Recompensation of Chronic Hepatitis C-Related Decompensated Cirrhosis Following Direct-Acting Antiviral Therapy: Prospective Cohort Study From a Hepatitis C Virus Elimination Program.

BACKGROUND & AIMS: Chronic hepatitis C-related decompensated cirrhosis is associated with lower sustained virologic response (SVR)-12 rates and variable regression of disease severity after direct-acting antiviral agents. We assessed rates of SVR-12, recompensation (Baveno VII criteria), and survival in such patients. METHODS: Between July 2018 and July 2023, patients with decompensated chronic hepatitis C-related cirrhosis after direct-acting antiviral agents treatment were evaluated for SVR-12 and then had 6-monthly follow-up. RESULTS: Of 6516 patients with cirrhosis, 1152 with decompensated cirrhosis (age 53.2 ± 11.5 years; 63% men; Model for End-stage Liver Disease-Sodium [MELD-Na]: 16.5 ± 4.6; 87% genotype 3) were enrolled. SVR-12 was 81.8% after 1 course; ultimately SVR was 90.8% after additional treatment. Decompensation events included ascites (1098; 95.3%), hepatic encephalopathy (191; 16.6%), and variceal bleeding (284; 24.7%). Ascites resolved in 86% (diuretic withdrawal achieved in 24% patients). Recompensation occurred in 284 (24.7%) at a median time of 16.5 (interquartile range, 14.5-20.5) months. On multivariable Cox proportional hazards analysis, low bilirubin (adjusted hazard ratio [aHR], 0.6; 95% confidence interval [CI], 0.5-0.8; P < 0.001), international normalized ratio (aHR, 0.2; 95% CI, 0.1-0.3; P < 0.001), absence of large esophageal varices (aHR, 0.4; 95% CI, 0.2-0.9; P = 0.048), or gastric varices (aHR, 0.5; 95% CI, 0.3-0.7; P = 0.022) predicted recompensation. Portal hypertension progressed in 158 (13.7%) patients, with rebleed in 4%. Prior decompensation with variceal bleeding (aHR, 1.6; 95% CI, 1.2-2.8; P = 0.042), and presence of large varices (aHR, 2.9; 95% CI, 1.3-6.5; P < 0.001) were associated with portal hypertension progression. Further decompensation was seen in 221 (19%); 145 patients died and 6 underwent liver transplantation. A decrease in MELDNa of ≥3 was seen in 409 (35.5%) and a final MELDNa score of <10 was seen in 335 (29%), but 2.9% developed hepatocellular carcinoma despite SVR-12. CONCLUSIONS: SVR-12 in hepatitis C virus-related decompensated cirrhosis in a predominant genotype 3 population led to recompensation in 24.7% of patients over a follow-up of 4 years in a public health setting. Despite SVR-12, new hepatic decompensation evolved in 19% and hepatocellular carcinoma developed in 2.9% of patients. (ClinicalTrials.gov, Number: NCT03488485).

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

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

Outpatient intensive nutrition therapy improves survival and frailty in males with Alcohol related ACLF - Randomised controlled trial.

BACKGROUND AND AIMS: Improvement in the nutritional status of Acute on Chronic Liver Failure(ACLF) patients may lead to reduction in morbidity and mortality. This study assessed the impact of dietician supported outpatient intensive nutrition therapy(OINT) on survival and frailty in patients with alcohol related ACLF METHODS: 70 patients with alcohol related ACLF(Asia Pacific Association for the Study of the Liver, APASL-criteria) and frailty were randomized 1:1 to receive standard medical therapy(SMT) plus OINT(intervention) versus SMT(control) alone. The primary outcome was an improvement in survival at 3 months. Secondary outcome measures included improvement in frailty, prognostic scores and hospitalization. RESULTS: There was a significant improvement in overall survival in the OINT group as compared to SMT after 3 months of follow up, 91.4% (Standard error (SE): 4.7%) vs. 57.1% (SE: 8.4%), P<.00). On cox regression model, inclusion in the intervention arm, baseline Skeletal Muscle Index(SMI), and Asia Pacific Association for the Study of the Liver ACLF Research Consortium(AARC score) were independent predictors of survival (P<.05). The Liver frailty index(LFI) score also significantly improved in the OINT as compared to SMT, Δ-0.93 -(0.71-1.13) vs. Δ -0.33 -(0.44-0.72)(P<.00). The disease severity including MELD, MELD-Na, and AARC score showed a significant improvement in the OINT group as compared to the SMT group(P<.05). The patients in OINT group had lesser number of hospitalizations 6(17%) versus 16(45.7%)(P=.01) as compared to SMT group. CONCLUSION: Outpatient intensive nutrition therapy significantly improves survival, frailty and disease severity with a reduction in number of hospitalizations and supports the key role of nutrition in treatment of alcohol related ACLF patients.

Liver Dysfunction and Systemic Inflammation Drive Organ Failures in Acute Decompensation of Cirrhosis: A Multi-Centric Study.

INTRODUCTION: Hospitalized patients with acute decompensation (AD) of cirrhosis are at risk of progressing to acute-on-chronic liver failure (ACLF), significantly increasing their mortality. This study aimed to identify key predictors and patient trajectories predisposing to ACLF. METHODS: In this multi-center, prospective study spanning two years, clinical, biochemical, and 90-day survival data were collected from 625 AD patients (EASL criteria) across North, South, and East India. We divided the cohort into a Derivation-cohort (DC: 318 patients) and a Validation-cohort (VC: 307 patients). Predictive models for pre-ACLF were derived, validated, and compared with established scores like MELD3.0 and CLIF-C AD. RESULTS: Of 625 patients, (mean age 49, 83% male, 77.5% with alcohol-related liver disease), 32.2% progressed to ACLF. Patients progressing to ACLF showed significantly higher bilirubin (10.9vs.8.1mg/dl), leukocyte counts (9400vs.8000 per mm3), INR (1.9 vs.1.8), and MELD3.0 (28vs.25), but lower sodium (131vs.134mEq/L) and survival (62% vs.86%) compared to those without progression (p<0.05) in the DC. Consistent results were noted with AH, infection and HE as additional risk factors in VC. Liver failure at presentation [OR: 2.4 (in DC), 6.9 (in VC)] and the seven-day trajectories of bilirubin, INR, and MELD3.0 significantly predicted ACLF progression (p<0.001). A new PRE-ACLF Model showed superior predictive capability (AUC of 0.71 in DC and 0.82 in VC) compared to MELD3.0 and CLIF-C AD scores (p<0.05). DISCUSSION: Approximately one-third of AD patients in this Indian cohort rapidly progressed to ACLF, resulting in high mortality. Early identification of patients at risk can guide targeted interventions to prevent ACLF.

Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in Metabolic Dysfunction Associated Fatty Liver Disease-Related Acute-on-Chronic Liver Failure.

INTRODUCTION: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute-on-chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS: Patients with MAFLD-ACLF were recruited from the Asian Pacific Association for the Study of the Liver-ACLF Research Consortium (AARC registry). The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease as MAFLD (or previous nomenclature such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or non-alcoholic steatohepatitis-cirrhosis). Patients with coexisting other etiologies of chronic liver disease (such as alcohol, hepatitis B virus, hepatitis C virus, etc.) were excluded. Data were randomly split into derivation (n = 258) and validation (n = 111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27% and hypertension in 29%. The dominant precipitants included viral hepatitis (hepatitis A virus and hepatitis E virus, 32%), drug-induced injury (drug-induced liver injury, 29%), and sepsis (23%). Model for End-Stage Liver Disease-Sodium (MELD-Na) and AARC scores on admission averaged 32 ± 6 and 10.4 ± 1.9. At 90 days, 51% survived. Nonviral precipitant, diabetes, bilirubin, international normalized ratio, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for nonviral precipitant), and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. DISCUSSION: Almost half of patients with MAFLD-ACLF die within 90 days. Diabetes and nonviral precipitants such as drug-induced liver injury and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for patients with MAFLD-ACLF.

Prevalence of Acute on Chronic Liver Failure in Autoimmune Hepatitis, Treatment Response and Mortality Burden Assessment: A Region-Predominant Systematic Review and Meta-Analysis.

Acute-on-chronic liver failure (ACLF) is a global health problem. Little scientific evidence exists on its prevalence in autoimmune hepatitis. Treatment response and mortality outcomes have also been reported differently. The study was conducted to estimate the overall prevalence of ACLF among patients with autoimmune hepatitis (AIH) and determine the associated treatment response and mortality. We scrutinized wide literature in Scopus, PubMed, Embase, Web of Science, and Cochrane, and assessed published articles completely, studies performed and reported from around the globe, until December 07, 2023, according to the PROSPERO registered protocol (CRD42023412176). Studies (retrospective and prospective cohort study type) that stated the ACLF development among established AIH cases were considered. Features of the study, duration of follow-up, and numeric patient information were retrieved from the studies included. The research paper quality was checked for risk of bias. Random effect meta-analysis with metaregression and subsection scrutinies were performed with R. The main outcome was the collective prevalence of ACLF in the AIH patients, whereas treatment response and mortality in AIH-associated ACLF were secondary outcomes. Six studies were involved with confirmed diagnoses in 985 AIH patients for the data synthesis. The pooled prevalence of ACLF in the explored patients was 12% (95% CI: 8-17) ( P =0.01). Heterogeneity was found to be high in the present meta-analysis ( I2 =72%; P < 0.01). For the secondary endpoint analysis, the pooled prevalence of complete remission at 1-year follow-up was 71% (0.52; 0.85), and mortality from the ACLF-AIH patient population was 32% (95% CI: 18-50). Sensitivity analysis showed no influence on the overall estimations of the pooled prevalence of ACLF by omitting studies one by one. One in 10 AIH patients likely present with ACLF. The response to treatment is seen in two-thirds of patients, and mortality is high.

Endoscopic Ultrasound-Guided Transgastric Shunt Obliteration for Recurrent Hepatic Encephalopathy.

INTRODUCTION: Occlusion of spontaneous portosystemic shunts (SPSSs) in patients with cirrhosis may be required in recurrent or refractory hepatic encephalopathy. We describe a novel method for occlusion of SPSS using endoscopic ultrasound (EUS). METHODS: EUS-guided transgastric shunt obliteration was performed by injecting glue and coils directly into SPSS. RESULTS: EUS-guided transgastric shunt obliteration was performed for 7 patients in 9 sessions. Complete cessation of Doppler flow was achieved in 6/7 cases. Adequate clinical response was observed in 6/7 patients. No procedure-related severe adverse events were seen. DISCUSSION: This novel technique is a potentially effective and efficient method for shunt obliteration.

Efficacy and safety of pan-genotypic sofosbuvir and velpatasvir in patients with hepatitis C and HIV coinfection on dolutegravir-based antiretroviral therapy.

Hepatitis C virus (HCV) infection is more prevalent in people living with HIV-AIDS (PLHA) and portends a poorer prognosis. Pharmacokinetic studies suggest the absence of significant interaction between velpatasvir and dolutegravir which has been recently recommended as part of preferred first-line antiretroviral therapy (ART) regimens by WHO. However, clinical data on the use of velpatasvir-based regimen in PLHA taking dolutegavir is lacking. Hence, we aimed to assess the efficacy and safety of sofosbuvir and velpatasvir (SOF + VEL) in HCV and HIV coinfected patients on dolutegravir-based ART. Forty-five consecutive PLHA with HCV coinfection on dolutegravir-based ART were prospectively enrolled. All patients were treated SOF + VEL for 12 weeks. Complete haemogram, liver and renal function tests were assessed at baseline, 4 weeks and at end of treatment. Sustained virological response (SVR) was assessed at 12 weeks after end of treatment. The majority were males (95.5%) with a mean age of 32.8 ± 12.3 years. Cirrhosis was present in 6 (13.3%) patients. All patients completed 12 weeks of therapy with SOF + VEL, but SVR could not be assessed in two patients. Forty-two (97.7%) of the remaining 43 patients attained SVR-12. SVR-12 rate was 97.7% and 93.3% by per protocol and intention to treat analysis, respectively. No grade III/IV adverse events were reported, and there was no worsening of blood counts, liver or renal function test parameters. The pan-genotypic regimen of SOF + VEL is safe and effective in PLHA with HCV coinfection who are on dolutegravir-based ART.

Frailty is associated with increased risk of cirrhosis disease progression and death.

BACKGROUND AND AIMS: The Liver Frailty Index (LFI) is a well-studied tool that evaluates frailty in patients with cirrhosis. Consisting of grip strength, chair stands, and balance testing, the LFI has been associated with increased mortality in patients awaiting liver transplant. We aimed to extend our understanding of frailty in cirrhosis by exploring the relationship between the LFI and the risk of (1) cirrhosis progression, (2) mortality, and (3) unplanned hospitalizations, in both compensated and decompensated disease. APPROACH AND RESULTS: Adult patients with cirrhosis from four centers in North America and one in India were included. Frailty was measured at baseline using the LFI and categorized as robust (LFI < 3.2), prefrail (LFI 3.2-4.5), and frail (LFI > 4.5). Progression of cirrhosis was defined by an increase in clinical stage, ranging from 1 to 5, from baseline using the D'Amico classification. Factors associated with progression, mortality, and hospitalizations were evaluated using multivariate regression models, with transplant as a competing risk. In total, 822 patients with cirrhosis were included. Average Model for End-Stage Liver Disease (MELD) score was 15.5 ± 6.0. In patients with compensated cirrhosis, being frail versus robust was associated with increased risk of progression to the next cirrhosis stage or to death (HR, 2.45; 95% CI, 1.14-5.29) and with an increased risk of unplanned hospitalizations (2.32; 95% CI, 1.13-4.79), after adjusting for age, sex, and MELD score. Similar HRs were observed in patients with decompensated cirrhosis. CONCLUSIONS: Frailty was an independent predictor of cirrhosis progression or death and unplanned hospitalization across patients with compensated and decompensated cirrhosis. Future studies are needed to evaluate the possibility of slowing cirrhosis disease progression by reversing or preventing frailty.

Assessment of Sarcopenia Using Muscle Ultrasound in Patients With Cirrhosis and Sarcopenic Obesity (AMUSE STUDY).

BACKGROUND AND AIMS: Sarcopenic obesity (SO) marks a confluence of 2 complex entities involving the muscle-liver-adipose tissue axis. Computed tomographic (CT) scan-derived skeletal muscle index (SMI) remains the gold standard for sarcopenia assessment in SO. However, it has intrinsic limitations of cost, radiation, and point of care applicability. We assessed the role of muscle ultrasound (US) in SO. METHODS: A total of 52 patients with cirrhosis and obesity were assessed for sarcopenia using SMI. US assessment of thigh and forearm muscles was done to record quadriceps muscle thickness (QMT), quadriceps feather index (QMFI), forearm muscle thickness (FMT), and forearm feather index (FFI), respectively. Evaluated US parameters were correlated with SMI and assessed for diagnostic accuracy using the area under the curve. RESULTS: A total of 40 (76.9%) males and 12 (23.1%) females [mean age: 50.9 y (43.8 to 53.5 y)] were included. QMT [0.45 cm/m 2 (0.42 to 0.48 cm/m 2 ) vs. 0.67 cm/m 2 (0.63 to 0.70 cm/m 2 )], QMFI [0.82 cm/m 2 (0.77 to 0.87 cm/m 2 ) vs. 1.12 cm/m 2 (1.06 to 1.19 cm/m 2 )], FMT [0.19 cm/m 2 (0.17 to 0.20 cm/m 2 ) vs. 0.25 cm/m 2 (0.23 to 0.27 cm/m 2 )], and FFI [0.38 cm/m 2 (0.35 to 0.412 cm/m 2 ) vs. 0.47 cm/m 2 (0.44 to 0.50 cm/m 2 )] were significantly lower in patients with SO ( P <0.01). A positive correlation with SMI was seen for all parameters in the entire cohort. The strongest correlation was exhibited by QMT ( r =0.70) and QMFI ( r =0.70) in males. The area under the curve of QMT, QMFI, FMT, and FFI were 0.98 (95% confidence interval: 0.96-1), 0.95 (0.89-1), 0.85 (0.75-0.96), and 0.80 (0.68-0.93), respectively. CONCLUSIONS: US-based assessment of sarcopenia has excellent diagnostic accuracy and correlates well with computed tomography-SMI in patients with SO. US may serve as an easy-to-use, point of care tool for assessing sarcopenia in SO with the advantage of repeated sequential assessment.

Machine learning can guide suitability of consultation and patient referral through telemedicine for hepatobiliary diseases.

BACKGROUND AND AIM: Telemedicine is an evolving tool to provide health-care services. We evaluated the suitability of telemedicine to deliver effective consultation for hepatobiliary disorders. METHODS: In this prospective study spanning over a year, we interviewed hepatologists delivering the teleconsultations through a pre-validated questionnaire. A consult was deemed suitable based on the physician's judgment in the absence of unplanned hospitalization. We evaluated factors determining the suitability through inferential statistics and machine learning models, namely, extreme gradient boosting (XGB) and decision tree (DT). RESULTS: Of 1118 consultations, 917 (82.0%) were deemed suitable. On univariable analysis, patients with skilled occupation, higher education, out-of-pocket expenses, and diseases such as chronic hepatitis B, C, and non-alcoholic fatty liver disease (NAFLD) without cirrhosis were associated with suitability (P < 0.05). Patients with cirrhosis (compensated or decompensated), acute-on-chronic liver failure (ACLF), and biliary obstruction were likely unsuitable (P < 0.05). XGB and DT models predicted suitability with an area under the receiver operating curve of 0.808 and 0.780, respectively. DT demonstrated that compensated cirrhosis with higher education or skilled occupation with age < 55 years had 78% chance of suitability whereas hepatocellular carcinoma, decompensated cirrhosis, and ACLF patients were unsuitable with a 60-95% probability. In non-cirrhotic liver diseases, hepatitis B, C, and NAFLD were suitable, with a probability of 89.7%. Biliary obstruction and previous failure of teleconsultation were unsuitable, with a probability of 70%. Non-cirrhotic portal fibrosis, dyspepsia, and dysphagia not requiring intervention were suitable (probability: 88%). CONCLUSION: A simple decision tree can guide the referral of unsuitable and the management of suitable patients with hepatobiliary diseases through telemedicine.

Home-based intensive nutrition therapy improves frailty and sarcopenia in patients with decompensated cirrhosis: A randomized clinical trial.

BACKGROUND AND AIM: The majority of patients with decompensated cirrhosis suffer from malnutrition, a potentially modifiable contributor to frailty and sarcopenia. The present study investigated the impact of a 6-month dietician-supported home-based intensive nutrition therapy (HINT) intervention on objective frailty and sarcopenia metrics in patients with decompensated cirrhosis. METHODS: One hundred adult patients with decompensated cirrhosis, frailty, and sarcopenia at baseline were randomized 1:1 to receive standard medical therapy (SMT) plus HINT (intervention) versus SMT (control) alone. The primary outcome was an improvement in frailty as measured by the liver frailty index (LFI). Secondary outcome measures included sarcopenia metrics, liver disease severity scores, hospitalization, and death. RESULTS: The LFI improved more in the intervention arm as compared with controls (0.8 vs 0.4; P < 0.001). Baseline and end-of-study skeletal muscle index (SMI) was available in a subset of 32 male patients, with greater improvements seen in the intervention arm compared with controls (6.36 vs 0.80; P = 0.02). Patients in the intervention arm had less hospitalizations over the 6-month follow-up (19 [38%] vs 29 [58%]; P = 0.04). On subgroup analysis, in the 64% of patients who were adherent to calorie and protein intake targets at 6 months, significant improvement was seen in liver disease severity scores and survival (P < 0.05). CONCLUSION: In patients with decompensated cirrhosis, frailty, and sarcopenia, a 6-month dietitian-supported home-based intensive outpatient nutrition therapy was associated with statistically and clinically relevant improvement in frailty. The subgroup of adherent patients showed improvement in their liver disease scores and reduction in mortality. These findings support the key role of food as medicine in the management of cirrhosis.

Prevalence, Risk Factors, and Impact of Bacterial or Fungal Infections in Acute Liver Failure Patients from India.

BACKGROUND: We evaluated the prevalence, risk factors, and impact of bacterial/fungal infections in acute liver failure (ALF) patients. METHODS: We analyzed clinical, biochemical, and microbiological data of ALF patients with and without bacterial/fungal infections admitted at an institute over the last 5 years. RESULTS: We enrolled 143 patients, 50% males, median age 25 years, with acute viral hepatitis (32.2%), drug-induced injury (18.2%), and tropical illness (14%) as aetiologies of ALF. 110 patients (76.9%) developed bacterial/fungal infections [Bacterial infection: MDR: 70%, PDR: 7%, ESBL: 40%, CRE: 30%, CRAB: 26.6%, MDR-EF: 13.3% and fungal infection: 19 (17.3%)]. On univariable analysis, SIRS (33.6% vs.3%), ICU admission (78.2% vs. 45.5%), mechanical ventilation (88.2% vs. 51.5%), inotropes (39.1% vs. 6.1%), invasive catheters (91.8% vs. 39.4%), and prolonged catheterization (6 days vs. 0 days) were significant risk factors for infections (p < 0.05, each). In contrast, SIRS and catheterization independently predicted infection on multivariable regression. Organ failures [3 (2-4) vs. 1 (0-2)], grade-III-IV HE (67.3% vs. 33.3%), circulatory failure (39.1% vs. 6.1%), coagulopathy (INR > 2.5: 58.2% vs. 33.3%), renal injury (28.2% vs. 6.1%) (p < 0.05), MELD (32.9 ± 8.2 vs. 26.7 ± 8.3) and CPIS [3(2-4) vs. 2(0-2)] were higher in infected vs. non-infected patients (p < 0.001). 30-day survival was significantly lower in infected vs. non-infected patients (17.3% vs. 75.8%, p < 0.001), while no patient survived with fungal infections. Refractory septic shock was the commonest cause of mortality in patients. CONCLUSIONS: Infections due to MDR organisms are high, fungal infections are fatal, and refractory septic shock is the dominant reason for mortality, implying bacterial and fungal infections as the major killer in ALF patients.

Antibody Response and Safety of ChAdOx1-nCOV (Covishield) in Patients with Cirrhosis: A Cross-Sectional, Observational Study.

INTRODUCTION: Patients with cirrhosis have a higher risk of severe COVID-19 and mortality and are high-priority patients for vaccination. However, cirrhotics were excluded from the phase 2/3 vaccine trials. Hence, we aimed to assess the antibody response and safety of Covishield (ChAdOx1nCoV-19) among patients with cirrhosis. METHODS: Patients who attended the tele-hepatology services at our institute from March 2020 to June 2021 and diagnosed with cirrhosis as per their medical records were telephonically interviewed in July 2021 using a pre-specified questionnaire. Patients who had completed 2 doses of ChAdOx1-nCOV (with the 2nd dose administered at least 2 weeks back) and without history of documented COVID-19 infection (pre- or post-vaccination) were tested for antibodies against the spike protein. Seropositive patients were divided into high, moderate, and low antibody responses based on the signal/cut-off. RESULTS: We interviewed 784 patients with cirrhosis. At least 1 dose of ChAdOx1-nCOV was received by 231 patients among whom 134 (58%) had received 2 doses. Documented COVID-19 was reported in 3.9% patients who received at least 1 dose of ChAdOx1-nCOV including breakthrough infections in 3.7% patients vaccinated with 2 doses. Local and systemic adverse events were reported by 42% and 22.1% patients. None developed anaphylaxis, acute decompensation, acute-on-chronic liver failure, or other serious adverse events requiring hospitalization. Seroconversion was documented in 81 (92%) out of 88 patients. No difference was observed in level of antibody response between patients with compensated and decompensated cirrhosis (p = 0.12). CONCLUSION: Our preliminary data suggest that ChAdOx1-nCOV is safe with high seroconversion rates in patients with cirrhosis.

Association of Heparin-Like Effect, Factor VII/XIII Deficiency and Fibrinolysis with Rebleeding Risk in Cirrhosis with Acute Variceal Bleeding.

BACKGROUND: Hyperfibrinolysis and coagulation dysfunction may occur in cirrhotic patients with acute variceal bleed (AVB) despite successful endotherapy. AIMS: To prospectively study the association of endogenous heparinoids and coagulation dysfunction with variceal rebleeding and outcome in cirrhosis. METHODS: Consecutive patients were assessed with conventional coagulation tests, SONOCLOT™ [(global(gb) and heparinase(h) treated] and factors VII, VIII, XIII, X, tissue plasminogen activator, and plasminogen activator inhibitor ELISA assays in a university hospital. Heparin-like-effect (HLE) was defined as ≥ 20% difference in paired gb/h-SONOCLOT™ traces for activated clotting time (ACT). RESULTS: Of 143 patients screened, 90 (46.4 ± 11.7 years, males 82.2%, ethanol-related 58.8%) were recruited, who bled from esophageal varices (81,90.0%), gastric varices (6,6.6%), or esophageal varices with portal hypertensive gastropathy (3,3.3%). Twenty (21.7%) had early rebleeding, mainly post-variceal ligation ulcer related (70%). Patients who rebled had low Factor XIII [1.6 (1.2-2.1) vs 2.4 ng/ml (2.0-2.8) P = 0.035] and Factor VII (94.1 ± 46.9 vs. 124.0 ± 50.4, P = 0.023). On receiver operating curve analysis, the gbACT > 252 s (sensitivity 86.8%, specificity 76.9%, P < 0.001), hACT > 215 s (sensitivity 71.1%, specificity 70.3%, P < 0.001), and HLE > 50% (sensitivity 69.5%, specificity 70.3%, P = 0.006) predicted rebleeding. Baseline Factor VIII (HR 1.26; 95% CI 1.17-1.34, P < 0.001), low factor VII (HR 0.89; 95% CI 0.76-0.98, P = 0.035), and lysis (HR 1.25, 95% CI 1.17-1.33, P < 0.001) predicted mortality. Endogenous heparinoids at baseline predicted sepsis (HR 1.8; 95% CI 1.4-6.5; P = 0.022), rebleeding events (HR 1.2; 95% CI 1.1-6.3; P = 0.030), and mortality (HR 1.1; 95% CI 1.0-4.6; P = 0.030). CONCLUSIONS: Hyperfibrinolysis, Factor VII/XIII deficiency, and HLE are associated with rebleeding after AVB. Trial Registration NCT04111120 available from https://clinicaltrials.gov/ct2/show/NCT04111120 .

Improvement of chronic HCV infection-related depression, anxiety, and neurocognitive performance in persons achieving SVR-12: A real-world cohort study.

Chronic hepatitis C virus (HCV) infection is associated with neuropsychiatric changes. Also, patients with cirrhosis may develop overt or minimal hepatic encephalopathy. Sustained virological response (SVR) with direct-acting antiviral agents (DAAs) may improve the neuropsychiatric manifestations and quality of life (QoL). Consecutive patients (with and without cirrhosis, all genders and aged 18-65 years) with hepatitis C were assessed at enrolment and at 12 weeks after therapy completion for mood (Beck's Depression Inventory [BDI]), anxiety (generalized anxiety disorder [GAD-7]), QoL (SF-36 ver.2) and computer-based tests for number connection (NCT), visual memory, Stroop test and reaction times. We recruited 385 viraemic chronic HCV patients (76.1% male, 21.0% cirrhotic, mean age 39.4 ± 14.2 years, 59.3% genotype 3, mean HCV RNA load 5.8 log). Overall SVR-12 rates were 90.6%, with cure rates 87.6% and 91.4% in patients with and without cirrhosis, respectively. Patients who achieved SVR-12 had mean percentage reduction in BDI (11.3%, p = .000), GAD (8.6%, p = .001) and Stroop test (58.4%, p = .001), with improved NCT (1.7%, p = .001), visual memory (13.7%, p = .001) and digit span (23.8%, p = .002). On multivariate logistic regression, adherence (OR, 17.5 [95% CI 2.80-110.50], p = .000), high ALT (OR 1.02 [95% CI 1.00-1.05]), and BDI score (OR 1.73 [95% CI 1.42-3.26] p = .039) predicted cure. SVR-12 was associated with improved visual memory ≥5.5 (AUC-0.708; sensitivity 62.5%, specificity 63%, p = .000) and % correct Stroop test responses >26.6% (AUC-0.918, sensitivity 94.4% specificity 80.4%, p = .000). In conclusion, given the cumulative evidence of the safety of DAAs and efficacy of improving cognitive and neuropsychological and quality-of-life outcomes irrespective of age and gender, as shown in our study, future recommendations should focus on integrated universal HCV care to enable HCV elimination.

Combined PEG3350 Plus Lactulose Results in Early Resolution of Hepatic Encephalopathy and Improved 28-Day Survival in Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality in those with hepatic encephalopathy (HE). Polyethylene glycol (PEG) 3350 electrolyte solution can ensure rapid gut catharsis, which may resolve HE more effectively than lactulose. In this open-label-randomized trial, we compared PEG+lactulose versus lactulose alone in ACLF with HE grade ≥2 for efficacy and outcome. PATIENTS AND METHODS: Patients were randomized to receive PEG (2 L q12 h) followed by lactulose (30 mL q8 h) or standard medical treatment [SMT, lactulose (titrated 30 mL q8 h)]. Endpoints were HE grade improvement at 24 hours, 48 hours, and 7 days using hepatic encephalopathy scoring algorithm (HESA), ammonia reduction, HE resolution, and survival benefit. RESULTS: Of 60 patients, 29 were randomized to PEG+lactulose arm and 31 to SMT. In the PEG arm, early reduction in HESA score was noted in more persons [18 (62.1%) vs. 10 (32.2%); P=0.021] with a shorter median time to HE resolution [4.5 (3 to 9) d vs. 9 (8 to 11) d; P=0.023]. On multivariate analysis, age [hazard ratio (HR),1.06 (1.00 to 1.13); P=0.03], HESA score [HR, 6.01 (1.27 to 28.5); P=0.024], and model for end-stage liver disease [HR, 1.26 (1.01 to 1.53); P=0.022] were predictors of mortality at 28 days. Ammonia level or reduction did not correlate with HE grades. Adverse events included excessive diarrhea (20.6% vs. 9.6%) in the PEG and SMT arms, albeit without dyselectrolytemia or worsened renal function. In the PEG versus SMT arm, survival at 28 days were 93.1% versus 67.7% (P=0.010) and at 90 days was 68.9% versus 48.3% (P=0.940), respectively, with fewer persons relapsing with HE in the PEG arm. CONCLUSIONS: PEG resulted in early and sustained HE resolution with improved short-term survival making, it a suitable and safe drug in patients with acute HE in ACLF.

Long-term hepatic and cardiac health in patients diagnosed with Sheehan's syndrome.

PURPOSE: Sheehan's syndrome (SS) is characterised by chronic pituitary insufficiency following a vascular insult to the pituitary in the peripartum period. There is a lack of substantial evidence on the long-term hepatic and cardiac consequences in these patients, following hormone replacement. METHODS: Patients with a diagnosis of SS were recruited for the study. Detailed clinico-biochemical and radiological evaluation were performed in all patients (n = 60). Hepatic and cardiac complications were assessed using fibroscan and echocardiography (2D speckle-tracking) respectively, in a subset of patients (n = 29) as well as age-and BMI-matched controls (n = 26). Controlled attenuation parameter (for steatosis) and liver stiffness measurement (for fibrosis) were used to define non-alcoholic fatty liver disease (NAFLD). Diastolic cardiac function was evaluated using standard criteria and systolic function by ejection fraction and global longitudinal strain (GLS). RESULTS: The mean age of the cohort was 42.7 ± 11.6 years. Multiple (≥ 2) hormone deficiencies were present in 68.8% of patients, with hypothyroidism (91.4%), hypocortisolism (88.3%), and growth hormone (GH) deficiency (85.7%) being the most common. At a mean follow-up of 9.8 ± 6.8 years, NAFLD was present in 63% of patients, with 51% having severe steatosis, which was predicted by the presence of GH deficiency and higher body mass index. Though the ejection fraction was similar, increased left ventricular GLS (18.8 vs. 7.7%) was present in a significantly higher number of patients versus controls. CONCLUSION: NAFLD, especially severe hepatic steatosis, is highly prevalent in SS. Subclinical cardiac systolic dysfunction (impaired GLS) is also more common, but of mild intensity.

Sofosbuvir plus velpatasvir combination for the treatment of chronic hepatitis C in patients with end stage renal disease on renal replacement therapy: A systematic review and meta-analysis.

INTRODUCTION: Sofosbuvir (SOF) and velpatasvir (VEL) is a pan-genotypic regimen for the treatment of Hepatitis C virus (HCV) infection. The data on the efficacy and safety of this regimen is end-stage renal disease (ESRD) is scanty. This systematic review and meta-analysis was done to ascertain the efficacy and safety of SOF and VEL in patients with chronic Hepatitis C (CHC) and ESRD on renal replacement therapy (RRT). METHODS: Systematic search of Pubmed, Embase, Scopus, and Google Scholar was conducted using the search term (end-stage renal disease OR renal replacement therapy OR chronic kidney failure OR severe renal impairment OR chronic kidney disease OR haemodialysis OR dialysis OR peritoneal dialysis) AND (sofosbuvir OR velpatasvir OR NS5A inhibitors OR directly acting antivirals). Pooled sustained virologic response (SVR) and adverse event rates with 95% confidence intervals were estimated. RESULTS: Seven studies (410 patients with CHC and ESRD on RRT) fulfilled our eligibility criteria. The overall pooled SVR rate of SOF and VEL in patients with HCV on RRT was 97.69% (95% CI: 95.71 to 98.92). There was no significant heterogeneity (I2 : 39.3%, p-value of Cochran's Q = 0.13) among the studies. The pooled estimate of efficacy of SOF-VEL combination among patients with cirrhosis was 91.94% (95% CI 77.03-98.52). Pooled SVR rates in genotype 3 infection [94.6%, (95%: CI 81.3-99.4)] was comparable to that in those with documented non-genotype 3 infection [94.63%, (95% CI 87.12-98.44)]. No serious adverse event attributable to SOF and VEL was reported in the included studies. CONCLUSION: The fixed-dose combination of SOF and VEL is effective and safe in CHC patients with ESRD on RRT.

NLRP3 Inflammasome Activation is a Prognostic Marker of Recovery in HEV-Infected Patients.

Hepatitis E contributes to 3.3 million acute hepatitis cases worldwide with 30% mortality in pregnant women. Pathogenesis of Hepatitis E is complex; thus, the present study was aimed at inflammasomes and associated cytokines in the immunopathogenesis of viral hepatitis E. PBMCs were isolated from 45 HEV IgM/HEV RNA-positive AVH/ALF and 19 healthy individuals and processed for mRNA expressions of NLRs, RLRs, and cytokines. PBMCs were cultured and stimulated with HEV-pORF-2 peptide in vitro for mRNA expression by RT-PCR and cytokines levels in serum/culture supernatant by ELISA. siRNA transfection and post-silencing effect in AVH PBMCs were also assessed by NLRP3 gene expression and IL-1ß and IL-18 levels by ELISA. The results demonstrated high viral load in ALF than AVH cases. mRNA expression of NLRP3 in AVH patients was found to be positively correlated with IL-18 (r = 0.74) and IL-1ß (r = 0.68); P < 0.0001***. Significant levels of serum IL-1ß and IL-18 cytokines were observed in AVH as compared to ALF patients. The levels of IL-1ß in the culture supernatant in mock and stimulated conditions were significantly higher in AVH than in ALF patients. Significant downregulation in NLRP3 gene expression was correlated with the reduced levels of IL-1ß and IL-18 cytokines in NLRP3-siRNA-transfected PBMCs. This study highlighted the significance of upregulated NLRP3 inflammasome leading to increased production of IL-18 and IL-1ß cytokines in sera of AVH patients. Thus, it indicated the role of Th1 response acting through the NLRP3 pathway which might have been helpful in the recovery of AVH patients. These promising results open multiple treatment avenues where specific inhibitors can be designed to modulate the progress of disease and its pathogenicity.