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.

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.

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.

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.

Granulocyte colony stimulating factor: A potential therapeutic rescue in severe alcoholic hepatitis and decompensated cirrhosis.

Liver cirrhosis accounts for over 2 million deaths annually worldwide. A subset of these patients - those with alcoholic hepatitis and decompensated cirrhosis, have abysmal short-term survival. Liver transplant is the only intervention of proven survival benefit; however organ availability is a major limitation. It is thus imperative to assess potential benefit of experimental therapies as a bridge to transplant. Stem cell therapies have shown some promise in patients with end-stage liver disease. Of these, bone-marrow derived hematopoietic stem cells have generated the most interest. Animal as well as human data suggest biological plausibility of stem cell translocation from bone marrow to liver, giving credence to cytokine therapies based on bone marrow stimulation. Granulocyte colony stimulating factor has been the most frequently used cytokine for this purpose. This intervention has shown encouraging results in terms of safety as well as survival benefits in small clinical trials. The evidence, however, is sparse and heterogeneous. In this review we describe the biological plausibility, mechanisms of action, and clinical evidence of the use of cytokine based stem cell therapy in patients with end-stage liver disease.

Comparative Efficacy of Treatment Options for Minimal Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis.

BACKGROUND & AIMS: We aimed to synthesize evidence for most effective treatments for minimal hepatic encephalopathy (HE) and prevention of overt HE in patients with cirrhosis. METHODS: We performed a systematic search of the PubMed, EMBASE, OvidSP, and Cochrane Central Register of Controlled Trials databases through July 26, 2018, for randomized controlled trials evaluating treatments for minimal HE in patients with cirrhosis, with primary outcomes of reversal of minimal HE or prevention of overt HE. We conducted a meta-analysis and then used network meta-analysis and surface under cumulated ranking (SUCRA) to pool the direct and indirect estimates and rank the different treatments. We appraised study quality using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Our meta-analysis and network meta-analysis included 25 trials, comprising 1563 participants. Agents found to be effective in reversing minimal HE compared with placebo or no treatment included rifaximin (odds ratio [OR], 7.53; 95% predictive interval [PrI], 4.45-12.73; SUCRA, 89.2%; moderate quality), lactulose (OR, 5.39; 95% PrI, 3.60-8.0; SUCRA, 67.2%; moderate quality), the combination of probiotics and lactulose (OR, 4.66; 95% PrI, 1.90-11.39; SUCRA, 52.4%; low quality), L-ornithine L-aspartate (OR, 4.45; 95% PrI, 2.67-7.42; SUCRA, 47.2%; low moderate quality), and probiotics (OR, 3.89; 95% PrI, 2.52-6.02; SUCRA, 34.1%; low quality). Agents found to be effective in preventing episodes of overt HE compared with placebo or no treatment included L-ornithine L-aspartate (OR, 0.19; 95% PrI, 0.04-0.91; SUCRA, 75.1%; high moderate quality), lactulose (OR, 0.22; 95% PrI, 0.09-0.52; SUCRA, 73.9%; moderate quality), and probiotics (OR, 0.27; 95% PrI, 0.11-0.62; SUCRA, 59.6%; low quality). CONCLUSIONS: In a meta-analysis of data from 25 trials, we found rifaximin and lactulose to be most effective for reversal of minimal HE in patients with cirrhosis. L-ornithine L-aspartate and lactulose are most effective in the prevention of overt HE. Lactulose was the only agent that was effective in reversing minimal HE, preventing overt HE, reducing ammonia, and improving quality of life, with tolerable adverse effects. International prospective register of systematic reviews ID: 107003.

Prediction of 28-day mortality in acute decompensation of cirrhosis through the presence of multidrug-resistant infections at admission.

BACKGROUND AND AIM: The aim of this study is to evaluate the epidemiology and impact of bacterial infections at admission in patients with acute decompensation (AD) of cirrhosis. METHODS: A cohort with AD of cirrhosis (European Association for the Study of the Liver criteria) admitted at a tertiary center was evaluated between 2013 and 2014 for the presence of bacterial infections at admission. Clinical, demographic, and microbiological data were collected prospectively till death, transplant, or 90 days. RESULTS: Of 179 patients with AD, 102 (56.9%) had bacterial infections at admission. The commonest infections were spontaneous bacterial peritonitis (SBP) (n = 65; 63.7%), spontaneous bacteremia (n = 10; 9.8%), pneumonia (n = 9; 8.8%), urinary tract infection (n = 8; 7.8%), spontaneous bacterial empyema (n = 4; 3.9%), and cellulitis (n = 2; 1.9%). The commonest source was community acquired (n = 85; 83.3%). Serum albumin and sodium levels were lower in infected as compared with non-infected cohort (P = 0.015; for both). Escherichia coli was the commonest organism isolated from SBP (n = 14; 21.5%), urinary tract infection (n = 5; 45.5%), and bacteremia (n = 3; 20%). There was a trend toward higher 28-day mortality in infected cohort as compared with non-infected cohort (48 [52.7%] vs 28 [32%]; P = 0.152). Multidrug-resistant organisms (MDROs) were isolated in 63% of all culture-positive infections. The presence of MDRO was an independent predictor of 28-day mortality. CONCLUSIONS: Infections are the leading reason for the occurrence of AD; SBP is the most common infection, and E. coli is the commonest microorganism based on this single-center study of Indian patients with AD of cirrhosis. There is a high prevalence of MDROs among culture-positive infections that independently predict 28-day mortality in AD of cirrhosis.

Decentralized care with generic direct-acting antivirals in the management of chronic hepatitis C in a public health care setting.

BACKGROUND & AIMS: The prevalence of anti-hepatitis C virus antibody in Punjab, India is 3.6%, with 728,000 people estimated to have viremic chronic hepatitis C (CHC). The Mukh-Mantri Punjab Hepatitis C Relief Fund, launched on 18th June 2016, provides no-cost generic direct-acting antivirals (DAAs) with sofosbuvir + ledipasvir ±â€¯ribavirin or sofosbuvir + daclatasvir ±â€¯ribavirin with the goal of eliminating CHC from Punjab. We assessed the safety and efficacy of decentralized treatment of CHC in a public health care setting. METHODS: Primary care providers from 3 university and 22 district hospitals were trained to provide algorithm-based DAA treatment and supervised by telehealth clinics conducted fortnightly. The diagnosis of cirrhosis was based on clinical and radiological evidence, including aspartate aminotransferase-to-platelet ratio index (APRI ≥2.0) and FIB-4 score (>3.25), or on liver stiffness measurement ≥12.5 kPa on Fibroscan®. RESULTS: We enrolled 48,088 individuals with CHC (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhosis; 69.9% genotype [GT] 3) between 18th June 2016 to 31st July 2018. While 36,250 (75.4%) patients completed treatment, 5,497 (11.4%) had treatment interruptions and 6,341 (13.2%) patients are currently ongoing treatment. Sustained virological response at 12 weeks after treatment completion (SVR12) was achieved in 91.6% of patients per protocol, 67.6% in intention-to-treat (ITT) analysis, where all interruptions were treated as failures, and 91.2% in a modified ITT analysis where all patients with successful SVR12 in the interruptions arm were included as cured. SVR12 rates in patients with and without cirrhosis and GT3 versus non-GT3 were comparable. The SVR12 rate was 84.4% in patients who had treatment interruptions. CONCLUSION: Decentralized care of patients with CHC using generic all-oral DAA regimens is safe and effective regardless of genotype or presence of cirrhosis. ClinicalTrials.gov number: NCT01110447. LAY SUMMARY: We assessed the safety and efficacy of public health care using no-cost all-oral generic direct-acting antiviral drugs against hepatitis C in the state of Punjab, India. The goal is elimination of chronic hepatitis C (CHC) by 2030 and involves primary care providers at 25 sites in the state. We enrolled 48,088 individuals (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhotic; 69.9% genotype 3) between 18th June 2016 to 31st July 2018. Cure was achieved in 91.6% of patients, demonstrating that decentralized care of CHC with generic all-oral regimens is safe and effective.

Direct-acting antiviral Therapy Is Safe and Effective in Pediatric Chronic Hepatitis C: The Public Health Perspective.

OBJECTIVES: We assessed the efficacy of decentralized public health services and safety of direct-acting antiviral agents (DAAs) in the treatment of pediatric chronic hepatitis C (CHC) in the Mukh-Mantri Punjab Hepatitis C Relief Fund, a public-health initiative for prevention and control of CHC in Punjab, India. METHODS: Consecutive children with CHC [age ≥12 to <18 years; both treatment-naïve (TN) and treatment-experienced (TE)] were enrolled. Genotyping was not recommended for non-cirrhotic patients and were treated with sofosbuvir (SOF)+ daclatasvir (DCV) for 12 weeks, while genotyping was recommended for patients with cirrhosis. Patients with cirrhosis and genotype (G2) were treated with SOF+DCV+ribavirin (RBV) for 12 weeks, G3 with SOF+DCV+RBV for 24 weeks and G1, 4, 5, and 6 patients were treated with SOF+ledipasvir (LDV)+RBV for 12 weeks. Treatment duration was increased to 24 weeks if RBV was not tolerated. RESULTS: In the first 16 months (June 18, 2016-October 31, 2017), 88 children (mean age 15.8 years; 69.3.3% boys, 72.3% rural) were enrolled. The mean baseline hepatitis C virus RNA log10 IU/mL was 6.0 (range 4.2-7.5 log10 IU/mL), 65.5% with G3, and 2 (2.5%) with cirrhosis. Of 57 with completed treatment, sustained virological response (SVR) 12 was achieved in 56 (98.2%). Unsafe medical practices (55.5%), IV drug abuse (11.1%), and prior surgery (2.7%) were risk-factors for transmission (n = 36). Comparable results were noted in G3 (SVR at 12 weeks [SVR12], 94.3%) versus non-G3 (SVR12, 100%; P = 0.073). No serious adverse effects like anemia and decompensation were reported. CONCLUSIONS: The study demonstrates that the decentralized algorithm-based public-health program can ensure high efficacy (SVR12, 98.2%) and low-cost DAA-based treatment of pediatric patients with CHC.

Assessment of Liver Fibrosis by Transient Elastography Should Be Done After Hemodialysis in End Stage Renal Disease Patients with Liver Disease.

BACKGROUND AND AIMS: The patients with end stage renal disease (ESRD) are at greater risk of acquiring chronic hepatitis B or C and subsequently development of liver disease. The aim of the study was to assess liver fibrosis by transient elastography (TE) and look for factors associated with change in liver stiffness measurement (LSM) with one session of hemodialysis (HD). METHODS: Consecutive ESRD patients on maintenance hemodialysis (MHD) with suspected liver disease were enrolled. They underwent LSM by TE before and after one session of HD. Bioelectric impedance analysis was done to evaluate the volume status at the time of TE. RESULTS: Sixty-eight patients with mean age of 40 ± 14 years were included. There was a significant reduction in LSM after HD (18.5 [95% CI 14.8-23.1] vs. 11.2 [95% CI 8.8-13.7] kPa, p < 0.001), with a mean LSM reduction of 7.2 [95% CI 5.25-9.19] kPa. On stratification in two groups by net ultrafiltration during HD (> or < 2.5 liters [L]), change in LSM was substantially higher in patients when total fluid removed was > 2.5 L (8.6 [95% CI 5.7-11.5] vs. 5.1 [95% CI 2.9-7.5], p = 0.05). In 18 patients who underwent liver biopsy, LSM after HD performed better at detecting significant fibrosis, with area under receiver operating characteristics curve 0.71 [95% CI 0.46-0.97], versus 0.64 [95% CI 0.38-0.90], respectively. An LSM value of 12.2 kPa after HD was 71% sensitive and 74% specific for detection of significant fibrosis (≥ F2), while values less than 9 kPa ruled out significant fibrosis with a sensitivity and specificity of 37 and 100%, respectively. CONCLUSION: LSM by TE decreases significantly after HD in patients with ESRD on long-term MHD. Hence, TE should be done after HD for accurate assessment of liver fibrosis.

Acute Liver Failure Due to Etodolac, a Selective Cycloxygenase- 2 (COX -2) Inhibitor Non-Steroidal Anti-Inflammatory Drug Established by RUCAM-Based Causality Assessment.

Drug induced liver injury is a common cause of acute liver failure (ALF). While most of these cases are due to dose dependent hepatotoxicity with acetaminophen, idiosyncratic drug-induced liver injury (DILI) is responsible for about 15% cases of ALF. Antibiotics are the most common cause of idiosyncratic DILI as well as DILI induced ALF. Etodolac is a selective cycloxygenase- 2 (COX -2) inhibitor non-steroidal anti-inflammatory drug used as an analgesic and anti-inflammatory in musculoskeletal diseases. Severe liver impairment is extremely rare. Till date, only 3 cases of ALF related to etodolac have been reported in the literature. Here we report two cases with a unique presentation of ALF occurring due to DILI caused by etodolac, as diagnosed by Roussel Uclaf Causality Assessment Method (RUCAM).