft cells which secrete interleukin (IL)-25, promoting goblet cell hyperplasia, and mucin production to maintain GB integrity; (e) enteroendocrine cells secrete glucagon-like peptides that induce tight junction proteins such as occludin, which ameliorate TNF-α-induced inflammation changes; and finally, (f) M cells of the small intestine take up additional antigens to prevent downstream inflammatory responses 14Allam-Ndoul B. Castonguay-Paradis S. Veilleux A. Gut microbiota and intestinal trans-epithelial permeability.Int J Mol Sci. 2020 Sep; 21: 6402Google Scholar, 15Shi N. Li N. Duan X. Niu H. Interaction between the gut microbiome and mucosal immune system.Mil Med Res. 2017 Apr; 4: 14Google Scholar, 16Farhadi A. Banan A. Fields J. Keshavarzian A. Intestinal barrier: an interface between health and disease.J Gastroenterol Hepatol. 2003 May; 18: 479-497Google Scholar, 17Stange E.F. Improvement of a 'leaky' intestinal barrier.Dig Dis. 2017 Feb; 35: 21-24Google Scholar. Tight junction proteins are responsible for paracellular transport and selective GB permeability. While claudin protein mediates the pore pathway, the leak pathway is regulated by occludin, zonula occludens, and myosin light-chain kinase proteins regulated by GM and their metabolites.18Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans.Gut. 2019 Aug; 68: 1516-1526Google Scholar,19Wang L. Llorente C. Hartmann P. Yang A.M. Chen P. Schnabl B. Methods to determine intestinal permeability and bacterial translocation during liver disease.J Immunol Methods. 2015 Jun; 421: 44-53Google Scholar Another major layer of defense is the gut vascular barrier, which controls the systemic dissemination of microbes and their metabolites via the portal circulation. Thus, a healthy GB is imperative for maintaining homeostatic immune mechanisms in the host (20Scaldaferri F. Pizzoferrato M. Gerardi V. Lopetuso L. Gasbarrini A. The gut barrier: new acquisitions and therapeutic approaches.J Clin Gastroenterol. 2012 Oct; 46: S12-S17Google Scholar,21Xue J. Ajuwon K.M. Fang R. Mechanistic insight into the gut microbiome and its interaction with host immunity and inflammation.Anim Nutr. 2020 Dec; 6: 421-428Google Scholar). The tolerogenic mechanisms that promote GB homeostasis include secretion of beneficial metabolites (SCFAs such as butyrate), clearance and conversion of damaging metabolites, and regulation of proinflammatory pathways through GM Akkermansia muciniphila, Bifidobacterium, Lactobacillus plantarum, and L. reuteri. Thus, it is evident that GB function, intestinal permeability, and host-related local and systemic immune and inflammatory responses are highly dependent on GM22Paradis T. Bègue H. Basmaciyan L. Dalle F. Bon F. Tight junctions as a key for pathogens invasion in intestinal epithelial cells.Int J Mol Sci. 2021 Mar; 22: 2506Google Scholar, 23Roxas J.L. Viswanathan V.K. Modulation of intestinal paracellular transport by bacterial pathogens.Comp Physiol. 2018 Mar; 8: 823-842Google Scholar, 24Krautkramer K.A. Fan J. Bäckhed F. Gut microbial metabolites as multi-kingdom intermediates.Nat Rev Microbiol. 2021 Feb; 19: 77-94Google Scholar. Another important aspect of GB function is bile acid metabolism and regulation of microbiota. After transformation, the secondary bile acids signal in the intestinal epithelium primarily through the farnesoid X receptor (FXR). FXR regulation via microbial products and metabolites in a healthy state can enhance GB and repair gut-vascular barrier disruption. Progressive liver failure impairs FXR regulation, synthesis, and excretion of bile acids, resulting in deficient total bile acids in the gut lumen and enhanced serum levels.25Sayin S.I. Wahlström A. Felin J. et al.Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.Cell Metabol. 2013 Feb; 17: 225-235Google Scholar,26Péan N. Doignon I. Tordjmann T. Gut microbiota and bile acids: an old story revisited (again).Clin Res Hepatol Gastroenterol. 2014 Apr; 38: 129-131Google Scholar The healthy GB components, their functions, and their relationship with GM and its metabolites in health are shown in Figure 1. The gut and liver communicate bidirectionally through the portal venous system, biliary tract, and indirectly via systemic circulation. Recent evidence has shed light on the importance of translocation of bacteria, bacterial products, and metabolites from the intestinal lumen into the systemic circulation as contributing factors in the pathogenesis of various liver diseases and portal hypertensive complications. Cirrhosis is associated with local and systemic immune, vascular, and inflammatory changes directly or indirectly linked to perturbations within the intestinal microbiota, functions, and intestinal mucosal integrity 27Tsiaoussis G.I. Assimakopoulos S.F. Tsamandas A.C. Triantos C.K. Thomopoulos K.C. Intestinal barrier dysfunction in cirrhosis: current concepts in pathophysiology and clinical implications.World J Hepatol. 2015 Aug; 7: 2058-2068Google Scholar. At the ultrastructural level, pertinent changes to the GB have been demonstrated. Dilatation of extracellular space between adjacent enterocytes (predominantly in the lower portion) reduces fractured and shorter, but thicker microvilli, intestinal mucosal atrophy, and infiltration of inflammatory cells into the lamina propria muscular layer are prominent. Additionally, irregularities of the glandular epithelia, loss of normal cylindrical shape, edematous villi, and loosening of the mucous membrane were associated with endotoxemia of cirrhosis 28Assimakopoulos S.F. Charonis A.S. Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: the pivotal role of enterocyte tight junctions and future perspectives.J Hepatol. 2013 Nov; 59: 1144-1146Google Scholar, 29Ponziani F.R. Zocco M.A. Cerrito L. Gasbarrini A. Pompili M. Bacterial translocation in patients with liver cirrhosis: physiology, clinical consequences, and practical implications.Expet Rev Gastroenterol Hepatol. 2018 Jul; 12: 641-656Google Scholar, 30Assimakopoulos S.F. Tsamandas A.C. Tsiaoussis G.I. et al.Altered intestinal tight junctions' expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability.Eur J Clin Invest. 2012 Apr; 42: 439-446Google Scholar. Animal model studies showed that lipid peroxidation within enterocytes promoted mitochondrial dysfunction and cellular instability. High levels of malondialdehyde (a marker of lipid peroxidation) were observed in the ileal and cecal mucosa of experimental cirrhotic models with ascites and bacterial translocation. These findings favor GB dysfunction in cirrhosis 31Bishehsari F. Magno E. Swanson G. et al.Alcohol and gut-derived inflammation.Alcohol Res. 2017; 38: 163-171Google Scholar,32Sommer F. Anderson J.M. Bharti R. Raes J. Rosenstiel P. The resilience of the intestinal microbiota influences health and disease.Nat Rev Microbiol. 2017 Oct; 15: 630-638Google Scholar. In cirrhosis, the immunological GB encompassing gut-associated lymphoid tissue comprises the Peyer’s patches, lamina propria lymphocytes, including dendritic cells, intraepithelial lymphocytes, and mesenteric lymph nodes that regulate both adaptive and innate immune defense mechanisms become dysfunctional. With a biological barrier breach, the proportion of activated T lymphocytes, monocytes, and dendritic cells in the lamina propria increases, resulting in disruptive cytokine expression that positively correlates with intestinal dysbiosis. With decompensation, this inflammatory milieu expands, increasing intestinal mucosal-activated macrophages and enhancing intestinal permeability, leading to augmentation of bacterial translocation. In advanced liver disease (as noted in cirrhotic mice), B cell and T cell dysfunction (reduction in memory cells, reduced ability to recruit T-cells, and weak T-regulatory cell function) result in a lack of commensal specific immunoglobulin response, which further worsens GB function, augmentation of bacterial translocation, seeding of gut pathogens to mesenteric lymph nodal sites, and switching commensal bacterial profile to a highly pathogenic one, which is notable in spontaneous bacterial peritonitis (SBP). The intestinal immune system in cirrhotic animal models is characterized by a switch to a Th1 regulatory pattern with an expansion of TNF-α - and IFN-c-expressing lymphocytes and concomitant Th17 depletion in the lamina propria 33Muñoz L. Borrero M.J. Ubeda M. et al.Intestinal immune dysregulation driven by dysbiosis promotes barrier disruption and bacterial translocation in rats with cirrhosis.Hepatology. 2019 Sep; 70: 925-938Google Scholar. Disruption of the GB, augmented by bacterial overgrowth and translocation, leads to dysbiosis resulting in a deficiency of endogenous gut-derived AMPS. Structural changes to the gut mucosa, reduced immunoglobulin A secretion, and persistent activation of toll-like receptors initiate a proinflammatory cascade, which results in the progression of cirrhosis to acute decompensation or acute on chronic liver failure (ACLF) associated with immune exhaustion. This is followed by highly reduced anti-inflammatory markers and immune mechanistic cellular failure (such as reduced monocyte HLA expression), leading to repeated or severe infections that promote organ failure in cirrhosis 34Mendes B.G. Schnabl B. From intestinal dysbiosis to alcohol-associated liver disease.Clin Mol Hepatol. 2020 Oct; 26: 595-605Google Scholar. The Bacteroidetes phylum contributes 79% of the lipopolysaccharide biosynthesis in healthy volunteers. In a healthy state, the total lipopolysaccharides produced in the human gut is “immune-silent” (due to predominance of under acylated lipid A structures in the order Bacteroidales); that is, it has a very limited capacity to activate inflammatory cytokines 35d'Hennezel E. Abubucker S. Murphy L.O. Cullen T.W. Total lipopolysaccharide from the human gut microbiome silences toll-like receptor signaling.mSystems. 2017 Nov; 2 (e00046-17)Google Scholar. The GB dysfunction as a cause for initiation and progression of cirrhosis is well documented with AALD, but not so in other etiologies. Furthermore, the GB dysfunction as an important aspect in the progression and severity of cirrhosis (of all etiologies) is well documented. Thus, GB dysfunction and dysbiosis may be a “correlation or causation” in cirrhosis and its progression. Gut microbial dysbiosis, bacterial overgrowth, chronic endotoxemia, systemic inflammation, hepatic stellate cell activation, local and systemic chemokines, cytokines, and growth factor dysregulation are all linked to post-bleed sepsis, hepatic encephalopathy (HE), hepatopulmonary syndrome, hepatorenal syndrome, SBP, and hepatocarcinogenesis 36Oikonomou T. Papatheodoridis G.V. Samarkos M. Goulis I. Cholongitas E. Clinical impact of microbiome in patients with decompensated cirrhosis.World J Gastroenterol. 2018 Sep; 24: 3813-3820Google Scholar,37Hartmann P. Chu H. Duan Y. Schnabl B. Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either.Am J Physiol Gastrointest Liver Physiol. 2019 May; 316: G563-G573Google Scholar. A schematic summarizing GB dysfunction and dysbiosis in cirrhosis is shown in Figure 2. Dysbiosis and GB dysfunction are directly involved in the pathogenesis of compensated cirrhosis and the type and severity of complications in decompensated cirrhosis, such as bacterial infections and encephalopathy. The role of GM in chronic liver disease, worsening small intestinal bacterial overgrowth, and associated complications have been well studied in animal models of chronic liver disease 36Oikonomou T. Papatheodoridis G.V. Samarkos M. Goulis I. Cholongitas E. Clinical impact of microbiome in patients with decompensated cirrhosis.World J Gastroenterol. 2018 Sep; 24: 3813-3820Google Scholar,37Hartmann P. Chu H. Duan Y. Schnabl B. Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either.Am J Physiol Gastrointest Liver Physiol. 2019 May; 316: G563-G573Google Scholar. Similarly, metagenomic studies in cirrhotic mice have shown Staphylococcaceae, Lactobacillaceae, and Streptococcaceae were related to brain and systemic inflammation and ammonia generation 38Kang D.J. Betrapally N.S. Ghosh S.A. et al.Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice.Hepatology. 2016 Oct; 64: 1232-1248Google Scholar. A large meta-analysis found that the association between bacterial overgrowth and chronic liver disease was not confined to patients with advanced cirrhosis. Small intestinal bacterial overgrowth was not a consequence of advanced liver disease but played a role in the progression of chronic liver disease 39Shah A. Shanahan E. Macdonald G.A. et al.Systematic review and meta-analysis: prevalence of small intestinal bacterial overgrowth in chronic liver disease.Semin Liver Dis. 2017 Nov; 37: 388-400Google Scholar. In cirrhosis with SBP or encephalopathy, lower levels of Firmicutes and higher levels of Bacteroidetes correlated with higher endotoxemia, whereas higher model for end-stage liver disease scores correlated with lower levels of commensal bacteria. Interestingly, in alcohol-associated cirrhosis, Bacteroidetes and Firmicutes change with more reduction in the former, whereas in other etiologies, the opposite occurs. The degree of dysbiosis, calculated using the Cirrhosis Dysbiosis Ratio, is the ratio of Lachnospiraceae + Ruminococcaceae + Veillonellaceae + Clostridiales Incertae sedis XIV) divided by (Bacteroidaceae + Enterobacteriaceae).40Bajaj J.S. Heuman D.M. Hylemon P.B. et al.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014 May; 60: 940-947Google Scholar,41Li F. McClain C.J. Feng W. Microbiome dysbiosis and alcoholic liver disease.Liver Res. 2019 Dec; 3: 218-226Google Scholar In patients with encephalopathy, Cirrhosis Dysbiosis Ratio decreases while Bacteroidetes species increase. In patients with minimal HE, the stool RA of Streptococcus salivarius increased with an increase in blood ammonia. Further studies have shown that Proteobacteria are correlated with endotoxemia and cognition in cirrhosis. Pathogenic taxa such as Enterococcaaceae, Staphlyococcaceae, Porphyromonadaceae (orally abundant pathogen), and Lactobacillaceae were positively correlated with magnetic spectroscopy findings, while autochthonous taxa were negatively correlated. The reduction of Bacteroidetes was associated with an increased risk of infection, mostly in alcohol-related cirrhosis 42Acharya C. Bajaj J.S. Altered microbiome in patients with cirrhosis and complications.Clin Gastroenterol Hepatol. 2019 Jan; 17: 307-321Google Scholar,43Acharya C. Sahingur S.E. Bajaj J.S. Microbiota, cirrhosis, and the emerging oral-gut-liver axis.JCI Insight. 2017 Oct; 2e94416Google Scholar. In another study, the authors found that in hospitalized patients with cirrhosis, dysbiosis at admission was correlated with an increased risk of extrahepatic organ failure, ACLF, and death, independent of clinical factors 44Bajaj J.S. Vargas H.E. Reddy K.R. et al.Association between intestinal microbiota collected at hospital admission and outcomes of patients with cirrhosis.Clin Gastroenterol Hepatol. 2019 Mar; 17: 756-765.e3Google Scholar. Similarly, using high-throughput analysis, the authors found that the progression of cirrhosis was associated with a profound reduction in gene and metagenomic species richness, which was highly expressed in patients with ALCF, associated with a significant increase in Enterococcus and Peptostreptococcus. In ACLF, the gut microbiome predicted three-month survival, associated with functional changes such as enrichment of pathways related to ethanol production, γ-aminobutyric acid metabolism, and endotoxin biosynthesis 45Solé C. Guilly S. Da Silva K. et al.Alterations in gut microbiome in cirrhosis as assessed by quantitative metagenomics: relationship with acute-on-chronic liver failure and prognosis.Gastroenterology. 2021 Jan; 160: 206-218.e13Google Scholar. Various specific changes in the GM have been demonstrated in metagenomic studies of cirrhosis. The GM in cirrhosis has reduced diversity, decreased relative abundance (RA) of potentially beneficial autochthonous taxa such as Ruminococcaceae and Lachnospiraceae, and increased overgrowth of pathogenic taxa such as Enterobacteriaceae, Staphylococcaceae, and Enterococcaceae. This microbiota profile worsens with disease progression, recurrent or worsening decompensation, repeated hospitalization, use of antimicrobials, and proton-pump inhibitors. This ultimately generates “pathobionts” and “resistome” associated with poor clinical outcomes 46Arab J.P. Martin-Mateos R.M. Shah V.H. Gut-liver axis, cirrhosis, and portal hypertension: the chicken and the egg.Hepatol Int. 2018 Feb; 12: 24-33Google Scholar,47Mandato C. Delli Bovi A.P. Vajro P. The gut-liver axis as a target of liver disease management.Hepatobiliary Surg Nutr. 2021 Jan; 10: 100-102Google Scholar. Bifidobacterium dentium was enhanced in hepatitis-b virus patients, whereas Bifidobacterium catenulatum and Bifidobacterium pseudocatenulatum were detected less frequently in hepatitis-b virus cirrhotic patients than in controls 48Xu M. Wang B. Fu Y. et al.Changes of fecal Bifidobacterium species in adult patients with hepatitis B virus-induced chronic liver disease.Microb Ecol. 2012 Feb; 63: 304-313Google Scholar. Neisseria and Gemella were discriminated between hepatitis-b virus-related cirrhosis and primary biliary cholangitis 49Chen Y. Ji F. Guo J. Shi D. Fang D. Li L. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology.Sci Rep. 2016 Sep; 6: 34055Google Scholar. Nonetheless, duodenal dysbiosis with a shift toward pathogenic bacteria genera such as Streptococcus, Shuttleworthia, and Rothia, associated with increased intestinal permeability and elevated markers of microbial translocation, was notable in alcohol use disorder patients with progressive steatohepatitis and steatofibrosis. In addition, this study also showed that increased GB dysfunction is related to dysbiotic changes in the GM50Maccioni L. Gao B. Leclercq S. et al.Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans.Gut Microb. 2020 Nov; 12: 1782157Google Scholar. In alcohol-associated liver disease (AALD), the antibacterial potency of mucosa-associated invariant T cells is compromised in dysbiosis due to exposure to microbial products and microbiota 50Maccioni L. Gao B. Leclercq S. et al.Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans.Gut Microb. 2020 Nov; 12: 1782157Google Scholar,51Riva A. Patel V. Kurioka A. et al.Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease.Gut. 2018 May; 67: 918-930Google Scholar. Furthermore, intestinal microbiota in patients with chronic hepatitis C with and without cirrhosis compared with healthy controls showed that the stage of liver disease and hepatitis C infection were associated with reduced alpha diversity and different microbial community patterns 52Heidrich B. Vital M. Plumeier I. et al.Intestinal microbiota in patients with chronic hepatitis C with and without cirrhosis compared with healthy controls.Liver Int. 2018 Jan; 38: 50-58Google Scholar. In a pilot study, authors found that among patients who used proton-pump inhibitors, the changes in Veillonella and Streptococcus were aggravated with progressing cirrhosis severity 53Goeser F. Münch P. Lesker T.R. et al.Neither black nor w

Portal Vein Thrombosis in Cirrhosis

Abstract: Patients with cirrhosis of the liver are at high risk of developing portal vein thrombosis (PVT), which has a complex, multifactorial cause. The condition may present with a myriad of symptoms and can occasionally cause severe complications. Contrast-enhanced computed tomography (CT) is the gold standard for the diagnosis of PVT. There are uncertainties regarding the effect on PVT and its treatment outcome in patients with cirrhosis. The main challenge for managing PVT in cirrhosis is analyzing the risk of hemorrhage compared to the risk of thrombus extension leading to complications. All current knowledge regarding non-tumor PVT in cirrhosis, including epidemiology, risk factors, classification, clinical presentation, diagnosis, impact on natural history, and treatment, is discussed in the present article.

Management of Portal Hypertension.

Abstract: Portal hypertension is the cause of the clinical complications associated with cirrhosis. The primary complications of portal hypertension are ascites, acute variceal bleed, and hepatic encephalopathy. Hepatic venous pressure gradient measurement remains the gold standard test for diagnosing cirrhosis-related portal hypertension. Hepatic venous pressure gradient more than 10 mmHg is associated with an increased risk of complications and is termed clinically significant portal hypertension (CSPH). Clinical, laboratory, and imaging methods can also aid in diagnosing CSPH non-invasively. Recently, deep learning methods have been demonstrated to diagnose CSPH effectively. The management of portal hypertension is always individualized and is dependent on the etiology, the availability of therapies, and the degree of portal hypertension complications. In this review, we discuss the diagnosis and management of cirrhosis-related portal hypertension in detail. Also, we highlight the history of portal hypertension and future research areas in portal hypertension.

European Working Group on Sarcopenia in Older People (EWGSOP2) Criteria With Population-Based Skeletal Muscle Index Best Predicts Mortality in Asians With Cirrhosis

Abstract:

Background/Aims

Multiple definitions of sarcopenia exist and the acceptable criterion that best predicts outcome is lacking. We estimated the prevalence of sarcopenia based on four criteria and assessed their utility in predicting mortality in cirrhotics.

Methods

In a prospective observational study, consecutive Asian patients with cirrhosis underwent testing for handgrip strength (HGS) and estimation of skeletal muscle index (SMI) using computed tomography at the third lumbar vertebra. Sarcopenia was defined based on the Western cut-off (WC; SMI < 50 cm²/m² for men and <39 cm²/m² for women), Asian cut-off (AC; SMI < 36.5 cm²/m² for men and 30.2 cm²/m² for women), European Working Group on Sarcopenia in Older People—2nd meeting (EWGSOP2) definition incorporating low HGS (<27 kg for men and <16 kg for women) with low SMI (defined by the WC), and EWGSOP2 definition with low HGS and low SMI (defined by AC). Risk factors for mortality were assessed using multivariate Cox-proportional hazards.

Results

We included 219 patients with cirrhosis (168 men; mean age 42.6 years) with 50.2% patients having decompensation. Alcohol was the commonest aetiology (33.3%). The prevalence of sarcopenia was highest with the WC (men: 82.1%; women: 62.7%). There was a weak concordance among all criteria (Fleiss' kappa 0.23, 95% confidence interval [CI] 0.10–0.37). Overall, 12-month survival was 86.1% (81.1–91.3%) over a median (interquartile range) follow-up of 12 (6–15) months. Ascites (hazards ratio [HR] 6.27 [95% CI 1.6–24.1]; P < 0.007) and SMI (HR 0.92 [0.85–0.98]; P = 0.021) were independent predictors of mortality. The 12-month mortality rate was higher in patients with sarcopenia, irrespective of criteria (log rank P < 0.05). Low HGS and low SMI (defined by AC) was the best for predicting mortality (HR 3.04 [1.43–6.43]; P = 0.004).

Conclusion

A weak concordance exists amongst various diagnostic definitions of sarcopenia. Sarcopenia diagnosed by a combination of low HGS and population-specific SMI cut-off (AC) best predicts mortality.

Current Medical Treatment for Alcohol-Associated Liver Disease.

Abstract: Alcohol-associated liver disease is one of the main causes of chronic liver disease. It comprises a clinical-histologic spectrum of presentations, from steatosis, steatohepatitis, to different degrees of fibrosis, including cirrhosis and severe necroinflammatory disease, called alcohol-associated hepatitis. In this focused update, we aim to present specific therapeutic interventions and strategies for the management of alcohol-associated liver disease. Current evidence for management in all spectra of manifestations is derived from general chronic liver disease recommendations, but with a higher emphasis on abstinence and nutritional support. Abstinence should comprise the treatment of alcohol use disorder as well as withdrawal syndrome. Nutritional assessment should also consider the presence of sarcopenia and its clinical manifestation, frailty. The degree of compensation of the disease should be evaluated, and complications, actively sought. The most severe acute form of this disease is alcohol-associated hepatitis, which has high mortality and morbidity. Current treatment is based on corticosteroids that act by reducing immune activation and blocking cytotoxicity and inflammation pathways. Other aspects of treatment include preventing and treating hepatorenal syndrome as well as preventing infections although there is no clear evidence as to the benefit of probiotics and antibiotics in prophylaxis. Novel therapies for alcohol-associated hepatitis include metadoxine, interleukin-22 analogs, and interleukin-1-beta antagonists. Finally, granulocyte colony-stimulating factor, microbiota transplantation, and gut-liver axis modulation have shown promising results. We also discuss palliative care in advanced alcohol-associated liver disease.

Low Volume Plasma Exchange and Low Dose Steroid Improve Survival in Patients With Alcohol-Related Acute on Chronic Liver Failure and Severe Alcoholic Hepatitis – Preliminary Experience

Abstract: BackgroundAlcohol-related acute on chronic liver failure (A-ACLF) patients have high short-term mortality and are poor candidates for steroid therapy. Plasma exchange (PLEX) improves survival in ACLF patients. We analyzed our experience with low volume PLEX (50% of plasma volume exchanged per session) and low dose steroids to treat A-ACLF patients.MethodsWe retrospectively compared the efficacy of low volume PLEX and low-dose steroids with standard medical treatment (SMT) in A-ACLF patients treated at our center between November 2017 to June 2019. The primary study outcome was one-year survival.ResultsTwenty-one A-ACLF patients in PLEX group [age 40 (29–56) years, median (range); MELD score 31 (29–46)] and 29 A-ACLF patients in SMT group [age 41.5 (28–63) years, MELD score 37 (21–48)] were studied. All 50 study patients had severe alcoholic hepatitis [mDF 84.7 (50–389)]. PLEX group patients had 3 (1–7) PLEX sessions with 1.5 (1.4–1.6) liters of plasma exchanged per session and oral Prednisolone 20 mg daily, tapered over 1 month. Kaplan Meier analysis showed better survival over 1 year in the PLEX group compared to the SMT group (P = 0.03). There was renal dysfunction in 10 patients in the PLEX group, which normalized in six patients after PLEX.ConclusionIn this preliminary report, compared to SMT, low volume PLEX and low dose steroid improved survival over one year in A-ACLF patients with severe alcoholic hepatitis. In patients with renal dysfunction, 60% showed improvement in renal function with PLEX. Studies with a larger number of patients are needed to validate these results. Alcohol-related acute on chronic liver failure (A-ACLF) patients have high short-term mortality and are poor candidates for steroid therapy. Plasma exchange (PLEX) improves survival in ACLF patients. We analyzed our experience with low volume PLEX (50% of plasma volume exchanged per session) and low dose steroids to treat A-ACLF patients. We retrospectively compared the efficacy of low volume PLEX and low-dose steroids with standard medical treatment (SMT) in A-ACLF patients treated at our center between November 2017 to June 2019. The primary study outcome was one-year survival. Twenty-one A-ACLF patients in PLEX group [age 40 (29–56) years, median (range); MELD score 31 (29–46)] and 29 A-ACLF patients in SMT group [age 41.5 (28–63) years, MELD score 37 (21–48)] were studied. All 50 study patients had severe alcoholic hepatitis [mDF 84.7 (50–389)]. PLEX group patients had 3 (1–7) PLEX sessions with 1.5 (1.4–1.6) liters of plasma exchanged per session and oral Prednisolone 20 mg daily, tapered over 1 month. Kaplan Meier analysis showed better survival over 1 year in the PLEX group compared to the SMT group (P = 0.03). There was renal dysfunction in 10 patients in the PLEX group, which normalized in six patients after PLEX. In this preliminary report, compared to SMT, low volume PLEX and low dose steroid improved survival over one year in A-ACLF patients with severe alcoholic hepatitis. In patients with renal dysfunction, 60% showed improvement in renal function with PLEX. Studies with a larger number of patients are needed to validate these results.

Overview of Complications in Cirrhosis.

Abstract: Cirrhosis is the outcome of chronic liver disease of any etiology due to progressive liver injury and fibrosis. Consequently, cirrhosis leads to portal hypertension and liver dysfunction, progressing to complications like ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, cirrhotic cardiomyopathy, sarcopenia, hepatocellular carcinoma, and coagulation disorders. End-stage liver disease leads to an impaired quality of life, loss of social and economic productivity, and reduced survival.This narrative review explains the pathophysiology of complications of cirrhosis, the diagnostic approach and innovative management, with focus on data from India. A comprehensive literature search of the published data was performed in regard with the spectrum, diagnosis, and management of cirrhosis and its complications.There is a change in the epidemiology of metabolic syndrome, lifestyle diseases, alcohol consumption and the spectrum of etiological diagnosis in patients with cirrhosis. With the advent of universal vaccination and efficacious long-term viral suppression agents for chronic hepatitis B, availability of direct-acting antiviral agents for chronic hepatitis C, and a booming liver transplantation programme across the country, the management of complications is essential. There are several updates in the standard of care in the management of complications of cirrhosis, such as hepatorenal syndrome, hepatocellular carcinoma, and hepatic encephalopathy, and new therapies that address supportive and palliative care in advanced cirrhosis.Prevention, early diagnosis, appropriate management of complications, timely transplantation are cornerstones in the management protocol of cirrhosis and portal hypertension. India needs improved access to care, outreach of public health programmes for viral hepatitis care, health infrastructure, and disease registries for improved healthcare outcomes. Low-cost initiatives like immunization, alcohol cessation, awareness about liver diseases, viral hepatitis elimination, and patient focused decision-making algorithms are essential to manage liver disease in India.

Liver Injury Following Tinospora Cordifolia Consumption: Drug-Induced AIH, or de novo AIH?

Abstract: There has been significant interest to study idiosyncratic liver injury due to conventional drugs and herbal and dietary supplements (HDS) over the last two decades in both, Europe1Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Spanish Group for the Study of Drug-Induced Liver Disease.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar, 2Björnsson E. Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.Hepatology. 2005; 42: 481-489Crossref PubMed Scopus (464) Google Scholar, 3Björnsson E.S. Bergmann O.M. Björnsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar and the United States.4Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 5Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury.The DILIN prospective study Gastroenterology. 2015; 48: 1340-1352Abstract Full Text Full Text PDF Scopus (431) Google Scholar, 6Vega M. Verma M. Beswick D. et al.The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the state of Delaware.Drug Saf. 2017; 40: 783-787Crossref PubMed Scopus (59) Google Scholar Several very interesting papers on this subject from Asian countries such as South Korea,7Suk K.T. Kim D.J. Kim C.H. et al.A prospective nationwide study of drug-induced liver injury in Korea.Am J Gastroenterol. 2012; 107: 1380-1387Crossref PubMed Scopus (119) Google Scholar China,8Shen T. Liu Y. Shang J. et al.Incidence and etiology of drug-induced liver injury in mainland China.Gastroenterology. 2019; 107: 1380-1387Google Scholar Taiwan,9Huang Y.S. Chang T.T. Peng C.Y. et al.Herbal and dietary supplement-induced liver injury in Taiwan: comparison with conventional drug-induced liver injury.Hepatology Int. 2019; 41: 2671-2680Google Scholar and India10Devarbhavi H. Joseph T. Kumar N.S. et al.The Indian network of Drug-induced liver injury: etiology, clinical features, outcomes and prognostic markers in 1288 patients.J Clin Exp Hepatol. 2021 May-Jun; 11: 288-298Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar have also been published. In prospective studies from the United States and Iceland, HDS-induced liver injury has accounted for 15–20% of cases,3Björnsson E.S. Bergmann O.M. Björnsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar, 4Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 5Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury.The DILIN prospective study Gastroenterology. 2015; 48: 1340-1352Abstract Full Text Full Text PDF Scopus (431) Google Scholar whereas a larger proportion of cases due to HDS has been reported from Asia.7Suk K.T. Kim D.J. Kim C.H. et al.A prospective nationwide study of drug-induced liver injury in Korea.Am J Gastroenterol. 2012; 107: 1380-1387Crossref PubMed Scopus (119) Google Scholar, 8Shen T. Liu Y. Shang J. et al.Incidence and etiology of drug-induced liver injury in mainland China.Gastroenterology. 2019; 107: 1380-1387Google Scholar, 9Huang Y.S. Chang T.T. Peng C.Y. et al.Herbal and dietary supplement-induced liver injury in Taiwan: comparison with conventional drug-induced liver injury.Hepatology Int. 2019; 41: 2671-2680Google Scholar However, in a recent large prospective study from India, almost half of the recruited patients suffered from drug-induced liver injury (DILI) due to antituberculosis drugs and 14% had HDS-induced liver injury,10Devarbhavi H. Joseph T. Kumar N.S. et al.The Indian network of Drug-induced liver injury: etiology, clinical features, outcomes and prognostic markers in 1288 patients.J Clin Exp Hepatol. 2021 May-Jun; 11: 288-298Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar which is similar to the 16% reported in two studies from the West.3Björnsson E.S. Bergmann O.M. Björnsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar,4Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar In the current issue, Nagral et al. reported a series of 6 patients suspected to have liver injury after consumption of Tinospora cordifolia.11Nagral A. Adhyaru K. Rudra O.S. Gharat A. Bhandare S. Herbal Immune booster-induced liver injury in the COVID-19 pandemic - a case series.J Clin Exp Hepatol. 2021 Jul 2; ([Online ahead of print])https://doi.org/10.1016/j.jceh.2021.06.021Abstract Full Text Full Text PDF Scopus (16) Google Scholar T. cordifolia (TC) is used frequently by Indian Ayurveda medicine and is called Giloy in Hindi.12https://herbs.indianmedicinalplants.info/index.php/61-guduci-tinospora-cordifolia.Google Scholar Although TC or its extract is extensively used in India for general health benefits, only a single case report of suspected liver injury has been previously published.13Karousatos C.M. Lee J.K. Braxton D.R. Fong T.L. Case series and review of Ayurvedic medication induced liver injury.BMC Complementary Medicine and Therapies. 2021; 21: 91Crossref PubMed Scopus (8) Google Scholar This convincing case report involved a 68-year-old South Asian female living in the United States who consumed Giloy Kwath and developed hepatocellular jaundice. Apart from a weakly positive antinuclear antibody (ANA), thorugh diagnostic testing failed to identify any other cause of liver injury. Within a month of discontinuing Giloy Kwath, the liver tests normalized.13Karousatos C.M. Lee J.K. Braxton D.R. Fong T.L. Case series and review of Ayurvedic medication induced liver injury.BMC Complementary Medicine and Therapies. 2021; 21: 91Crossref PubMed Scopus (8) Google Scholar In the current series, 4 out of 6 patients were of female gender, -median age of 55 and a median duration of use of 3 months (range 3 weeks–7 months). The Giloy was taken both as commercially available syrup containing ingredients of the plant or boiled TC plant twigs. According to the authors, Giloy has recently gained popularity during the COVID-19 pandemic as the plant is believed to serve as an “immunity booster” and might fight the SARS-CoV-2. The indications for Giloy in the current series are not clearly stated but presumed to be related to the pandemic. All patients presented with hepatocellular jaundice, and AST was higher than ALT at presentation in all patients. Interestingly, 5 out of 6 had evidence of serological markers of autoimmunity, such as elevated ANA, smooth muscle antibody (SMA), and/or elevated IgG, and liver histology was compatible with autoimmune hepatitis in all patients. Three patients received corticosteroids. One patient died of liver failure, whereas the others recovered seemingly without sequelae. Unfortunately, currently, there is no diagnostic biomarker that can be used to confirm the diagnosis of drug- or herbal-induced idiosyncratic liver injury. How convincing are these cases reported by Nagral et al.? The authors of this editorial, with combined decades-long research experience in DILI, readjudicated each case using the DILIN causality adjudication process. The consensus causality of liver injury by TC was highly likely in two (cases 1 and 3), probable in two (cases 2 and 6) and possible in 2 cases (cases 4 and 5) (Table 1).Table 1Three Editorialists’ Readjudication of Six Reported Cases by Nagral et al.Case #Causality ScoreLikelihood that liver injury event is related to drug exposureComments from the editorialistsCase 1Highly likely>75%–95%Temporal relationship to consumption of TC plant twig, exclusion of common competing etiologies, recovery without corticosteroids upon dechallenge, and 5-month follow-up make this a convincing case of TC-related liver injury. This is a case of DI-AIH that was resolved upon stopping the implicated agent.Case 2Probable>50%–75%Prolonged exposure to TC plant twig, unimpressive autoimmune markers, normal immunoglobulin G levels, and mixed pattern liver injury on liver biopsy favor DILI, but the response to steroid therapy and lack of follow-up upon tapering off prednisolone lower our confidence.Case 3Highly likely>75%–95%Prolonged exposure to TC plant twig-boiled and extract, unimpressive autoimmune markers, normal immunoglobulin G levels, liver histology consistent with DILI, and recovery without corticosteroids upon dechallenge make this a convincing case of TC-related liver injury. Ultrasound showed diffuse fatty infiltration, but there is no description of hepatic steatosis on liver biopsy.Case 4Possible>25%–50%Relatively brief exposure to TC extract containing syrup, high ANA, positive ASMA, underlying cirrhosis, and relapse following steroid withdrawal indicates that this individual likely had longstanding AIH leading to cirrhosis with an acute flare, which possibly may have been triggered by TC consumption. Overall, this case is more likely to represent de novo AIH rather than one that is related to TC.Case 5Possible>25%–50%Relatively brief exposure to TC plant boiled extract, high immunoglobulin G, underlying cirrhosis, response to corticosteroids, and maintenance steroid therapy indicates that this woman likely had longstanding AIH with an acute flare that may possibly have been triggered by TC consumption. Overall, this case is more likely to represent de novo AIH rather than one that is related to TC.Case 6Probable>50%–75%Three-month exposure to commercially available TC containing tablet high immunoglobulin G levels, liver histology consistent with autoimmune hepatitis, recovery without corticosteroid upon dechallenge favor DI-AIH. However, bridging fibrosis on liver biopsy raises the possibility that there may have been chronic injury initiated before the exposure to TC started. Open table in a new tab All individuals included in this series had clinical, laboratory, and histological features indicative of autoimmune hepatitis (revised AIH score was definite in four and probable in two cases). So, are these cases of de novo AIH or drug-induced autoimmune hepatitis (DI-AIH)? DI-AIH has a well-documented clinical, immunological, and biochemical phenotype and can be due to drugs such as nitrofurantoin, alpha-methyl dopa, hydralazine, minocycline, and infliximab15de Boer Y.S. Kosinski A.S. Urban T.J. et al.Features of autoimmune hepatitis in patients with drug-induced liver injury.Clin Gastroenterol Hepatol. 2017; 15: 103-112Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 16Björnsson H.K. Gudbjörnsson B. Björnsson E.S. Infliximab-induced liver injury: clinical phenotypes, autoimmunity and the role of corticosteroid treatment.J Hepatol. 2021 Sep 3; (S0168-8278(21)02022-5 [Online ahead of print])https://doi.org/10.1016/j.jhep.2021.08.024Abstract Full Text Full Text PDF Scopus (4) Google Scholar More than 30 drugs and HDS have been suspected of causing DI-AIH.17Guzman G. Kallwitz E.R. Wojewoda C. et al.Liver injury with features mimicking autoimmune hepatitis following the use of black cohosh.Case Report Med. 2009; : 918156PubMed Google Scholar, 18Riyaz S. Imran M. Gleeson D. Karajeh M.A. Khat (Catha Edulis) as a possible cause of autoimmune hepatitis.World J Hepatol. 2014; 6: 150-154Crossref PubMed Scopus (19) Google Scholar, 19Czaja A.J. Drug-induced autoimmune-like hepatitis.Dig Dis Sci. 2011; 56: 958-976Crossref PubMed Scopus (173) Google Scholar However, for many of these drugs, the documented evidence is very limited and consists of a single report and/or short follow-up, which makes it difficult to distinguish DI-AIH from AIH.19Czaja A.J. Drug-induced autoimmune-like hepatitis.Dig Dis Sci. 2011; 56: 958-976Crossref PubMed Scopus (173) Google Scholar It is well known that autoantibodies can found in patients with other liver diseases than AIH, such as in chronic liver diseases such fatty liver disease,20Adams L.A. Lindor K.D. Angulo P. The prevalence of autoantibodies and autoimmune hepatitis in patients with non alcoholic fatty liver disease.Am J Gastroenterol. 2004; 99: 1316-1320Crossref PubMed Scopus (155) Google Scholar,21Ravi S. Shoreibah M. Raff E. et al.Autoimmune markers do not impact clinical presentation or natural history of steatohepatitis-related liver disease.Dig Dis Sci. 2015; 60: 3788-3793Crossref PubMed Scopus (22) Google Scholar acute liver failure,22Bernal W, Ma Y, Smith HS, Portmann B, Wendon J, Vergani D. The significance of autoantibodies and immunoglobulins in acute liver failure: A cohort study. Journal of Hepatology; 47: 664-670.Google Scholar DILI due to prescription agents or HDS.23Lammert C. Zhu C. Lian Y. et al.Exploratory study of autoantibody profiling in drug-induced liver injury with an autoimmune phenotype.Hepatol Commun. 2020; 4: 1651-1663Crossref PubMed Scopus (5) Google Scholar,24Philips C.A. Paramaguru Joy A.K. Antony K. Augustine P. Clinical outcomes, histopathological patterns, and chemical analysis of Ayurveda and herbal medicine associated with severe liver injury—a single-center experience from southern India.Indian J Gastroenterol. 2018; 37: 9-17Crossref PubMed Scopus (5) Google Scholar Unfortunately, there is still no consensus on the criteria for DI-AIH and the experts do not agree on the definitions.23Lammert C. Zhu C. Lian Y. et al.Exploratory study of autoantibody profiling in drug-induced liver injury with an autoimmune phenotype.Hepatol Commun. 2020; 4: 1651-1663Crossref PubMed Scopus (5) Google Scholar,24Philips C.A. Paramaguru Joy A.K. Antony K. Augustine P. Clinical outcomes, histopathological patterns, and chemical analysis of Ayurveda and herbal medicine associated with severe liver injury—a single-center experience from southern India.Indian J Gastroenterol. 2018; 37: 9-17Crossref PubMed Scopus (5) Google Scholar Patients with DI-AIH present similarly to de novo AIH clinically, immunologically, and histologically. The only feature that may distinguish DI-AIH from de novo AIH is the lack of relapse after discontinuation of the immunosuppression in DI-AIH. Another pertinent question is, when is it reasonable to use corticosteroids in patients with suspected DI-AIH, as was undertaken in 3 of the 6 patients in the current report. We agree with the authors that corticosteroids are unnecessary in patients who show prompt improvement in liver tests after the implicated agent has been stopped (i.e., positive dechallenge). However, patients with DILI with autoimmune features who show worsening of liver tests and/or no improvement or slow and incomplete recovery, clinically and biochemically, should be treated with corticosteroids.16Björnsson H.K. Gudbjörnsson B. Björnsson E.S. Infliximab-induced liver injury: clinical phenotypes, autoimmunity and the role of corticosteroid treatment.J Hepatol. 2021 Sep 3; (S0168-8278(21)02022-5 [Online ahead of print])https://doi.org/10.1016/j.jhep.2021.08.024Abstract Full Text Full Text PDF Scopus (4) Google Scholar Notwithstanding the autoimmune aspects of the cases presented by Nagral et al, there are other factors to consider whenever HDS are implicated as the cause for liver injury; that is, how can one be sure that the HDS is the cause for liver injury? Among the most critical factors in this context are the complexity of HDS and the approach to diagnosing HDS DILI. In reality, although products may be marketed as a specific agent or ingredient, the actual HDS consumed are highly complex and contain many different ingredients (or phytochemicals). This is the case simply because of the complex nature of naturally occurring compounds, unpredictable growing conditions, and methods of commercial preparation. Additionally, it is well-known that HDS are susceptible to inaccurate labels and intentional or inadvertent inclusion of ingredients. In fact, the Drug-Induced Liver Injury Network has shown that supplements implicated in liver injury are frequently mislabeled in the United States.25Navarro V. Avula B. Khan I. et al.The contents of herbal and dietary supplements implicated in liver injury in the United States are frequently mislabeled.Hepatol Commun. 2019; 3: 792-794Crossref PubMed Scopus (18) Google Scholar Such ingredients can be botanical or nonbotanical and could have been intentionally added to achieve some specific result, or inadvertent as may occur during the production process. Importantly, botanical ingredients could result from various raw material plant parts such as the leaves, stems (twigs), or roots. In the current case series, four patients consumed TC after boiling the twigs. The method of the commercial preparation of a processed botanical compound may affect its hepatotoxic potential. An example of this phenomenon is Polygonum multiflorum (PM), a popular botanical product in traditional Chinese Medicine (TCM) used for myriad purposes that has been implicated in hepatotoxicity.26Teka T. Wang L. Gao J. et al.Polygonum multiflorum: recent updates on newly isolated compounds, potential hepatotoxic compounds and their mechanisms.J Ethnopharmacol. 2021; : 271Google Scholar The hydrolysis of PM plant glycosides during preparation is thought to affect toxicity.27Wei Y. Liu M. Liu J. Li H. Influence factors on the hepatotoxicity of polygoni Multiflori Radix.Evid Based Complement Alternat Med. 2019; : 1-12Google Scholar Other manufacturing methods and approach to extraction may affect the chemical composition, potency, and toxic potential of the phytochemicals within HDS, as has been shown with Kuding tea (Kudingcha), another popular agent in TCM.28Wüpper S. Lüersen K. Rimbach G. Chemical composition, bioactivity and safety aspects of Kuding tea-from beverage to herbal extract.Nutrients. 2020; 12: 2796Crossref Scopus (6) Google Scholar Chemical analysis of implicated HDS would seem to be a useful tool to identify a culprit ingredient for injury. Chemical analysis is performed commonly through High-Performance Liquid Chromatography (HPLC). Through this, phytochemicals and other agents such as pharmaceuticals appear as peaks on a chromatogram, which then can be compared against a library of known peaks for actual identification. Ostensibly, such an approach would be very useful to identify an ingredient that may explain the injury. However, most botanical products have many ingredients, any one of which (or combination thereof) may be responsible. Therefore, chemical analysis in the diagnosis of HDS-induced liver injury, or identifying the culprit ingredient, has a very limited role in a clinical setting. The causality assessment in cases of suspected HDS DILI is challenging, and we believe it is best addressed with a structured causality assessment approach complemented by expert opinion. The addition of expert opinion permits flexibility to consider information that may be excluded in structure causality assessment but pertinent to HDS associated liver injury. For example, some products may be used for a very long time before toxicity arises (prolonged latency) and have specific patterns of injury that trigger the diagnostician’s memory to link injury to the product. In summary, the report by Nagral et al., suggests that some patients may very rarely develop liver injury following TC consumption. Temporal relationship to exposure, positive dechallenge, and clinical picture suggest that this liver injury represents DI-AIH, at least in some cases, rather than de novo AIH. This report raises more questions than answers. TC has been consumed for a very long time in the Indian subcontinent with no previous reports of liver injury, so why now? One might speculate that it could be due to a spike in its usage due to the ongoing pandemic. It is unclear if TC caused the toxicity or if there was a contaminant that contributed to the liver injury. Further, it is unknown if there are any predisposing factor such as dose, duration, or type of preparation, genetic variants, comorbidities, or concomitant medications for developing liver injury upon consuming TC. If there are continued reports of liver injury associated with TC consumption, the hepatology community should consider a systematic approach to investigate the risk factors and optimal ways to mitigate the risk. All three authors contributed equally to this editorial. Dr. Björnsson reports no conflicts of interest. Dr. Navarro reports no conflicts of interest related to this paper. Dr. Chalasani declares no conflicts of interests related to this paper. For disclosure, Dr. Chalasani has had paid consulting agreements with Abbvie, Zydus, Galectin, Madrigal, Foresite, Altimmune, and Boehringer-Ingelheim. He receives research grant support from Exact Sciences, DSM , and Galectin. He has equity ownership in RestUp, LLC, a healthcare placement start-up company.

Remarks on “Herbal Immune Booster-Induced Liver Injury in the COVID-19 Pandemic - A Case Series”

Abstract: We read the case series by Nagral et al.1Nagral A. Adhyaru K. Rudra O.S. Gharat A. Bhandare S. Herbal Immune Booster-Induced Liver Injury in the COVID-19 Pandemic - A case series.J Clin Exp Hepatol. 2021; https://doi.org/10.1016/j.jceh.2021.06.021Abstract Full Text Full Text PDF Scopus (25) Google Scholar in “JCEH” with great interest, wherein the authors have reported six cases with drug-induced autoimmune-like hepatitis and proclaimed it secondary to the consumption of Tinospora cordifolia (TC). The case series has highlighted a very limited set of observations without covering several beneficial aspects of TC.1.There is published evidence in animal models and clinical studies suggesting TC as a safe and natural remedy for hepatoprotection.2Sharma V. Pandey D. Protective role of Tinospora cordifolia against lead-induced hepatotoxicity.Toxicol Int. 2010; 17 (https://doi.org/10.4103/0971-6580.68343. PMID: 21042467; PMCID: PMC2964743): 12-17Crossref PubMed Scopus (57) Google Scholar, 3Upadhyay A.K. Kumar K. Kumar A. Mishra H.S. Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi) - validation of the Ayurvedic pharmacology through experimental and clinical studies.Int J Ayurveda Res. 2010; 1 (https://doi.org/10.4103/0974-7788.64405. PMID: 20814526; PMCID: PMC2924974): 112-121Crossref PubMed Google Scholar, 4Kavitha B.T. Shruthi S.D. Rai S.P. Ramachandra Y.L. Phytochemical analysis and hepatoprotective properties of Tinospora cordifolia against carbon tetrachloride-induced hepatic damage in rats.J Basic Clin Pharm. 2011 Jun; 2 (Epub 2011. PMID: 24826014; PMCID: PMC3979222): 139-142PubMed Google Scholar, 5Bishayi B. Roychowdhury S. Ghosh S. Sengupta M. Hepatoprotective and immunomodulatory properties of Tinospora cordifolia in CCl4 intoxicated mature albino rats.J Toxicol Sci. 2002; 27 (https://doi.org/10.2131/jts.27.139, PMID: 12238138): 139-146Crossref PubMed Scopus (129) Google Scholar, 6Sharma B. Dabur R. Protective effects of Tinospora cordifolia on hepatic and gastrointestinal toxicity induced by chronic and moderate alcoholism.Alcohol Alcohol. 2016; 51 (https://doi.org/10.1093/alcalc/agv130. Epub 2015 Nov 19. PMID: 26589585): 1-10Crossref PubMed Scopus (23) Google Scholar2.Nagral et al. do not clarify from the patient’s history, which variety of Tinospora was consumed by the patient, as the two varieties (T. cordifolia and T. crispa) look similar in the morphology, and people may mistake T. crispa for T. cordifolia.7Sharma R. Bolleddu R. Maji J.K. Ruknuddin G. Prajapati P.K. In-vitro α-amylase, α-glucosidase inhibitory activities and in-vivo anti-hyperglycemic potential of different dosage forms of Guduchi (Tinospora Cordifolia [Willd.] Miers) prepared with Ayurvedic Bhavana Process.Front Pharmacol. 2021 May 10; 12 (https://doi.org/10.3389/fphar.2021.642300. PMID: 34040519; PMCID: PMC8141809): 642300Crossref PubMed Scopus (20) Google Scholar T. cordifolia is referred to as Giloy in Ayurveda; however, T. crispa is known to be hepatotoxic.8Huang W.T. Tu C.Y. Wang F.Y. Huang S.T. Literature review of liver injury induced by Tinospora crispa associated with two cases of acute fulminant hepatitis.Complement Ther Med. 2019; 42 (https://doi.org/10.1016/j.ctim.2018.11.028. Epub 2018 Dec 6. PMID: 30670256): 286-291Crossref PubMed Scopus (18) Google Scholar,9Langrand J. Regnault H. Cachet X. et al.Toxic hepatitis induced by a herbal medicine: Tinospora crispa.Phytomedicine. 2014 Jul-Aug; 21 (https://doi.org/10.1016/j.phymed.2014.04.031. Epub 2014 24. PMID: 24867504): 1120-1123Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar The same concern about the nature of the prescribed medicine has also been raised by Ministry of AYUSH in a press release.10Press Information Bureau, Government of India. https://pib.gov.in/PressReleasePage.aspx?PRID=1733260, last accessed on August 14 2021.Google Scholar3.Case 1 may have self-consumed TC in excess. The reported findings of drug-induced liver injury (DILI) are further weakened as the patient took two additional herbs in an undefined dosage. Cases 2 and 4 were diabetic, Case 3 had beta-thalassemia minor, while Cases 5 and 6 had hypothyroidism, which are also confounders. Therefore, presenting TC as a sole factor for autoimmunity development in these patients has confounding factors. Further, the authors have mentioned that certain non-hepatotropic viruses were not tested in the study, which could alter the findings.4.Cases 2 to 6 might be taking some concomitant conventional medications (unclear from the publication) e.g. for diabetes and hypothyroidism, which may be associated with DILI as confounders.11Kawakami T. Tanaka A. Negoro S. et al.Liver injury induced by levothyroxine in a patient with primary hypothyroidism.Intern Med. 2007; 46 (https://doi.org/10.2169/internalmedicine.46.0086. Epub 2007 Jul 17. PMID: 17634708): 1105-1108Crossref PubMed Scopus (12) Google Scholar,12Stine J.G. Lewis J.H. Drug-induced liver injury: a summary of recent advances.Expert Opin Drug Metab Toxicol. 2011 Jul; 7 (https://doi.org/10.1517/17425255.2011.577415. Epub 2011 Apr 21. PMID: 21510822): 875-890Crossref PubMed Scopus (49) Google Scholar Effect of all drugs and drug-drug interactions on liver health should have been discussed.5.All cases had a history of unsupervised consumption of TC. Four cases consumed twigs (undefined amount), while Ayurveda clearly advocates using thumb-sized mature stems.7Sharma R. Bolleddu R. Maji J.K. Ruknuddin G. Prajapati P.K. In-vitro α-amylase, α-glucosidase inhibitory activities and in-vivo anti-hyperglycemic potential of different dosage forms of Guduchi (Tinospora Cordifolia [Willd.] Miers) prepared with Ayurvedic Bhavana Process.Front Pharmacol. 2021 May 10; 12 (https://doi.org/10.3389/fphar.2021.642300. PMID: 34040519; PMCID: PMC8141809): 642300Crossref PubMed Scopus (20) Google Scholar Two cases consumed commercial syrup and tablet with TC as one of the ingredients where a chance of adulteration is possible. Excessive, prolonged, and unscrupulous use of any herb could be dangerous. Ayurveda does not recommend the continuous unsupervised use of TC for several months. Also, the methods to prepare a decoction or any dosage form and administration methods are unique in Ayurveda, and such medications should be taken only under the supervision of a qualified physician.7Sharma R. Bolleddu R. Maji J.K. Ruknuddin G. Prajapati P.K. In-vitro α-amylase, α-glucosidase inhibitory activities and in-vivo anti-hyperglycemic potential of different dosage forms of Guduchi (Tinospora Cordifolia [Willd.] Miers) prepared with Ayurvedic Bhavana Process.Front Pharmacol. 2021 May 10; 12 (https://doi.org/10.3389/fphar.2021.642300. PMID: 34040519; PMCID: PMC8141809): 642300Crossref PubMed Scopus (20) Google Scholar,12Stine J.G. Lewis J.H. Drug-induced liver injury: a summary of recent advances.Expert Opin Drug Metab Toxicol. 2011 Jul; 7 (https://doi.org/10.1517/17425255.2011.577415. Epub 2011 Apr 21. PMID: 21510822): 875-890Crossref PubMed Scopus (49) Google Scholar6.The authors have not studied whether the patients had subclinical COVID-19 infection. It is also quite possible these 6 patients already were suffering from an autoimmune condition that may have manifested due to drug-drug interactions after consumption of over-the-counter TC-based preparations. Contrary to widespread belief, natural products with medicinal value are not always safe. One needs to be cautious while administering herbal medications, and administration should always be under the supervision of a trained physician in prescribed doses.13Sharma R. Galib Prajapati P.K. Remarks on "Tinospora cordifolia: one plant, many roles".Anc Sci Life. 2014; 33 (https://doi.org/10.4103/0257-7941.144627. PMID: 25538358; PMCID: PMC4264311): 194PubMed Google Scholar We recommend that Ayurvedic guidelines for therapeutic use should be followed, and hazards of misuse of any Ayurvedic herbal medicine should be clearly understood before projecting it as “unsafe” or “toxic.” It seems that the author’s claim of the TC inducing liver injury is not substantiated, and they have not accounted for many important basic criteria to conclude the hepatotoxicity of the drug. Conceptualization, data collection, and writing - original manuscript, R.S.; Editing and proofreading, P.K.P. All authors approved submission of the final manuscript. The authors have none to declare.

Hepatoprotective Effects of Aureobasidium pullulans Derived β 1,3-1,6 Glucans in a Murine Model of Non-alcoholic Steatohepatitis.

Abstract: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent conditions characterized by inflammation and fibrosis of the liver, which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Conventional modalities are mainly symptomatic, with no definite solution. Beta-glucan-based biological response modifiers are a potential strategy in lieu of their beneficial metabolic effects. Aureobasidium pullulans strains AFO-202 and N-163 beta-glucans were evaluated for anti-fibrotic and anti-inflammatory hepatoprotective potentials in a NASH animal model in this study.In the STAM™ murine model of NASH, five groups were studied for 8 weeks: (1) vehicle (RO water), (2) AFO-202 beta-glucan; (3) N-163 beta-glucan, (4) AFO-202+N-163 beta-glucan, and (5) telmisartan (standard pharmacological intervention). Evaluation of biochemical parameters in plasma and hepatic histology including Sirius red staining and F4/80 immunostaining were performed.AFO-202 beta-glucan significantly decreased inflammation-associated hepatic cell ballooning and steatosis. N-163 beta-glucan decreased fibrosis and inflammation significantly (P value < 0.05). The combination of AFO-202 with N-163 significantly decreased the NAFLD Activity Score (NAS) compared with other groups.This preclinical study supports the potential of N-163 and AFO-202 beta-glucans alone or in combination as potential preventive and therapeutic agent(s), for NASH.

Epidemiology and Disease Burden of Alcohol Associated Liver Disease.

Abstract: Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol consumption. Moreover, the burden of alcohol associated liver disease (ALD) accounts for 5.1% of all disease and injury worldwide. Alcohol use disorder (AUD) affects men more than women globally with significant years of life loss to disability in low, middle and well-developed countries. Precise data on global estimates of alcohol related steatosis, alcohol related hepatitis, and alcohol related cirrhosis have been challenging to obtain. In the United States (US), alcohol related steatosis has been estimated at 4.3% based on NHANES data which has remained stable over 14 years. However, alcohol-related fibrotic liver disease has increased over the same period. In those with AUD, the prevalence of alcohol related hepatitis has been estimated at 10-35%. Globally, the prevalence of alcohol-associated cirrhosis has been estimated at 23.6 million individuals for compensated cirrhosis and 2.46 million for those with decompensated cirrhosis. The contribution of ALD to global mortality and disease burden of liver related deaths is substantial. In 2016 liver disease related to AUD contributed to 50% of the estimated liver disease deaths for age groups 15 years and above. Data from the US report high cost burdens associated with those admitted with alcohol-related liver complications. Finally, the recent COVID-19 pandemic has been associated with marked increase in alcohol consumption worldwide and will likely increase the burden of ALD.

Post-COVID-19 Cholangiopathy: A Systematic Review

Abstract: What is known?•A strong correlation between liver injury and COVID-19 infection.•COVID-19 has an affinity to ACE-2 receptors on the hepatocytes.•Little is known about COVID-19-induced injury to cholangiocytes. What is new here?•Post-COVID-19 cholangiopathy (PCC) is rare.•Review the demographics, presentation, and natural history of PCC.•Review of the evidence and mechanism of injury related to PCC.•Identify potential risk factors for PCC.•Clarify the evidence behind the role of liver transplantation for patients with PCC. ObjectivesPost-COVID-19 cholangiopathy (PCC) is a rare but poorly understood and serious complication of COVID-19 infection. We sought to better understand the epidemiology, mechanism of action, histology, imaging findings, and outcomes of PCC.MethodsWe searched PubMed, Cochrane Library, Embase, and Web of Science from December 2019 to December 2021. Mesh words used “post-Covid-19 cholangiopathy,” “COVID-19 liver injury,” “Covid-19 and cholangiopathy,” and “COVID-19 liver disease.” The data on epidemiology, mechanism of action, histology, imaging findings, and outcomes were collected.ResultsPCC was reported in 30 cases during the study period. The mean (standard deviation [SD]) age was 53.7 (5). Men accounted for cases (83.3%). All patients had required intensive level of care and mechanical ventilation. Mean (SD) number of days from COVID infection to severe disease or liver disease was 63.5 (38). Peak mean (SD) alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin were 2014 (831.8) U/L, 1555 (2432.8) U/L, 899.72 (1238.6) U/L, and 10.32 (9.32) mg/dl, respectively. Four patients successfully underwent liver transplantation.ConclusionPCC is a severe and progressive complication of COVID-19 infection. More research is needed to better understand the pathophysiology and best treatment approach. Clinicians should suspect PCC in patients with cholestatic liver injury following COVID-19 infection. Post-COVID-19 cholangiopathy (PCC) is a rare but poorly understood and serious complication of COVID-19 infection. We sought to better understand the epidemiology, mechanism of action, histology, imaging findings, and outcomes of PCC. We searched PubMed, Cochrane Library, Embase, and Web of Science from December 2019 to December 2021. Mesh words used “post-Covid-19 cholangiopathy,” “COVID-19 liver injury,” “Covid-19 and cholangiopathy,” and “COVID-19 liver disease.” The data on epidemiology, mechanism of action, histology, imaging findings, and outcomes were collected. PCC was reported in 30 cases during the study period. The mean (standard deviation [SD]) age was 53.7 (5). Men accounted for cases (83.3%). All patients had required intensive level of care and mechanical ventilation. Mean (SD) number of days from COVID infection to severe disease or liver disease was 63.5 (38). Peak mean (SD) alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin were 2014 (831.8) U/L, 1555 (2432.8) U/L, 899.72 (1238.6) U/L, and 10.32 (9.32) mg/dl, respectively. Four patients successfully underwent liver transplantation. PCC is a severe and progressive complication of COVID-19 infection. More research is needed to better understand the pathophysiology and best treatment approach. Clinicians should suspect PCC in patients with cholestatic liver injury following COVID-19 infection.

Recognizing Dysfunctional Innate and Adaptive Immune Responses Contributing to Liver Damage in Patients With Cirrhosis

Abstract: The human host immune system wards off attacks by enemies such as viruses by mounting an inflammatory response which may sometimes injure self-tissues. Dysfunctional immune/inflammatory response by the host may affect the functioning of vital organs. The largest number of innate immune cells in the body resides in the liver. On encountering a new insult or injury to the liver, the innate immune system responds quickly to counter it. Acute liver insults may trigger acute liver failure or acute on chronic liver failure; these disorders are associated with a predominant innate immune response. Activation of the reticuloendothelial system (part of the innate immune response) predicts short-term and medium-term survival in patients with acute on chronic liver failure. Liver diseases associated with an aberrant adaptive immune response like autoimmune hepatitis respond well to treatment with steroids and other immunosuppressants, while those associated with innate immune dysfunction like acute on chronic liver failure do not respond well to steroids; recent reports suggest that the latter disorders may respond to therapeutic plasma exchange. How does the immune system in a patient with liver disease respond to SARS CoV2 infection? While commonly used tests in routine clinical practice provide clues to activation of different arms of immune response in patients with cirrhosis, specialized tests may help characterize this further. This review discusses the tests which reflect aberrant immune responses and treatment of patients with cirrhosis.

New Portal Vein Thrombosis in Cirrhosis - is the Thrombophilia Exacerbated due to Vaccine or COVID-19?

Abstract: Portal vein thrombosis (PVT), defined as thrombosis of the main portal vein (PV), or its branches or the splenic vein (SV) or superior mesenteric vein (SMV) of the spleno-portal axis, is a well-known complication of the hypercoagulable state of cirrhosis.1Northup P.G. Garcia-Pagan J.C. Garcia-Tsao G. et al.Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American association for the study of liver diseases.Hepatology. 2021; 73: 366-413https://doi.org/10.1002/hep.31646Crossref PubMed Scopus (175) Google Scholar However, thrombosis of deep veins, pulmonary microcirculation, and arterial thrombosis has also been reported as a consequence of COVID-19 infection or vaccination.2Rico-Mesa J.S. Rosas D. Ahmadian-Tehrani A. White A. Anderson A.S. Chilton R. The role of anticoagulation in COVID-19-induced hypercoagulability.Curr Cardiol Rep. 2020; 22: 53https://doi.org/10.1007/s11886-020-01328-8Crossref PubMed Scopus (68) Google Scholar The post-COVID-19 thrombophilia is of great relevance in hepatology practice as it predisposes to PVT related increased portal pressures and variceal bleeding, hepatic venous outflow tract obstruction, or post-transplant vascular complications.3Premkumar M. Sarin S.K. Current concepts in coagulation profile in cirrhosis and acute-on-chronic liver failure.Clin Liver Dis (Hoboken). 2020; 16: 158-167https://doi.org/10.1002/cld.976Crossref PubMed Scopus (14) Google Scholar Herein we report six cases of new-onset PVT, who were on hepatocellular carcinoma (HCC) surveillance imaging and were diagnosed with new main PVT or branch PVT following COVID 19 infection in three cases and following vaccination with ChAdOx1 nCoV-19 Coronavirus vaccine (recombinant)in three cases. The surveillance protocol at our institute is based on Ultrasound Doppler imaging every 3 months and a semi-annual triple computed tomography (CT) or magnetic resonance imaging (MRI). All 6 patients had confirmed PVT on either CT or MRI (Table 1). The mean time since the last screening imaging was 95 ± 22.5 days.Table 1Clinical Characteristics of the 6 Patients Who Presented with New Onset PVT.Patient DetailsCase 1Case 2Case 3Case 4Case 5Case 6Age (Years)384553555648SexMaleMaleMaleFemaleFemaleMaleEtiology of Liver DiseaseEthanolEthanolEthanolHCVNAFLDNAFLDCo morbidityNoneHypertensionNoneNoneDiabetes mellitusDiabetes mellitusCOVID19 InfectionYesYesNoYesYesNoSeverity of COVID-infectionMildModerate (Oxygen requiring)Moderate (Oxygen requiring)MildVaccinationNoNoYesYesNoYesNumber of doses received112Use of anticoagulation in the last 6 monthsNoNoNoYes. 5 days of LMW heparin.NoNoUse of Steroids in the last 6 monthsNoNoNoNoYesNoTime period between COVID19 to detection of PVT (Days)7090NA9060NATime period between COVID19 vaccination to detection of PVT (Days)NANA11060NA90Time period between date of last surveillance ultrasound Doppler examination till detection of new PVT (Days)12090609090120PVTMainMainEccentric PVTBranchMainMainSMVTNoNoYesNoNoNoSTNoNoYesNoNoNoPresentationPainVariceal BleedingPainIncreasing ascitesVariceal BleedingNew onset ascitesOther DecompensationAscitesHepatic EncephalopathyAscitesCTP999121312MELDNa111314151818COVID antibody titre (CLIA)14.912.5Not done8.5Not done7.45JAK2 mutationNegativeNegativeNegativeNegativeNegativeNegativeFactor V Leiden mutationNegativeNegativeNegativeNegativeNegativeNegativeTreatmentOn Variceal EradicationOn Variceal EradicationOn DabigatranExpired due to secondary sepsis, bacterial pneumoniaExpired due to systemic sepsis, difficult to treat SBP.On variceal eradicationHill’s CriteriaTemporality++++++++++++Biological Plausibility++++++++Likelihood of causal relationship with VaccineProbable associationPossible associationProbable associationAbbreviations: CTP, Child Turcotte Pugh score; CLIA, chemiluminescent immunoassay; JAK2, Janus kinase 2 gene mutation; PVT, portal vein thrombosis; LMWH, low molecular weight heparin; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; SBP, spontaneous bacterial peritonitis. Open table in a new tab Abbreviations: CTP, Child Turcotte Pugh score; CLIA, chemiluminescent immunoassay; JAK2, Janus kinase 2 gene mutation; PVT, portal vein thrombosis; LMWH, low molecular weight heparin; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; SBP, spontaneous bacterial peritonitis. These patients were aged 49.1 ± 7.7 years, 3 (50%) were ethanol related, 66.6% were male, with 2 patients with nonalcoholic fatty liver disease (NAFLD) having diabetes mellitus and one having hypertension as comorbidities. None of the patients had associated HCC, and all tested negative for JAK2 and Factor V Leiden mutation. One patient presented with acute variceal bleeding requiring endotherapy, while the others had mild epigastric pain. Table 1 summarizes the clinical presentations and timeline to thrombosis of each patient. Using Hill’s criteria to establish causality, a probable association was found for two of the patients who had strong temporal association of developing PVT after vaccination. A detailed drug history did not reveal the use of any medicine that could have caused thrombosis. Although cirrhosis per se is a procoagulant condition, we were unable to find any other confounders or underlying hematological conditions that could have caused the PVT. Figure 1 shows the imaging of patients 3, 4, and 6, which shows the acute PVT and early formation of collaterals. This case series illustrates the thrombophilia that is associated with the COVID-19 infection per se and reported with the ChAdOx1 nCoV-19 Coronavirus vaccine. It is not possible to establish causality, although all patients tested negative for COVID-19 on RT PCR test at the time of the PVT diagnosis, four of them had prior COVID-19 illness, some of the others who were subsequently vaccinated may have had undiagnosed subclinical COVID-19 infection in the past.4Kulkarni A.V. Tevethia H.V. Premkumar M. et al.Impact of COVID-19 on liver transplant recipients-A systematic review and meta-analysis.EClinicalMedicine. 2021; 38: 101025https://doi.org/10.1016/j.eclinm.2021.101025Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Nonetheless, this case series shows data that suggests clinicians should be cognizant of vascular complications following COVID-19, and/or vaccination and should assess for venous thrombosis specifically in all patients with cirrhosis, as early diagnosis and treatment with suitable anticoagulation can improve outcomes.5Huh K. Na Y. Kim Y.E. Radnaabaatar M. Peck K.R. Jung J. Predicted and observed incidence of thromboembolic events among Koreans vaccinated with ChAdOx1 nCoV-19 vaccine.J Korean Med Sci. 2021; 36: e197https://doi.org/10.3346/jkms.2021.36.e197Crossref PubMed Scopus (13) Google Scholar The incidence of thrombotic disease in patients with COVID-19 is as high as 31% and affects overall outcomes.2Rico-Mesa J.S. Rosas D. Ahmadian-Tehrani A. White A. Anderson A.S. Chilton R. The role of anticoagulation in COVID-19-induced hypercoagulability.Curr Cardiol Rep. 2020; 22: 53https://doi.org/10.1007/s11886-020-01328-8Crossref PubMed Scopus (68) Google Scholar In our series on patients with COVID-19, we used global coagulation tests to identify and treat patients with a hypercoagulable profile with systemic anticoagulation. Of 215 patients with COVID -19, 74 patients requiring intensive care (53 ± 16 years; 64%male) were recruited. The patients were divided into three groups with 11 (14.9%), 34 (45.9% and 29 (39.2%) on low-flow O2 therapy, high-flow O2 therapy, and invasive ventilation, respectively. A procoagulant profile was seen in 45.5%, 32.4%, and 20.7% in low-flow, high-flow, and invasive ventilation.6Premkumar M, Loganathan S, Hazarika A, et al. Hypocoagulable Coagulation Profile and Endogenous Heparinoids Are Associated with Invasive Ventilation and Mortality in COVID-19. Available at SSRN: https://ssrn.com/abstract=3802514 or https://doi.org/10.2139/ssrn.3802514.Google Scholar We were able to perform COVID antibody testing for 4 (66%) patients, all of whom were reactive for the same. In conclusion, the key message that needs to be propagated is that COVID-19 vaccines are safe and prevent deaths due to SARS-CoV-2. All eligible patients with chronic liver disease should be offered vaccination to protect them from COVID-19-related mortality. However, the thrombotic perturbations uncovered in the COVID-19 era have critical relevance for patients with cirrhosis and surveillance for venous and arterial thromboembolism needs to be incorporated in clinical practice in the post-COVID era.7Kantarcioglu B. Iqbal O. Walenga J.M. et al.An update on the pathogenesis of COVID-19 and the reportedly rare thrombotic events following vaccination.Clin Appl Thromb Hemost. 2021; 27 (10760296211021498. https://doi.org/10.1177/10760296211021498)Crossref Scopus (29) Google Scholar MP: concept, writing, and critical revision, HB, VS, AD: writing and critical revision; TK, HB, SBC: Radiological tests, writing, and critical revision, HK: Data collection and hematological tests. The authors have none to declare. The authors received no financial support to produce this manuscript. Informed Consent was taken from the patients before writing the manuscript, and all images have been suitably anonymized.

Surgical Risk Assessment in Patients with Chronic Liver Diseases.

Abstract: Chronic liver diseases (CLD) is one of the leading causes of morbidity and mortality. The overall life span of patients with CLD has increased and so is the number of surgical procedures these patients undergo. Pathophysiological and hemodynamic changes in cirrhosis make these patients more susceptible to hypotension and hypoxia during surgery. They also have a high risk of drug induced liver injury, renal dysfunction and post-operative liver decompensation. Patients with CLD planned for elective or semi-elective surgery should undergo detailed preoperative risk assessment. Patients should be evaluated for the presence of clinically significant portal hypertension and cirrhosis. In the absence of both cirrhosis and clinically significant portal hypertension, patients with CLD can undergo surgery with minimal or low risk. Various risk assessment tools available for patients with advanced CLD are-CTP score, MELD Score, Mayo risk score, VOCAL-Penn score. A Child class C and/or Mayo risk score >15 in general is associated with high risk of post-operative mortality and elective surgery should be deferred in these patients. In patients with Child class, A and MELD 10-15 surgery is permissible with caution (except liver resection and cardiac surgery) while in Child A and MELD <10 surgery is well tolerated. VOCAL-Penn score is a new promising tool and can be the better alternative of CTP, MELD, and Mayo risk score models but more prospective studies with large patients' population are warranted. Certain surgeries like Hepatic resection, intraabdominal, and cardiothoracic have higher risk than abdominal wall hernia repair and orthopedic surgery. Laparoscopic approaches have better outcomes and less risk of liver failure than open surgery. Minimally invasive alternatives like colonic stent placement in case of obstruction can be considered in high-risk cases. Perioperative optimization and management of ascites, HE, bleeding, liver decompensation, and nutrition should be done with multidisciplinary approach. Patients with cirrhosis undergoing high risk elective surgery can develop liver failure in post-operative period and should be evaluated and counseled for liver transplantation if not contraindicated.

Saroglitazar for Nonalcoholic Fatty Liver Disease: A Single Centre Experience in 91 Patients

Abstract: BackgroundSaroglitazar is a novel, dual peroxisome proliferator-activated receptors-α/γ agonist and is being investigated for the treatment of nonalcoholic fatty liver disease (NAFLD).Patients and methodsConsecutive overweight (body mass index [BMI] >23 kg/m2) patients of NAFLD, diagnosed based on controlled attenuation parameter (CAP) >248 dB/m, and attending the outpatient department of a tertiary care centre in New Delhi, were enrolled. Patients with cirrhosis (liver stiffness measurement [LSM] >13.5 kPa) and those with concomitant liver disease due to other aetiologies (alcohol, viral, etc.) were excluded. All patients received saroglitazar 4 mg/day; in addition, they were advised to reduce weight and were counselled regarding diet and exercise. At 3-month follow-up, patients were categorized into those who were able to reduce ≥5% body weight and those who could n’ot, and both these groups were compared.ResultsA total of 91 patients (median age 45 years [range 18–66 years]; 81% men) were included in the study. The median BMI was 29.3 kg/m2 (range 23.6–42.2 kg/m2). The baseline median (range) aspartate transaminase, alanine transaminase, gamma glutamyl transferase, LSM and CAP values were 40 IU/dL (range 22–144 IU/dL), 48 IU/dL (range 13–164 IU/dL), 42 IU/dL (range 4–171 IU/dL), 6.7 kPa (range 3.6–13.1 kPa), and 308 dB/m (range 249–400 dB/m). All patients tolerated saroglitazar well. At 3-month, 57 patients (63%) were able to reduce ≥5% weight, whereas in the remaining 34 patients (37%), the weight reduction was <5% from baseline. Transaminases values improved in both the groups; however, LSM and CAP values improved only in patients who reduced weight.ConclusionIn overweight patients with NAFLD, a 3-month therapy with saroglitazar is able to improve transaminases but not LSM and CAP values unless accompanied by weight reduction of at least 5%. Larger randomized controlled trials are needed to document the independent effect of saroglitazar in these patients. Saroglitazar is a novel, dual peroxisome proliferator-activated receptors-α/γ agonist and is being investigated for the treatment of nonalcoholic fatty liver disease (NAFLD). Consecutive overweight (body mass index [BMI] >23 kg/m2) patients of NAFLD, diagnosed based on controlled attenuation parameter (CAP) >248 dB/m, and attending the outpatient department of a tertiary care centre in New Delhi, were enrolled. Patients with cirrhosis (liver stiffness measurement [LSM] >13.5 kPa) and those with concomitant liver disease due to other aetiologies (alcohol, viral, etc.) were excluded. All patients received saroglitazar 4 mg/day; in addition, they were advised to reduce weight and were counselled regarding diet and exercise. At 3-month follow-up, patients were categorized into those who were able to reduce ≥5% body weight and those who could n’ot, and both these groups were compared. A total of 91 patients (median age 45 years [range 18–66 years]; 81% men) were included in the study. The median BMI was 29.3 kg/m2 (range 23.6–42.2 kg/m2). The baseline median (range) aspartate transaminase, alanine transaminase, gamma glutamyl transferase, LSM and CAP values were 40 IU/dL (range 22–144 IU/dL), 48 IU/dL (range 13–164 IU/dL), 42 IU/dL (range 4–171 IU/dL), 6.7 kPa (range 3.6–13.1 kPa), and 308 dB/m (range 249–400 dB/m). All patients tolerated saroglitazar well. At 3-month, 57 patients (63%) were able to reduce ≥5% weight, whereas in the remaining 34 patients (37%), the weight reduction was <5% from baseline. Transaminases values improved in both the groups; however, LSM and CAP values improved only in patients who reduced weight. In overweight patients with NAFLD, a 3-month therapy with saroglitazar is able to improve transaminases but not LSM and CAP values unless accompanied by weight reduction of at least 5%. Larger randomized controlled trials are needed to document the independent effect of saroglitazar in these patients.

“Does Transaminitis Predict Severity and Mortality in COVID 19 Patients?”

Abstract: BackgroundThe most dreaded pandemic grappling world now, the Coronavirus Disease 2019 (COVID-19), chiefly involves the respiratory system; nevertheless, it is a multisystem disorder. Its involvement of the hepatic system is considerable; however, still emerging are its clinical implications and the effects on morbidity and mortality.AimThe aim of this study is to report on the various aspects of its hepatic involvement by describing the alterations in tests of liver function and its significance in the disease outcome in a cohort of hospitalized COVID-19 patients at a tertiary center in northern India.MethodsThis is a retrospective cohort study conducted in a tertiary-care hospital in northern India. All confirmed hospitalized COVID-19 cases aged 15 and above from Apr to Oct 2020 with no pre-existing liver disease were included. The primary endpoint was death at 28 days. Statistical analysis included descriptive analysis, sensitivity-specificity, and univariable and multivariable regression analysis as well as survival analysis.ResultsA total of 708 patients with COVID-19 fulfilled the inclusion criteria included 561 (79.2%) males and 147 (20.8%) females. The median age was 49 (IQR = 25) years. Mild and moderate/severe disease were seen in 508 (71.8%) and 200 (28.2) patients, respectively. Serum bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were elevated in 6.92%, 69.91%, and 80.22% of patients, respectively. In univariable logistic regression, AST [odds ratio; OR 1.008 95% CI (1.005–1.012) per 1 IU/L increase] and ALT [OR 1.005 95% CI (1.002–1.007) per 1 IU/L increase] were significantly associated with the odds of moderate to severe disease but only AST was significant after adjustment to age, sex, and comorbidity [adjusted odds ratio; aOR 1.007 95% CI (1.003–1.011) per 1 IU/L increase]. Serum albumin was negatively associated with the odds of moderate to severe disease and remained significant in the adjusted model [aOR 0.217 95%CI (0.149–0.316) per 1 g/dL increase].Ninety-six patients succumbed to illness [case fatality rate; CFR 13.6%). In adjusted Cox Proportional-Hazards Model for mortality, AST [adjusted hazard ratio; aHR 1.002 95% CI (1.000–1.003) per 1 IU/L increase] and serum albumin [aHR 0.396 95% CI (0.285–0.549) per 1 g/dL increase] showed significant association with mortality.ConclusionLiver function abnormalities are common in patients with COVID-19. In particular, AST and serum albumin levels are effective predictors of disease severity and mortality and can be used as markers of fatal disease in the management as well as prognostication of COVID-19. The most dreaded pandemic grappling world now, the Coronavirus Disease 2019 (COVID-19), chiefly involves the respiratory system; nevertheless, it is a multisystem disorder. Its involvement of the hepatic system is considerable; however, still emerging are its clinical implications and the effects on morbidity and mortality. The aim of this study is to report on the various aspects of its hepatic involvement by describing the alterations in tests of liver function and its significance in the disease outcome in a cohort of hospitalized COVID-19 patients at a tertiary center in northern India. This is a retrospective cohort study conducted in a tertiary-care hospital in northern India. All confirmed hospitalized COVID-19 cases aged 15 and above from Apr to Oct 2020 with no pre-existing liver disease were included. The primary endpoint was death at 28 days. Statistical analysis included descriptive analysis, sensitivity-specificity, and univariable and multivariable regression analysis as well as survival analysis. A total of 708 patients with COVID-19 fulfilled the inclusion criteria included 561 (79.2%) males and 147 (20.8%) females. The median age was 49 (IQR = 25) years. Mild and moderate/severe disease were seen in 508 (71.8%) and 200 (28.2) patients, respectively. Serum bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were elevated in 6.92%, 69.91%, and 80.22% of patients, respectively. In univariable logistic regression, AST [odds ratio; OR 1.008 95% CI (1.005–1.012) per 1 IU/L increase] and ALT [OR 1.005 95% CI (1.002–1.007) per 1 IU/L increase] were significantly associated with the odds of moderate to severe disease but only AST was significant after adjustment to age, sex, and comorbidity [adjusted odds ratio; aOR 1.007 95% CI (1.003–1.011) per 1 IU/L increase]. Serum albumin was negatively associated with the odds of moderate to severe disease and remained significant in the adjusted model [aOR 0.217 95%CI (0.149–0.316) per 1 g/dL increase]. Ninety-six patients succumbed to illness [case fatality rate; CFR 13.6%). In adjusted Cox Proportional-Hazards Model for mortality, AST [adjusted hazard ratio; aHR 1.002 95% CI (1.000–1.003) per 1 IU/L increase] and serum albumin [aHR 0.396 95% CI (0.285–0.549) per 1 g/dL increase] showed significant association with mortality. Liver function abnormalities are common in patients with COVID-19. In particular, AST and serum albumin levels are effective predictors of disease severity and mortality and can be used as markers of fatal disease in the management as well as prognostication of COVID-19.

COVID-19 Masquerading as Autoimmune Hepatitis (AIH) Flare—The First Report

Abstract: Liver involvement is well known in coronavirus disease-2019 (COVID-19).1Kulkarni A.V. Kumar P. Tevethia H.V. et al.Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19.Aliment Pharmacol Ther. 2020; ([published online ahead of print, 2020 Jul 8]) (10.1111/apt.15916)https://doi.org/10.1111/apt.15916Crossref Scopus (143) Google Scholar,2Kulkarni A.V. Tevethia H.V. Premkumar M. et al.Impact of COVID-19 on liver transplant recipients-A systematic review and meta-analysis.EClinicalMedicine. 2021; 38: 101025https://doi.org/10.1016/j.eclinm.2021.101025Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar However, there are no reports of COVID-19 leading to autoimmune hepatitis (AIH) flare from India. Here, we present a case of AIH who developed a flare after COVID-19 in the initial days of the pandemic. The idea of COVID-19 induced AIH flare was not accepted, leading to natural death. A 50-year-old man was treated with prednisolone and azathioprine for biopsy-proven AIH (simplified score—7/8) for ten months. He achieved biochemical remission and was on azathioprine (100 mg/day). He now presented with complaints of jaundice, ascites, and altered behavior for seven days. On examination, the patient had icterus, pedal edema, ascites, and flaps. Cross-sectional imaging of the abdomen revealed ascites with altered liver morphology but no evidence of portal vein thrombosis. His SpO2 was 97% at room air. His initial laboratory investigations are as follows: total bilirubin (TB) was 7.8 mg/dl, aspartate transaminase (AST) was 203U/L, alanine transaminase (ALT) was 113 U/L, serum albumin was 2.0 g/dl (N: 3.5–5.1 g/dl), and the international normalized ratio (INR) was 3.17. His total serum immunoglobulin G (IgG) was 5,052 mg/dl. Sepsis screen was negative (Table 1).Table 1Laboratory Investigation of the Patient.VariablesDay of admissionDay 3 (post-steroid)Normal valuesTotal bilirubin (mg/dl)7.83.20.3–1.3Direct bilirubin (mg/dl)4.11.50–0.2Alanine transaminase (U/L)11379Upto 40Aspartate transaminase (U/L)203133Upto 40Alkaline phosphatase (U/L)16110630–120Total protein (g/dl)7.77.5Serum albumin (g/dl)2.02.33.5–5.1Serum creatinine (mg/dl)1.00.7–1.3INR3.172.89<1.3AFP31.9<7Hemoglobin (g/dl)10.613.0–17.0White cell counts (cells/mm3)53004000–10000Platelets (lakh/mm3)1.31.5–4.1Lactate dehydrogenase (U/L)683225–450C-reactive protein (mg/l)5.03<6Procalcitonin (ng/ml)0.37<0.5Hepatitis A (IgM), B (surface antigen), C (antibody), E (IgM)NegativeBlood and urine cultureSterileAscitic fluid evaluationHigh SAAG (1.3), low protein (1.9 g/dl), no SBP (100 cells/mm3)Total IgG (mg/dl)5052791–1643SARS-CoV-2 RT-PCRPositiveINR, international normalized ratio; AFP, alfa-fetoprotein; SAAG, serum ascites albumin gradient; SBP, spontaneous bacterial peritonitis; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RT-PCR, reverse transcriptase–polymerase chain reaction. Open table in a new tab INR, international normalized ratio; AFP, alfa-fetoprotein; SAAG, serum ascites albumin gradient; SBP, spontaneous bacterial peritonitis; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RT-PCR, reverse transcriptase–polymerase chain reaction. The patient was started on antibiotic therapy (cefoperazone), human albumin infusions (20 g/day), and anti-encephalopathy measures. Chest radiography and cardiac echocardiography were normal. Given the high suspicion of AIH flare (with high total IgG) presenting as acute-on-chronic liver failure (ACLF), steroid therapy (intravenous methylprednisolone 40 mg) was initiated. He was planned for a living donor liver transplantation in case of no response. On the third day, laboratory investigations revealed a TB of 3.2 mg/dl, AST of 133 U/L, ALT of 79 U/L, and INR of 2.89. His sensorium improved. Severe acute respiratory syndrome coronavirus-2 reverse transcriptase–polymerase chain reaction was reported as positive on day 4 of admission (performed on the day of admission given the history of travel). C-reactive protein was 5.03 mg/dl. Antibiotic and supportive care was continued. The patient was asymptomatic for six days and was discharged on day 12. At discharge, TB was 2.1 mg/dl with AST, ALT, and IgG of 102 U/L, 42 U/L, and 2,231 mg/dl, respectively. This is the first unique report of COVID-19 masquerading as an AIH flare from India. COVID-19 can lead to ACLF and is associated with poor outcomes.3Kumar P. Sharma M. Sulthana S.F. et al.Severe acute respiratory syndrome coronavirus 2-related acute-on-chronic liver failure.J Clin Exp Hepatol. 2021 May-Jun; 11: 404-406https://doi.org/10.1016/j.jceh.2020.12.007Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar,4Kulkarni A.V. Parthasarathy K. Kumar P. et al.Early liver transplantation after COVID-19 infection: the first report.Am J Transplant. 2021; 21: 2279-2284https://doi.org/10.1111/ajt.16509Crossref PubMed Scopus (32) Google Scholar The abnormalities in liver function tests in COVID-19 could be due to virus-related cytopathic effects or nonviral causes such as cytokine storm, hypoxia, and hepatotoxic medications.1Kulkarni A.V. Kumar P. Tevethia H.V. et al.Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19.Aliment Pharmacol Ther. 2020; ([published online ahead of print, 2020 Jul 8]) (10.1111/apt.15916)https://doi.org/10.1111/apt.15916Crossref Scopus (143) Google Scholar,5Kumar P. Sharma M. Kulkarni A. et al.Pathogenesis of liver injury in coronavirus disease 2019.J Clin Exp Hepatol. 2020; ([published online ahead of print, 2020 May 20])https://doi.org/10.1016/j.jceh.2020.05.006Abstract Full Text Full Text PDF Scopus (19) Google Scholar Steroid therapy probably contained the initial cytokine storm and aided in rapid recovery. Early administration of dexamethasone can reduce the severity of COVID-19.6Villar J. Ferrando C. Martínez D. et al.Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.Lancet Respir Med. 2020; 8: 267-276https://doi.org/10.1016/S2213-2600(19)30417-5Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar It may be argued that the liver chemistry abnormalities can be due to COVID-19 itself; however, the acute development of decompensation with elevated liver enzymes and exponentially high serum IgG suggests COVID-19 induced AIH flare. A transjugular liver biopsy would have added more knowledge about the disease. However, given the sick presentation, a liver biopsy could not be performed at the time of flare. Recently, there are reports of AIH developing after COVID-19 vaccination.7Bril F. Al Diffalha S. Dean M. et al.Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty?.J Hepatol. 2021 Jul; 75: 222-224https://doi.org/10.1016/j.jhep.2021.04.003Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar The vaccines are derivatives of the virus itself.8Khuroo M.S. Khuroo M. Khuroo M.S. Sofi A.A. Khuroo N.S. COVID-19 vaccines: a race against time in the middle of death and devastation!.J Clin Exp Hepatol. 2020; 10: 610-621https://doi.org/10.1016/j.jceh.2020.06.003Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The COVID-19 virus can induce AIH flare in predisposed individuals, as demonstrated in our case report. Similarly, COVID-19 vaccines can lead to AIH because of molecular mimicry in predisposed individuals.9Vojdani A. Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases.Clin Immunol. 2020; 217: 108480https://doi.org/10.1016/j.clim.2020.108480Crossref PubMed Scopus (292) Google Scholar Although patients with AIH and infected with COVID-19 may not have poor outcomes, they need to be identified early for timely intervention.10Efe C. Dhanasekaran R. Lammert C. et al.Outcome of COVID-19 in patients with autoimmune hepatitis: an international multicenter study.Hepatology. 2021; 73: 2099-2109https://doi.org/10.1002/hep.31797Crossref PubMed Scopus (40) Google Scholar COVID-19 should be suspected in patients presenting as AIH flare even in the absence of predominant respiratory symptoms. Yes. Dr. Anand V. Kulkarni is the article guarantor. AVK and PNR made the study concept and design; Data collection by SV and AVK; compilation and critical revision by AVK, MS, DNR and PNR. All members approved the final draft. The authors have none to declare. The authors have none to declare.

Invasive Pulmonary Aspergillosis and Tuberculosis Complicated by Hemophagocytic Lymphohistiocytosis - Sequelae of COVID-19 in a Liver Transplant Recipient

Abstract: Liver transplant recipients are at an increased risk of opportunistic infections due to use of immunosuppression. Coronavirus disease of 2019 (COVID-19) increases the risk of these infections further due to associated immune dysfunction and use of high dose steroids. We present a case of liver transplant recipient who developed disseminated tuberculosis and invasive pulmonary aspergillosis complicated by acquired hemophagocytic lymphohistiocytosis after recovering from severe COVID-19.