Combination of carvedilol with variceal band ligation in prevention of first variceal bleed in Child-Turcotte-Pugh B and C cirrhosis with high-risk oesophageal varices: the 'CAVARLY TRIAL'.

OBJECTIVES: Beta-blockers and endoscopic variceal band ligation (VBL) have been preferred therapies for primary prophylaxis of variceal bleeding. However, the choice of therapy in patients with advanced liver disease with high-risk varices is not clear. A comparison of these therapies alone or in combination to prevent the first variceal bleed in advanced cirrhosis patients was carried out. DESIGN: 330 Child-Turcotte-Pugh (CTP) B and C cirrhosis patients, with 'high-risk' varices were prospectively enrolled (n=110 per group) to receive carvedilol (group A), VBL (group B) or combination (group C). Primary endpoint was reduction in the incidence of first variceal bleed at 12 months. The secondary endpoints included overall mortality, bleed-related mortality, new-onset decompensation, change in hepatic vein pressure gradient (HVPG) and treatment-related adverse events. RESULTS: The patients were predominantly males (85.2%), aged 51.4±10.5 years with CTP score of 8.87±1.24, MELD score 15.17±3.35 and HVPG-16.96±3.57 mm Hg. The overall incidence of variceal bleed was 23.8% (n=78) at 1 year. Intention-to-treat analysis showed that the combination arm (group C) significantly reduced the incidence of first variceal bleed by 62.9% as compared with group B (HR 0.37, 95% CI 0.192 to 0.716, p<0.003) and by 69.3% as compared with group A (HR 0.31, 95% CI 0.163 to 0.578, <0.001). The overall mortality was 13.6% (45/330). The 1-year mortality in group C was lowest among the three groups (A, B, C=20%, 14.5%, 6.3%, p=0.012). Reduction in HVPG (20.8% vs 25.1%, p=0.54) and the rate of non-response to carvedilol (53.4% vs 41.25%, p=0.154) were not different between group A and C patients. The incidence of new-onset ascites, spontaneous bacterial peritonitis, shock, and acute kidney injury and postbleed organ failure was also comparable between the groups. CONCLUSION: In CTP B and C cirrhosis patients with high-risk varices, combination of carvedilol and VBL is more effective than either therapy alone, for primary prevention of variceal bleeding. TRIAL REGISTRATION NUMBER: NCT03069339.

Predictors and Outcomes of Post-transjugular Intrahepatic Portosystemic Shunt Liver Failure in Patients with Cirrhosis.

BACKGROUND: Post-transjugular intrahepatic portosystemic shunt (TIPS) liver failure (PTLF) is a serious complication of TIPS procedure with poor patient prognosis. This study tried to investigate the incidence of PTLF following elective TIPS procedure and evaluated possible predictive factors for the same. METHODS: A retrospective analysis of patients who underwent elective TIPS placement between 2012 and 2022 and was conducted to determine development of PTLF (≥ 3-fold bilirubin and/or ≥ 2-fold INR elevation from the baseline) within 30 days following TIPS procedure. Medical record review was done and factors predicting development of PTLF and the 90-day transplant-free survival was determined. RESULTS: Thirty of 352 (8.5%) patients developed PTLF within 30 days of TIPS (mean age 54.2 ± 9.8 years, 83% male). The etiology of cirrhosis was related to non-alcoholic steatohepatitis (NASH) in 50%, alcohol in 33.3%, and hepatitis B/C virus infection in 16.7% of the patients. The mean Child-Turcotte-Pugh (CTP) score was 9.5 ± 1.2 and mean model for end stage liver disease (MELD) score was 14.6 ± 4.5 at the time of admission in patients who developed PTLF. The indication for TIPS was recurrent variceal bleed in 50% (15 of 30) and refractory ascites in 46.7% (14 of 30) patients with PTLF. Multivariate analysis identified prior HE (OR 6.1; CI 2.57-14.5, p < 0.0001) and higher baseline CTP score (OR 1.47; CI 1.07-2.04; p = 0.018) as predictors of PTLF. PTLF was associated with significantly lower 90-day transplant-free survival, as compared to patients without PTLF (40% versus 96%, p < 0.001). CONCLUSION: Almost 10% of patients with cirrhosis develop post-TIPS liver failure and is associated with significant early mortality and morbidity. Higher baseline CTP score and prior HE were identified as predictors for PTLF.

A randomised-controlled trial (TARGET-C) of high vs. low target mean arterial pressure in patients with cirrhosis and septic shock.

BACKGROUND & AIMS: A high mean arterial pressure (MAP) target has been associated with improved renal outcomes in patients with cirrhosis, though it has not been studied in critically ill patients with cirrhosis and septic shock (CICs). We compared the efficacy of a high (80-85 mmHg; H-MAP) vs. low (60-65; L-MAP) target MAP strategy in improving 28-day mortality in CICs. METHODS: We performed open-label 1:1 randomisation of 150 CICs (H-MAP 75; L-MAP 75). The primary endpoint was 28-day mortality and secondary endpoints included reversal of shock, acute kidney injury (AKI) at day 5, the incidence of intradialytic hypotension (IDH), and adverse events. Endothelial markers were analysed in a subset of patients. RESULTS: The baseline characteristics were comparable. On intention-to-treat analysis, 28-day mortality (65% vs. 56%; p = 0.54), reversal of shock (47% vs. 53%; p = 0.41) and AKI development (45% vs. 31%;p = 0.06) were not different between the H-MAP and L-MAP groups, respectively. A lower incidence of IDH (12% vs. 48%; p <0.001) and higher adverse events necessitating protocol discontinuation (24% vs. 11%; p = 0.031) were noted in the H-MAP group. On per-protocol analysis (L-MAP 67; H-MAP 57), a significantly higher reversal of AKI (53% vs. 31%; p = 0.02) and a lower incidence of IDH (4% vs. 53%; p <0.001) were observed in the H-MAP group. Endothelial repair markers such as ADAMTS (2.11 ± 1.13 vs. 1.15 ± 0.48; p = 0.002) and angiopoietin-2 (74.08 ± 53.00 vs. 41.80 ± 15.95; p = 0.016) were higher in the H-MAP group. CONCLUSIONS: A higher MAP strategy does not confer a survival benefit in CICs, but improves tolerance to dialysis, lactate clearance and renal recovery. Higher adverse events indicate the need for better tools to evaluate target microcirculation pressures in CICs. IMPACT AND IMPLICATIONS: Maintaining an appropriate organ perfusion pressure during sepsis is the ultimate goal of haemodynamic management. A higher mean arterial pressure (MAP) improves renal outcomes in patients with hepatorenal syndrome. Patients with cirrhosis and septic shock have severe circulatory disturbances, low MAP, and poor tissue perfusion. In these patients, targeting higher MAP vs. lower MAP does not confer any survival benefit but is associated with more adverse events. A higher target strategy was associated with better tolerance and lesser episodes of hypotension on dialysis. Patients who could achieve the higher target MAP, without the development of adverse events, had improved renal outcomes and better lactate clearance. Higher MAP was also associated with improvements in markers of endothelial function. A higher target MAP strategy, with close monitoring of adverse events, may be recommended for patients with cirrhosis and septic shock. CLINICAL TRIAL NUMBER: NCT03145168.

Diagnostic yield and therapeutic impact of novel motorized spiral enteroscopy in small-bowel disorders: a single-center, real-world experience from a tertiary care hospital (with video).

BACKGROUND AND AIMS: Novel motorized spiral enteroscopy (NMSE) is a recent advancement in the field of enteroscopy and offers multiple features, including self-propulsion, better irrigation, and shorter enteroscope length with a larger channel. The aim of this study was to evaluate the efficacy in terms of diagnostic yield and therapeutic success of NMSE in patients undergoing enteroscopy by antegrade and/or retrograde approaches for suspected small-bowel disease. METHODS: We retrospectively evaluated consecutive patients with symptomatic small-bowel disease who underwent enteroscopy over a 6-month period. Diagnostic yield, therapeutic success, total enteroscopy rate (TER), technical success, total procedural time, depth of maximal insertion, and adverse events related to the NMSE procedure were noted. RESULTS: Of 61 patients (mean age, 45.67 ± 15.37 years; 43 men) included for NMSE, 57 patients underwent successful enteroscopy with a technical success of 93.4%. The overall diagnostic yield was 65.5% (95% confidence interval, 52.31-77.27) and 70.1% (95% confidence interval, 56.60-81.57) in patients who underwent successful NMSE; TER was 60.6%: 31.1% by the antegrade approach and 29.5% by a combined antegrade and retrograde approach. Depth of maximal insertion and procedural time was of 465 cm (range, 100-650) and 40 minutes (range, 25-60), respectively, by the antegrade approach and 140 cm (range, 50-200) and 35 minutes (range, 30-60) by the retrograde route. Lesions were classified as inflammatory (n = 25), vascular (n = 10), and mass (n = 4). Biopsy specimens were obtained in 50.8% subjects, and 23% patients underwent therapeutic procedures. No major adverse events were seen. CONCLUSIONS: NMSE is a promising technology, showing high efficacy as a diagnostic and therapeutic tool in the management of otherwise difficult-to-treat small-bowel disease.

APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

PIRO-CIC model can predict mortality and futility of care in critically ill cirrhosis patients in the intensive care unit.

BACKGROUND: Dynamic assessment of critically ill patients with cirrhosis (CICs) is required for accurate prognostication. OBJECTIVE: Development of a dynamic model for prediction of mortality and decision on futility of care in CICs. DESIGN AND SETTING: In a prospective cohort study, we developed the PIRO-CIC model (predisposition, injury, response, organ failure for critically ill cirrhotics)] in a derivative cohort (n = 360) and validated it (n = 240) for patients admitted to the Liver ICU. PATIENTS: Decompensated cirrhosis admitted to ICU. The model was developed using Cox-regression analysis, and futility was performed by decision-curve analysis. RESULTS: CICs aged 48 ± 11.5 years, 87% males, majority being alcoholics, were enrolled, of which 73.5% were alive at one month. Factors significant for P component were INR [hazard ratio 1.12, 95% confidence interval 1.07-1.18] and CystatinC [2.25, 1.70-2.97]; for I component were sepsis [4.69, 1.90-11.57], arterial lactate[1.40, 1.02-1.93] and alcohol as etiology [2.78, 1.85-4.18]; for R component-systemic inflammatory response syndrome [1.97, 1.14-3.42] and urine neutrophil-gelatinase-associated lipocalin [HR 2.37, 1.59-3.53]; for O component-low PaO2/FiO2 ratio and need of mechanical ventilation [7.41, 4.63-11.86]. The PIRO-CIC model predicted one-month mortality with a C-index of 0.83 in the derivation and 0.80 in the validation cohorts. It predicted futility of care better than other prognostic scores. The immediate risk of mortality increased by 39% with each unit increase in PIRO-CIC score. LIMITATIONS: Not applicable for acute-on-chronic liver failure and patients requiring emergency liver transplant. CONCLUSIONS: Assessment and stratification of CICs with the dynamic PIRO-CIC model could determine one-month mortality and futility in the first week. Targeted and aggressive management of coagulation, kidneys, sepsis, and severe systemic inflammation may improve outcomes of CICs.

Ictal Blinking in Hepatic Encephalopathy Pre- and Post-Liver Transplant: Report of Eight Patients.

Objective Seizures are reported in 20 to 30% of cases with chronic liver disease in association with hepatic encephalopathy. Majority of these are focal seizures. Ictal blinking is reported first time in these patients pre- and post-liver transplant. Methods From November 2018 to October 2021, retrospective data was analyzed in patients with end-stage liver disease and hepatic encephalopathy, both pre- and post-liver transplant. Results Eight patients had ictal blinking, four were pre-transplant and four post-transplant. Five patients (four after liver transplant and one pre-transplant) were seizure free, three died of liver disease and multiorgan dysfunction, and one did not follow-up. Conclusion Ictal blinking in relation to liver disease and hepatic encephalopathy is reported, often missed and requires short duration antiepileptic medications.

Use of thiopurines in inflammatory bowel disease: an update.

Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.

Single-use duodenoscope in the management of an elderly patient with difficult bile duct stones: laser lithotripsy using a disposable cholangioscope.

Video 1Single-use duodenoscope in the management of an elderly patient with difficult bile duct stones using laser lithotripsy and a disposable cholangioscope.

Efficacy and safety of obeticholic acid in liver disease-A systematic review and meta-analysis.

BACKGROUND AND AIMS: Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA. METHODS: We performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67 ULN) in PBC, and the adverse effects of OCA. RESULTS: Seven RCTs (n = 2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47-2.59; p < 0.001)]. With the 10 mg OCA dose, the odds of improvement was 1.61 (1.03-2.51; p = 0.03), while with the 25 mg dose, it was 2.23 (1.55-3.18; p < 0.001). However, 25 mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42-3.02); p < 0.001)] compared with 10 mg OCA [0.95 (0.6-1.5); p = 0.84] in NASH patients. In PBC patients, the response to 5 mg OCA was better than with the higher doses [5 mg: 7.66 (3.12-18.81; p < 0.001), 10 mg: 5.18 (2-13.41; p = 0.001), 25 mg: 2.36 (0.94-5.93; p = 0.06), 50 mg: 4.08 (1.05-15.78; p = 0.04)]. The risk of pruritus was lowest with 5 mg OCA. CONCLUSIONS: Lower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10 mg OCA is effective for NASH fibrosis regression, only 5 mg OCA is required for PBC.

Impact of COVID-19 on liver transplant recipients-A systematic review and meta-analysis.

BACKGROUND: Immunosuppression and comorbidities increase the risk of severe coronavirus disease-2019 (COVID-19) in solid organ transplant (SOT) recipients. The outcomes of COVID-19 in liver transplant (LT) recipients remain unclear. We aimed to analyse the outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients. METHODS: The electronic databases were searched for articles published from 1 December 2019 to 20 May 2021 with MeSH terms COVID-19, SARS-CoV-2, and liver transplantation. Studies reporting outcomes in more than 10 LT recipients were included for analysis. LT vs non-LT patients with COVID-19 infection were compared for all-cause mortality, which was the primary outcome studied. We also evaluated the relation between the timing of COVID-19 infection post-LT (< one year vs > one year) and mortality. FINDINGS: Eighteen articles reporting 1,522 COVID-19 infected LT recipients were included for the systematic review. The mean age (standard deviation [SD]) was 60·38 (5·24) years, and 68·5% were men. The mean time (SD) to COVID-19 infection was 5·72 (1·75) years. Based on 17 studies (I2 = 7·34) among 1,481 LT recipients, the cumulative incidence of mortality was 17·4% (95% confidence interval [CI], 15·4-19·6). Mortality was comparable between LT (n = 610) and non-LT (n = 239,704) patients, based on four studies (odds ratio [OR], 0·8 [0·6-1·08]; P = 0·14). Additionally, there was no significant difference in mortality between those infected within one year vs after one year of LT (OR, 1·5 [0·63-3·56]; P = 0·35). The cumulative incidence of graft dysfunction was 2·3% (1·3-4·1). Nearly 23% (20·71-25) of the LT patients developed severe COVID-19 infection. Before infection, 71% and 49% of patients were on tacrolimus and mycophenolate mofetil, respectively. Immunosuppression was modified in 55·9% (38·1-72·2) patients after COVID-19 infection. INTERPRETATION: LT and non-LT patients with COVID-19 have a similar risk of adverse outcomes.

To assess the efficacy of safety measures adopted during endoscopy in the Corona Virus Disease-19 era for health care professionals-A single-centre tertiary care hospital experience.

BACKGROUND AND OBJECTIVES: During Corona Virus Disease-19 (COVID-19) pandemic, it has been estimated that approximately 10% of health care professionals (HCPs) have been diagnosed contacting  COVID-19. Aerosol-generating procedures have led to change in safety practices among HCPs. We thus evaluated the efficacy of the endoscopic safety measures among HCPs posted in the endoscopy unit. METHODS: In this retrospective analysis, all endoscopic procedures performed over a period of 4 months, from 1 April to 31 July 2020 were included. We noted indications and number of COVID-positive procedures as well as comprehensive screening of HCPs posted in our endoscopy unit. The aim of the study was to evaluate the incidence and outcome of COVID-19 among HCPs. RESULTS: Three thousand four hundred and sixty procedures were included in the analysis. Indications were divided as urgent (n = 190, 5.49%), semi-urgent (n = 553, 16%) and non-urgent group (n = 2717, 78.52%). Thirty-four procedures (0.98%) were done on diagnosed COVID-19 patients. The most common indications were gastrointestinal bleed (n = 12/34, 35.30%) followed by biliary sepsis (n = 9/34, 26.5%). Among the HCPs, the incidence of symptomatic COVID-19 was 6.58% (n = 5/76). All HCPs recovered with excellent outcomes. A comprehensive screening showed 7.90% (n = 6/76) HCPs having Immunoglobulin G (IgG) antibody in their sera. CONCLUSION: Addition of safety measures in endoscopy leads to low risk of transmission among HCPs.

Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19.

BACKGROUND: The incidence of elevated liver chemistries and the presence of pre-existing chronic liver disease (CLD) have been variably reported in COVID-19. AIMS: To assess the prevalence of CLD, the incidence of elevated liver chemistries and the outcomes of patients with and without underlying CLD/elevated liver chemistries in COVID-19. METHODS: A comprehensive search of electronic databases from 1 December 2019 to 24 April 2020 was done. We included studies reporting underlying CLD or elevated liver chemistries and patient outcomes in COVID-19. RESULTS: 107 articles (n = 20 874 patients) were included for the systematic review. The pooled prevalence of underlying CLD was 3.6% (95% CI, 2.5-5.1) among the 15 407 COVID-19 patients. The pooled incidence of elevated liver chemistries in COVID-19 was 23.1% (19.3-27.3) at initial presentation. Additionally, 24.4% (13.5-40) developed elevated liver chemistries during the illness. The pooled incidence of drug-induced liver injury was 25.4% (14.2-41.4). The pooled prevalence of CLD among 1587 severely infected patients was 3.9% (3%-5.2%). The odds of developing severe COVID-19 in CLD patients was 0.81 (0.31-2.09; P = 0.67) compared to non-CLD patients. COVID-19 patients with elevated liver chemistries had increased risk of mortality (OR-3.46 [2.42-4.95, P < 0.001]) and severe disease (OR-2.87 [95% CI, 2.29-3.6, P < 0.001]) compared to patients without elevated liver chemistries. CONCLUSIONS: Elevated liver chemistries are common at presentation and during COVID-19. The severity of elevated liver chemistries correlates with the outcome of COVID-19. The presence of CLD does not alter the outcome of COVID-19. Further studies are needed to analyse the outcomes of compensated and decompensated liver disease.