Tranexamic acid in upper gastrointestinal bleed in patients with cirrhosis: A randomized controlled trial.

BACKGROUND AND AIMS: Patients with Child-Turcotte-Pugh class B and C cirrhosis with upper gastrointestinal bleeding (UGIB) have systemic as well as localized (in the mucosa of the esophagus and stomach) fibrinolysis. The aim of this study was to evaluate the efficacy and safety of tranexamic acid in the treatment of acute UGIB in patients with cirrhosis. APPROACH AND RESULTS: A total of 600 patients with advanced liver cirrhosis (Child-Turcotte-Pugh class B or C) presenting with UGIB were randomly allocated to either the tranexamic acid (n=300) or the placebo group (n=300). The primary outcome measure was the proportion of patients developing 5-day treatment failure. Failure to control bleeding by day 5 was seen in 19/300 (6.3%) patients in the tranexamic acid group and 40/300 (13.3%) patients in the placebo group ( p =0.006). Esophageal endoscopic variceal ligation (EVL) site as a source of failure to control bleeding by day 5 among patients undergoing first-time esophageal EVL (excluding patients with a previous post-EVL ulcer as a source of bleed) was seen in 11/222 (4.9%) patients in the tranexamic acid group and 27/225 (1212.0%) patients in the placebo group ( p =0.005). However, 5-day and 6-week mortality was similar in the tranexamic acid and placebo groups. CONCLUSIONS: Tranexamic acid significantly reduces the failure to control bleeding by day 5 and failure to prevent rebleeding after day 5 to 6 weeks in patients with advanced liver cirrhosis (Child-Turcotte-Pugh class B or C) presenting with UGIB, by preventing bleeding from the EVL site.

Clinical and Genomic Perspective of SARS CoV-2 Infection in Liver Disease Patients: A Single-Centre Retrospective Study.

The limited literature on the clinical course of COVID-19 among patients with underlying liver disease (LD) is available from India. The present study aimed to evaluate the clinical and mutational profile of SARS-CoV-2 among LD cases. This was a retrospective study including admitted LD cases in whom SARS-CoV-2 RT-PCR testing was performed. Complete demographic and clinical details were retrieved from Hospital Information System. Detailed mutational analysis was performed by comparing LD COVID-19 positive study group, i.e. LD-CoV(+) with COVID-19 positive outpatients without any underlying LD as control, i.e. NLD-CoV(+). Out of 232 enrolled LD cases, 137 (59.1%) were LD-CoV(+). LD cases with existing co-morbidities were affected more (P = 0.002) and had 2.29 times (OR 2.29, CI 95%, 1.25-4.29) higher odds of succumbing to COVID-19 (P = 0.006). On multivariate regression analysis, ascites (P = 0.05), severe COVID-19 pneumonia (P = 0.046), and an increased levels of bilirubin (P = 0.005) and alkaline phosphatase (P = 0.003) were found to be associated with adverse outcome in LD-CoV(+).On mutational analysis, we found certain differences between LD- and NLD-CoV(+) infected with Delta [LD- and NLD-CoV (+ /D)] and Omicron [LD- and NLD-CoV(+/O)]. More mutations were shared between LD- and NLD-CoV(+/O) compared to LD- and NLD-CoV(+/D). There were differences in prevalence of indel mutations specific to LD-CoV ( +) for both Delta and Omicron. Moreover, we also reported an interesting genic bias between LD- and NLD-CoV( +) in harbouring deleterious/tolerated mutations. To conclude, LD cases with comorbidities were affected more and had higher odds of mortality due to COVID-19. The definite difference between LD- and NLD-CoV(+) groups with respect to frequency of harboured mutations and an inherent genic bias between them is of noteworthy importance.

Hepatopulmonary syndrome is associated with low sphingosine-1-phosphate levels and can be ameliorated by the functional agonist fingolimod.

BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS) is characterised by a defect in arterial oxygenation induced by pulmonary vascular dilatation in patients with liver disease. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, suppresses vasodilation by reducing nitric oxide (NO) production. We investigated the role of S1P in patients with HPS and the role of fingolimod as a therapeutic option in an experimental model of HPS. METHODS: Patients with cirrhosis with HPS (n = 44) and without HPS (n = 89) and 25 healthy controls were studied. Plasma levels of S1P, NO, and markers of systemic inflammation were studied. In a murine model of common bile duct ligation (CBDL), variations in pulmonary vasculature, arterial oxygenation, liver fibrosis, and inflammation were estimated before and after administration of S1P and fingolimod. RESULTS: Log of plasma S1P levels was significantly lower in patients with HPS than in those without HPS (3.1 ± 1.4 vs. 4.6 ± 0.2; p <0.001) and more so in severe intrapulmonary shunting than in mild and moderate intrapulmonary shunting (p <0.001). Plasma tumour necrosis factor-α (76.5 [30.3-91.6] vs. 52.9 [25.2-82.8]; p = 0.02) and NO (152.9 ± 41.2 vs. 79.2 ± 29.2; p = 0.001) levels were higher in patients with HPS than in those without HPS. An increase in Th17 (p <0.001) and T regulatory cells (p <0.001) was observed; the latter inversely correlated with plasma S1P levels. In the CBDL HPS model, fingolimod restored pulmonary vascular injury by increasing the arterial blood gas exchange and reducing systemic and pulmonary inflammation, resulting in improved survival (p = 0.02). Compared with vehicle treatment, fingolimod reduced portal pressure (p <0.05) and hepatic fibrosis and improved hepatocyte proliferation. It also induced apoptotic death in hepatic stellate cells and reduced collagen formation. CONCLUSIONS: Plasma S1P levels are low in patients with HPS and even more so in severe cases. Fingolimod, by improving pulmonary vascular tone and oxygenation, improves survival in a murine CBDL HPS model. IMPACT AND IMPLICATIONS: A low level of plasma sphingosine-1-phosphate (S1P) is associated with severe pulmonary vascular shunting, and hence, it can serve as a marker of disease severity in patients with hepatopulmonary syndrome (HPS). Fingolimod, a functional agonist of S1P, reduces hepatic inflammation, improves vascular tone, and thus retards the progression of fibrosis in a preclinical animal model of HPS. Fingolimod is being proposed as a potential novel therapy for management of patients with HPS.

Utility and diagnostic accuracy of intraoperative frozen sections in hepato-pancreato-biliary surgical pathology.

BACKGROUND AND PURPOSE: Hepato-pancreato-biliary (HPB) surgeries are one of the most challenging and complex procedures. Intraoperative frozen section (IFS) diagnosis plays a pivotal role in management decisions. Comprehensive large cohort studies evaluating utility of IFS in HPB malignancies are lacking. This study aimed to evaluate the accuracy of frozen section analysis and to analyse discrepancies and impact of IFS on the surgical decisions. PATIENTS AND METHODS: This was a retrospective study of IFS received for the HPB specimens between years 2009 and 2021. The results were compared to the permanent sections to evaluate diagnostic accuracy, sensitivity and specificity. Indications, disagreements and impact on the surgical management were analysed. RESULTS: A total of 1008 specimens were evaluated: bile duct margin (279; 27.7%), gallbladder (203; 20.1%), liver lesions (125 cases; 12.4%), lymph nodes (147; 14.6%), pancreatic margin (120; 11.9%) and deposits (134; 13.3%). IFS were diagnosed as negative for malignancy (805; 79.9%), positive for dysplasia (8; 0.8%), suspicious for malignancy (6; 0.6%) and positive for malignancy (189; 18.8%). The overall diagnostic accuracy was 98.4%, and the discordant rate was 1.6%. The sensitivity, specificity, positive predictive value and negative predictive value were 94.7%, 99.4%, 97.5% and 98.6% respectively. The most important reason of discordant results was technical, followed by interpretational and sampling errors. CONCLUSION: The study demonstrates high diagnostic accuracy (98.4%) of IFS in a large dataset of HPB specimens. This comprehensive analysis apprises of the indications, errors and the impact of IFS diagnosis on subsequent HPB surgical management.

Incidence, Risk Factors, and Outcomes of Transition of Acute Kidney Injury to Chronic Kidney Disease in Cirrhosis: A Prospective Cohort Study.

Transition to chronic kidney disease (CKD) after an episode of acute kidney injury (AKI) is known in patients without cirrhosis. We studied the incidence and risk factors for development of CKD in patients with cirrhosis. Competing risk analysis was performed to identify risk factors for CKD development. Of 818 patients with cirrhosis (age, 50.4 ± 11.8 years; 84% males; Model for End-Stage Liver Disease [MELD], 19.9 ± 9.9), 36% had AKI at enrollment, 27% had previous AKI, and 61% developed new episodes of AKI during the follow-up period. CKD developed in 269 (33%) patients. Serum cystatin C (CysC; subdistribution hazard ratio [SHR], 1.58; 1.07-2.33), episodes of previous AKI (SHR, 1.26; 1.02-1.56), and AKI stage at enrollment (no AKI [SHR, 1] vs. stage 1 [SHR, 3.28; 1.30-8.25] vs. stage 2 [SHR, 4.33; 1.76-10.66] vs. stage 3 [SHR, 4.5; 1.59-12.73]) were identified as baseline risk factors for CKD development. On time-varying competing risk analysis, MELD (SHR, 1.01; 1.00-1.03), number of AKI episodes (SHR, 1.25; 1.15-1.37), and CysC (SHR, 1.38; 1.01-1.89) predicted CKD development. Development of CKD was associated with higher risk of death. Reduction in glomerular filtration rate (GFR) not meeting CKD criteria was observed in 66% of patients with cirrhosis, more so in those with previous AKI episodes and a high CysC level and MELD score. Renal histology, available in 55 patients, showed tubulointerstitial injury in 86%, cholemic nephrosis in 29%, and glomerular changes in 38%. Conclusion: Almost two-thirds of patients with cirrhosis develop episodes of AKI and reduction in GFR; one-third progress to CKD, resulting in adverse outcomes. Higher MELD and CysC levels and number of AKI episodes predict development of CKD in patients with cirrhosis.

Thromboelastography-Guided Blood Component Use in Patients With Cirrhosis With Nonvariceal Bleeding: A Randomized Controlled Trial.

Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet [PLT] count), and its use may avoid unnecessary blood component transfusion in patients with advanced cirrhosis and significant coagulopathy who have nonvariceal upper gastrointestinal (GI) bleeding. A total of 96 patients with significant coagulopathy (defined in this study as INR >1.8 and/or PLT count < 50 × 109 /L) and nonvariceal upper GI bleed (diagnosed after doing upper gastrointestinal endoscopy, which showed ongoing bleed from a nonvariceal source) were randomly allocated to TEG-guided transfusion strategy (TEG group; n = 49) or standard-of-care (SOC) group (n = 47). In the TEG group, only 26.5% patients were transfused with all three blood components (fresh frozen plasma [FFP], PLTs, and cryoprecipitate) versus 87.2% in the SOC group (P < 0.001). Although 7 (14.3%) patients in the TEG group received no blood component transfusion, there were no such patients in the SOC group (P = 0.012). Also, there was a significantly lower use of blood components (FFP, PLTs, and cryoprecipitate) in the TEG group compared with the SOC group. Failure to control bleed, failure to prevent rebleeds, and mortality between the two groups were similar. Conclusion: In patients with advanced cirrhosis with coagulopathy and nonvariceal upper GI bleeding, TEG-guided transfusion strategy leads to a significantly lower use of blood components compared with SOC (transfusion guided by INR and PLT count), without an increase in failure to control bleed, failure to prevent rebleed, and mortality.

Circulating extracellular vesicles induce monocyte dysfunction and are associated with sepsis and high mortality in cirrhosis.

BACKGROUND: Sepsis is common in cirrhosis and is often a result of immune dysregulation. Specific stimuli and pathways of inter-cellular communications between immune cells in cirrhosis and sepsis are incompletely understood. Immune cell-derived extracellular vesicles (EV) were studied to understand mechanisms of sepsis in cirrhosis. METHODS: Immune cell-derived EV were measured in cirrhosis patients [Child-Turcotte-Pugh (Child) score A, n = 15; B n = 16; C n = 43 and Child-C with sepsis (n = 38)], and healthy controls (HC, n = 11). In vitro and in vivo functional relevance of EV in cirrhosis and associated sepsis was investigated. RESULTS: Monocyte, neutrophil and hematopoietic stem cells associated EV progressively increased with higher Child score (P < .001)and correlated with liver disease severity indices (r2  > 0.3, P < .001), which further increased in Child C sepsis than without sepsis(P < .001); monocyte EV showing the highest association with disease stage [P = .013; Odds ratio-4.14(1.34-12.42)]. A threshold level of monocyte EV of 53/µl predicted mortality in patients of Child C with sepsis [Odds ratio-6.2 (2.4-15.9), AUROC = 0.76, P < .01]. In vitro EV from cirrhotic with sepsis compared without sepsis, induced mobilization arrest in healthy monocytes within 4 hours (P = .004), reduced basal oxygen consumption rate (P < .001) and induced pro-inflammatory genes (P < .05). The septic-EV on adoptive transfer to C57/BL6J mice, induced sepsis-like condition within 24 h with leukocytopenia (P = .005), intrahepatic inflammation with increased CD11b + cells (P = .03) and bone marrow hyperplasia (P < .01). CONCLUSION: Extracellular vesicles induce functional impairment in circulating monocytes and contribute to the development and perpetuation of sepsis. High levels of monocyte EV correlate with mortality and can help early stratification of sicker patients.

Heparin-like Effect Associated With Risk of Bleeding, Sepsis, and Death in Patients With Severe Alcohol-Associated Hepatitis.

BACKGROUND & AIMS: Endogenous heparinoids or heparin-like effects (HLEs) can cause coagulation failure in patients with cirrhosis and sepsis. We performed a prospective study of the association between HLE and bleeding events, sepsis, and outcomes of patients with severe alcohol-associated hepatitis. METHODS: Our final analysis comprised 78 patients with severe alcohol-associated hepatitis (44.3 ± 11.7 years; all male; discriminant function >32) who presented without sepsis at a single center in India from August 2015 through August 2016. Blood samples were collected at days 0, 3, and 7 after presentation and assessed by a global coagulation assay; by SONOCLOT (global and heparinase treated); and in assays for factor VIII, von Willebrand factor, protein C, and antithrombin. Patients were followed for sepsis, bleeding and outcome. The primary outcome was association of HLE with survival 28 days after presentation. RESULTS: HLEs were observed in 32 patients (41%) at day 0, 27 patients (34.6%) at day 3, and 28 patients (35.9%) patients at day 7. Factors associated with mortality at day 0 were factor VIII activity >160% (hazard ratio [HR], 3.1; 95% CI, 1.4-9.5; P = .026), level of protein C <34% (HR, 0.7; 95% CI, 0.5-0.8; P = .037), antithrombin activity <28% (HR, 0.7; 95% CI, 0.3-1.1; P = .008) and international normalized ratio >2.6 (HR, 2.3; 95% CI, 1.8-9.7; P = .010). In multivariate analyses, only factor VIII activity (HR, 2.3; 95% CI, 1.6-7.8; P = .046), international normalized ratio (1.9; 95% CI, 1.2-4.3; P = .039), level of protein C (HR, 0.9; 95% CI, 0.7-1.1; P = .052) and model for end-stage liver disease score (HR, 3.2; 95% CI, 1.9-10.2; P = .042) were associated with mortality. Episodes of epistaxis, hemorrhoid bleeding, hemoperitoneum, and pulmonary hemorrhage occurred in 10.2%, 12.3%, 3.4%, and 4.5% of patients respectively. The presence of HLE at day 0 increased the risk of sepsis (HR, 2.5; 95% CI, 2.2-4.3; P = .002), bleeding (HR, 1.4; 95% CI, 1.2-5.3; P = .004) and death (HR, 1.2; 95% CI, 1.4-1.7; P = .044). CONCLUSIONS: In a prospective study of patients with severe alcohol-associated hepatitis, we associated HLE with coagulation abnormalities, risk of sepsis, and mortality. Clinicaltrials.govNCT02307409.

Flare of Autoimmune Hepatitis Causing Acute on Chronic Liver Failure: Diagnosis and Response to Corticosteroid Therapy.

Autoimmune hepatitis (AIH) is considered less common in the Asia Pacific region. Due to this, AIH flare as a cause of acute on chronic liver failure (ACLF) is often overlooked and treatment delayed. We aimed at the defining clinical and histopathological spectrum and role of steroid therapy in AIH-ACLF. Patients with AIH-ACLF, prospectively recruited and followed between 2012 and 2017, were analyzed from the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) data base. Diagnosis of AIH was confirmed using International Autoimmune Hepatitis Group score or simplified AIH score with histopathological evidence. Of 2,825 ACLF patients, 82 (2.9%) fulfilled criteria of AIH (age 42.1 ± 18.1 years, 70% female). At baseline, mean bilirubin was 18.6 ± 8.2 mg/dL, Child-Turcotte-Pugh score was 11.7 ± 1.4, and Model for End-Stage Liver Disease (MELD) score was 27.6 ± 6.5. Mean immunoglobulin G was 21.61 ± 7.32 g/dL, and this was elevated ≥1.1 times in 97% of cases; 49% were seronegative. Liver histology was available in 90%, with median histological activity index of 10 (interquartile range, 7-12); 90% with moderate to severe interface activity; 56% showing significant parenchymal necrosis (bridging and confluent necrosis); and cirrhosis in 42%. Twenty-eight (34%) patients received steroid therapy and showed shorter intensive care unit (ICU) stay (median 1.5 versus 4 days, P < 0.001) and improved 90-day survival (75% versus 48.1%, P = 0.02) with comparable incidence of sepsis (P = 0.32) compared to those who did not. Patients of advanced age, more severe liver disease (MELD >27; 83.3% sensitivity, 78.9% specificity, area under the receiver operating characteristic curve 0.86), presence of hepatic encephalopathy, and fibrosis grade ≥F3 had an unfavorable response to corticosteroid therapy. Conclusion: AIH presenting as ACLF is not uncommon in Asian patients; a low threshold for liver biopsy is needed to confirm the diagnosis as nearly half the patients are seronegative; early stratification to steroid therapy or liver transplantation (MELD >27, hepatic encephalopathy in ≥F3) would reduce ICU stay and improve outcomes.

Targeted delivery of microRNA-199a-3p using self-assembled dipeptide nanoparticles efficiently reduces hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC) is an aggressive tumor with limited systemic and locoregional modalities of treatment. Although microRNA (miRNA) based therapies have significant potential, their targeted delivery remains a major challenge. miR-199a-3p functions as an important tumor suppressor in HCC, which regulates various cellular processes. Recently, peptide-based nanoparticles (NPs) have been developed to deliver oligonucleotides including miRNA. Here, we describe the synthesis and characterization of arginine α,ß-dehydrophenylalanine (RΔF) nanoparticles for the selective delivery of miR-199a-3p to restore dysregulated gene expression in HCC. Targeted delivery was achieved by conjugating lactobionic acid (LA) with RΔF NPs (RΔF-LA NPs), a ligand for the asialoglycoprotein receptor known to be overexpressed in HCC cell lines. RΔF-LA NPs condensed miR-199a-3p had an average size of ∼60nm and a zeta potential of ∼+2.54 mV. RΔF-LA/miR NPs were found to be stable in serum as well as against RNase attack. RΔF-LA/miR NPs showed an enhanced cellular uptake and an efficient delivery of miR-199a-3p leading to a significant increase in miR-199a-3p levels (over 500 fold). The increased miR-199a-3p levels remarkably suppressed cell proliferation and migration as well as induced cellular apoptosis and downregulation of the specific target gene (mTOR) in vitro. RΔF-LA/miR NPs showed high tumor/ low organ ratios after intravenous injection into HCC tumor bearing nude mice. RΔF-LA/miR NPs treated mice demonstrated>50% decline in tumor growth, which also corresponded well with suppression of mTOR protein expression, tumor cell proliferation and increased survival rate (P < 0.05). CONCLUSION: RΔF-LA/miR NPs showed significantly enhanced delivery of the miRNA which underscores their potential for further development as a therapeutic approach for HCC. (Hepatology 2018;67:1392-1407).

Positive familial history for metabolic traits predisposes to early and more severe alcoholic cirrhosis: A cross-sectional study.

BACKGROUND & AIMS: Familial aggregation of metabolic traits in NAFLD is well documented. However, relevance of these traits in alcoholic cirrhosis is not well studied. We aimed to explore the association of family history of metabolic traits with age at diagnosis, severity and complications of alcoholic cirrhosis. METHODS: In a cross-sectional study, all consecutive patients with alcoholic cirrhosis presenting to our tertiary care centre were included. Family and personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. The amount and duration of alcohol consumption were also carefully recorded. RESULTS: Out of 1084 alcoholic cirrhotics (age 48.5 ± 10.1 years, all males), family history for metabolic traits was documented in 688 (63.5%) patients. These patients had younger age at diagnosis, increased incidence of jaundice, ascites, variceal bleed and hepatic encephalopathy with consequently higher MELD and CTP score. These patients developed cirrhosis despite shorter median duration (13 years, IQR 7-20 vs 21, IQR 18-25) and lesser amount of alcohol consumption (74 g/d, IQR 24-96 vs 144, IQR 100-148). Patients with both family and personal history of metabolic traits had a higher risk by 3.3 times (95% CI 2.2-4.8) of an early age at diagnosis, 13.2 times (95% CI 8.7-20.1) of progression to cirrhosis with lesser amount of alcohol consumption and 4.6 times (95% CI 3.1-6.9) with lesser duration of alcohol consumption. CONCLUSIONS: Positive family and personal history of metabolic traits predispose to alcoholic cirrhosis with an earlier age at onset and more severity despite lesser exposure to alcohol.

Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis.

BACKGROUND: Exogenous growth factor-mobilized bone marrow (BM) stem cells have shown a differential response in the management of decompensated cirrhosis (DC). This study was designed to evaluate potential clinical benefit of adding Erythropoietin (EPO) in granulocyte-colony stimulating factor (G-CSF)-mobilized stem cell therapy, possible mechanisms of regeneration and predictive factors of regenerative response. METHODS: Sixty consecutive DC patients received either G-CSF with EPO (Group A; n = 30) or G-CSF and placebo (Group B; n = 30) for 2 months and were carefully followed up for 1 year. Baseline and post-treatment liver biopsy, BM biopsy and BM aspirate were analysed for fibro-inflammatory and regenerative response and BM hematopoietic reservoir. RESULTS: Addition of EPO to G-CSF showed a significant improvement in Child-Pugh score (P = 0.03) and MELD score (P = 0.003) as compared to G-CSF alone, with reduction in mortality (16.6% vs 36.7%, P = 0.09). The combination arm also demonstrated a decreased incidence of acute kidney injury (P < 0.001), encephalopathy (P = 0.005) and refilling of ascites (P = 0.03). Compared to monotherapy, it increased CD163+ macrophages (P = 0.013), Ki67+ index (P < 0.001) with decrease in α-SMA levels (P < 0.001) in liver tissue. The response was better with grade 1 and 2 than with grade 3 ascites; Child B cirrhosis and MELD < 16. Non-responders had lower hematopoietic stem cells (HSCs) at baseline. On multivariate analysis, the liver disease severity (MELD < 16) and a relatively preserved BM (BM-HSCs > 0.4) predicted therapeutic response (AUROC = 0.82). CONCLUSIONS: Early DC (MELD < 16) patients with mild-moderate ascites and those with a healthy cellular baseline BM respond better to growth factor therapy. Addition of EPO to G-CSF provides better regenerative response than G-CSF monotherapy.

Coagulation failure is associated with bleeding events and clinical outcome during systemic inflammatory response and sepsis in acute-on-chronic liver failure: An observational cohort study.

BACKGROUND: Patients with acute-on-chronic liver failure (ACLF) have coagulation failure in the setting of systemic inflammatory syndrome (SIRS), sepsis and extra-hepatic organ failures. METHODS: Consecutive ACLF patients without sepsis at baseline were assessed at days 0, 3 and 7 with thromboelastography (TEG) and specific assays (Factor VIII, von Willebrand factor [vWF], protein C and antithrombin III [ATIII]) and followed for development of sepsis, bleeding and outcome. RESULTS: Of 243 patients, 114 (63% ethanol related; mean age 44.3 ± 11.7 years; 90% male) were recruited. SIRS was noted in 39 (34.2%), 45 (39.5%) and 46 (40%) patients at days 0, 3 and 7 and sepsis in 28 (24%) and 52 (56.1%) patients at days 3 and 7 respectively. The 28- and 90-day survivals were 62% and 51% respectively. A hypocoagulable TEG at baseline was a predictor of bleeding (hazard ratio [HR] 2.1; CI 1.6-4.9; P = 0.050) and mortality (HR 1.9; CI 1.3-7.9; P = 0.043). ACLF patients had increased Factor VIII, vWF, tissue factor levels and tissue plasminogen activator (tPA) activity with reduced protein C and ATIII. Coagulation parameters like Coagulation Index (HR 2.1; CI 1.1-4.5; P = 0.044),clot lysis (HR 3.2; CI 1.9-3.4; P = 0.033), low protein C < 30% (HR 2.1; CI 1.5-2.8; P = 0.017), ATIII (HR 1.4; CI 1.7-3.1; P = 0.052) and tPA (HR 1.5; CI 1.1-2.4; P = 0.052) were predictors of mortality at day 28. Protein C activity <30% (HR 1.3; CI 1.0-2.9; P = 0.042) and tPA >20 ng/mL (HR 1.2; CI 1.1-2.1; P = 0.040) predicted mortality when adjusted for age, gender and baseline MELD. CONCLUSIONS: Dynamic coagulation derangements, measured by TEG, determine the likelihood of bleeding and mortality in ACLF.

Donor CD163 and nestin-positive cells predict graft function in living donor liver transplant.

AIMS: To evaluate the effect of donor liver resident mesenchymal cells, M2 macrophages on liver graft outcome after living donor liver transplantation. MATERIALS AND METHODS: Seventy donor biopsies were included in the study. Outcomes at day 3, 7, 30, and 180 postliver transplantation were assessed. Mesenchymal stem cells and M2 macrophages in donor liver biopsies were evaluated. RESULTS: Mean age of recipients was 40.9 ± 13.6 years. Sex mismatched transplants were 44 (M→F = 9; F→M = 35). On area under receiver operative curve analysis, donor biopsy (DB) nestin ≥3 and CD 163 ≥ 32/200x at day 3; CD163 ≥ 32 at day 7; CD 163 > 32, pRBC of <6.5 units at day 30, and DB nestin ≥3, CD 163 ≥ 32 and pRBC<6.5 units at day 180 predicted adequate graft functions. On multivariate analysis, higher DB nestin (P = .009) and lower cryoprecipitate (P = .009) usage at day 3, higher DB CD163 (P = .006) at day 7, higher DB CD163 (P = .018) and reduced transfusion of packed cell (pRBC) (P = .014) at day 30 and higher DB nestin (P = .011), higher CD163 (P = .009), and reduced pRBC (P = .045) at day 180 were the predictors of better outcome. CONCLUSIONS: Donor liver biopsy nestin+ and CD163+ can predict early graft outcome in living donor liver transplantation.

Spectrum of Pediatric Autoimmune Liver Disease and Validation of Its Diagnostic Scores in Indian Children.

OBJECTIVES: There is limited literature on the spectrum of pediatric autoimmune liver disease (AILD, encompassing both autoimmune hepatitis/AIH and autoimmune sclerosing cholangitis [ASC]) in Asian populations and its diagnostic scores similarly require further validation. This work thus aimed to study the clinical characteristics, and to validate available diagnostic criteria in the local pediatric AILD cohort. METHODS: A review of all pediatric AILD cases, presenting over a 6-year (2011-2017) period was done, along with comparison of the available diagnostic scores: original (1999), simplified (2008) score, and new proposed (2017) score. RESULTS: A total of 85 subjects (AIH = 70 and ASC = 15) were diagnosed as having AILD. Majority of the cases in both groups presented with advanced hepatic disease (portal hypertension and/or hepatic decompensation). Overall 38 (44.7%) subjects had extrahepatic autoimmune disorders. Good outcome (survival with native liver with medically controllable disease), was seen in 80% AIH subjects, while poor outcome (death/need for liver transplantation or LT) was seen in 13% subjects, with similar results in the ASC cohort. All the 3 available scores had area under receiver operating characteristic (AUROC) curves exceeding 0.9 suggestive of excellent discrimination of AILD (to non-AILD patients), with no statistical difference between them (P >0.05). CONCLUSIONS: In Indian subcontinent, pediatric AILD subjects usually present with advanced hepatic disease, but may have a good outcome if timely therapy can be instituted. Associated autoimmune disorders should be carefully screened. There is no difference in the predictive value of the available diagnostic scores for pediatric AILD.

Bile duct paucity in childhood-spectrum, profile, and outcome.

We studied the etiological spectrum, clinicolaboratory and histological profile, and outcome of infants and children under 18 years of age presenting between December 2010 and May 2016 with histological evidence of paucity of intralobular bile ducts (PILBD, bile ducts to portal tract ratio < 0.6) Post-transplant PILBD was excluded. Of 632 pediatric liver biopsies screened, 70 had PILBD-44 were infants. PILBD was classified histologically into destructive (n = 50) and non-destructive PILBD (n = 20). Presentations were jaundice (98%), organomegaly (94%), pale stools (50%), and pruritus (43%). Infants had more cholestasis but less fibrosis on histology. Overall, 29 required liver transplantation (LT) for portal hypertension (n = 26), decompensation (n = 25), growth failure (n = 20), intractable pruritus (n = 5), and recurrent cholangitis (n = 2). Destructive PILBD has an odds for poor outcome (decompensation or need for LT within 1 year) of 1.53 (95% CI = 1.15-2.04). On binary logistic regression analysis, poor outcome was related to advanced fibrosis on liver biopsy [Exp (B) = 5.46, 95% CI = 1.56-19.04]. CONCLUSION: PILBD was present in 11% of pediatric liver biopsies and has a varied etiological spectrum. Destructive PILBD has poor outcome. Need for LT is guided by the presence of advanced fibrosis. What is Known: • Natural history of syndromic ductal paucity (Alagille syndrome) is complex. • Duct loss is commonly seen with late presentation of biliary atresia. What is New: • The study classifies the etiological spectrum of ductal paucity histologically into destructive and non-destructive. • Destructive duct loss carries poor prognosis regardless of the etiology of liver disease with subsequent need for liver transplantation.

Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver.

UNLABELLED: Bone marrow (BM) is a reservoir for immune and hematopoietic cells and critical for tissue repair and regeneration. All of these functions are severely altered in cirrhosis. We investigated the cellular and functional state of BM in cirrhosis patients. We studied the histological, cellular, and molecular changes in BM of cirrhosis patients (n = 168) and controls (n = 44). Hematopoietic stem cells (HSCs) and associated niche cells, mesenchymal stem cells, Schwann cells, neural fibers, and endothelial cells were evaluated by immunohistochemistry. Cytokines and growth factors were analyzed in peripheral blood and BM plasma. Cirrhotic BM showed an inverse correlation between cluster of differentiation 34+HSCs and Model of End-Stage Liver Disease (ρ = -0.582, P < 0.001) and Child's scores (P < 0.038). BMs of cirrhosis patients with higher Model of End-Stage Liver Disease (>15) showed significantly decreased HSCs, mesenchymal stem cells, Schwann cells, and neural fibers; increased interleukin-1ß (P = 0.004), tumor necrosis factor-α (P = 0.040), and interferon-γ (P = 0.03); and decreased oncostatin M (P = 0.04), stem cell factor (P = 0.05), and stromal cell-derived factor 1 (P = 0.03) compared to those with lower Model of End-Stage Liver Disease scores (≤15). The cluster of differentiation 34+ cell population was a predictor for the development of sepsis (P < 0.001), and per unit loss increased the probability of sepsis by 16%. Cirrhosis patients with fewer HSCs had lower hemoglobin (P = 0.05) and platelet counts (P = 0.05) and showed early graft dysfunction. CONCLUSIONS: Increasing severity of cirrhosis causes derangement of the hematopoietic niche and loss of HSCs, contributing to the hematological and immunological dysfunctions and reduced potential for regeneration; restoring BM functions could provide new therapeutic options in cirrhosis. (Hepatology 2016;64:1273-1288).

Impact of family history of metabolic traits on severity of non-alcoholic steatohepatitis related cirrhosis: A cross-sectional study.

BACKGROUND & AIMS: Familial aggregation of metabolic traits with fatty liver disease is well documented. However, there is scarcity of data regarding such association with non-alcoholic steatohepatitis (NASH)-related cirrhosis. This study was aimed to explore the association of family history of metabolic traits with severity of cirrhosis. METHODS: In a cross-sectional study, all consecutive patients with NASH-related cirrhosis presenting to our tertiary care centre were included. Family history, personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. RESULTS: Of the 1133 cirrhotics (68.1% males, age 51.4±10.9 years); 779 (68.8%) had family history for metabolic traits. These patients had lower age at diagnosis (45.4±10.6 vs 49.6±11.2 years), higher Child-Turcotte-Pugh (CTP) score (7.8±1.9 vs 6.6±1.5), higher model for end stage liver disease (MELD) score (12.9±6.1 vs 10.9±4.1) and more incidence of decompensation in the form of ascites (46.3% vs 25.7%), jaundice (12.1% vs 6.2%) and hepatic encephalopathy (26.1% vs 11.0%). Patients with family and personal history of metabolic traits, had an increased risk of an early diagnosis of cirrhosis at<45 years of age (OR: 3.1, 95% CI 2.1-4.4), CTP≥10 (OR: 4.6, 95% CI 2.3-9.1), MELD>15 (OR: 6.6, 95% CI 3.8-11.5) with ≥1 features of decompensation (OR: 4.2, 95% CI 2.9-6.1). Family history of diabetes alone, also had higher risk of cirrhosis with MELD>15 (OR: 4.3, 95% CI 2.4-5.3, P<.001). CONCLUSION: Family and personal history of metabolic traits are associated with early age at diagnosis of cirrhosis with more severity and decompensation and so, has a prognostic importance in NASH-related cirrhotics.

Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure.

BACKGROUND AND AIM: There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients. PATIENTS AND METHODS: Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997). RESULTS: Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(<12 mg/dL,OR 1) vs (12-30 mg/dL,OR 1.45, 95% 1.1-2.63) vs (≥30 mg/dL,OR 2.6, 95% CI 1.3-5.2)], serum potassium [(<3 mmol/LOR-1) vs (3-4.9 mmol/L,OR 2.7, 95% CI 1.05-1.97) vs (≥5 mmol/L,OR 4.34, 95% CI 1.67-11.3)] and blood urea (OR 3.73, 95% CI 2.5-5.5); for I component nephrotoxic medications (OR-9.86, 95% CI 3.2-30.8); for R component,Systemic Inflammatory Response Syndrome,(OR-2.14, 95% CI 1.4-3.3); for O component, Circulatory failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (P<.001) in both the derivation and validation cohorts. CONCLUSIONS: The PIRO model identifies and stratifies acute on chronic liver failure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure.