Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial.

BACKGROUND AND AIMS: Carvedilol is effective in the primary prophylaxis for large oesophageal varices. We investigated its use in preventing progression of small to large oesophageal varices. METHODS: Consecutive cirrhotics with small oesophageal varices were prospectively randomised to either carvedilol (n=70) or placebo (n=70) and followed up for a minimum of 24 months. Endoscopy was done at baseline and six monthly intervals. Hepatic vein pressure gradient (HVPG) was measured at baseline and at 12 months. The primary endpoint was development of large varices. RESULTS: Baseline characteristics in two groups were comparable. The predominant aetiology of cirrhosis was non-alcoholic fatty liver disease in both the groups. The mean dose of carvedilol administered was 12±1.67 mg/day and the target heart rate achieved was 58±3 bpm. A higher proportion of patients in carvedilol group had non-progression to large varices than placebo (79.4% vs 61.4%; p=0.04); the mean time of non-progression to large varices was 20.8 months (95% CI 19.4 to 22.4) in carvedilol group and 18.7 months (95% CI 17.1 to 20.4) in placebo group (p=0.04). There was a modest reduction of HVPG at 1 year in carvedilol group (-8.64%) compared with placebo (+0.33%) (p=0.22). None of the patients in either group died of variceal bleeding or liver-related causes. No major adverse events were observed in either group. CONCLUSIONS: Carvedilol is safe and effective in delaying the progression of small to large oesophageal varices in patients with cirrhosis. TRIAL REGISTRATION NUMBER: NCT01196507; post-results.

A randomized trial comparing terlipressin and noradrenaline in patients with cirrhosis and septic shock.

BACKGROUND & AIMS: The choice of vasopressor for treating cirrhosis with septic shock is unclear. While noradrenaline in general is the preferred vasopressor, terlipressin improves microcirculation in addition to vasopressor action in non-cirrhotics. We compared the efficacy and safety of noradrenaline and terlipressin in cirrhotics with septic shock. PATIENTS AND METHODS: Cirrhotics with septic shock underwent open label randomization to receive either terlipressin (n=42) or noradrenaline (n=42) infusion at a titrated dose. The primary outcome was mean arterial pressure (MAP) >65 mm Hg at 48 h. RESULTS: Baseline characteristics were comparable between the terlipressin and noradrenaline groups.SBP and pneumonia were major sources of sepsis. A higher proportion of patients on terlipressin were able to achieve MAP >65 mm of Hg (92.9% vs 69.1% P=.005) at 48 h. Subsequent discontinuation of vasopressor after hemodynamic stability was better with terlipressin (33.3% vs 11.9%, P<.05). Terlipressin compared to noradrenaline prevented variceal bleed (0% vs 9.5%, P=.01) and improved survival at 48 h (95.2% vs 71.4%, P=.003). Percentage lactate clearance (LC) is an independent predictor of survival [P=.0001, HR=3.9 (95% CI: 1.85-8.22)] after achieving the target MAP.Therapy related adverse effect were comparable in both the arms (40.5% vs 21.4%, P=.06), mostly minor (GradeII-88%) and reversible. CONCLUSIONS: Terlipressin is as effective as noradrenaline as a vasopressor in cirrhotics with septic shock and can serve as a useful drug. Terlipressin additionally provides early survival benefit and reduces the risk of variceal bleed. Lactate clearance is a better predictor of outcome even after achieving target MAP, suggesting the role of microcirculation in septic shock.

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.

Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis.

BACKGROUND & AIMS: Patients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis. METHODS: In a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 µg/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin α(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months. RESULTS: Baseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group. CONCLUSIONS: In a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and darbopoietin α survived for 12 months more than patients given only placebo. The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. Clinicaltrials.gov ID: NCT01384565.

Identification and full-length molecular characterization of rare hepatitis C virus genotype 5a from India.

This report presents a molecular characterization of the complete genome of a rare hepatitis C virus (HCV) genotype (GT5a) from India. Sequence homology of full genome revealed that the strain belonged to HCV GT5a. To trace the origin of this virus and to understand its evolutionary pattern, a phylogenetic reconstruction was carried out on full HCV genome sequences using Bayesian coalescent methods. The phylogenetic tree reconstruction revealed genotypic divergence, with formation of distinct clades. This analysis revealed that HCV genotype 5 might have originated from HCV genotype 3, as they have a recent common ancestor.

Thrombophilia Profile in Budd-Chiari Syndrome and Splanchnic Vein Thrombosis: A Study from Western India.

AIM: To estimate the prevalence of inherited prothrombotic risk factors in patients with splanchnic venous thrombosis (SVT) and Budd-Chiari syndrome (BCS) and to compare the risk factor profiles between these two groups. METHODS: In this prospective study, patients with abdominal venous thrombosis were studied. The patients were divided into two groups on the basis of the veins involved; splanchnic venous thrombosis group [portal (PVT), splenic, superior mesenteric veins (SMV)] and Budd-Chiari group (hepatic vein, IVC thrombosis). Thrombophilia profile including protein C, protein S, antithrombin III, factor V Leiden mutation, activated protein C, factor VIII level, CD55, CD59, IgM cardiolipin, IgG cardiolipin, anti-ß2 glycoprotein, JAK2 mutation, homocysteine levels, MTHFR and lupus anticoagulant was done in all patients. RESULTS: Out of 30 patients, 23 patients had SVT, 7 had BCS, including 2 of the 23 patients with SVT had mixed venous thrombosis, PVT and SMV thrombosis. Risk factors were found in 21/30 (70%) patients [17/23 (73.9%) of PVT. 4/7 (57.1% of BCS] and multiple risk factors were overall present in 8/23(34.7%) patients of SVT. CONCLUSIONS: Hereditary risk factors play an important role in the etiopathogenesis of abdominal venous thrombosis and hyperhomocysteinemia and protein S deficiency are the most common risk factors.

Bleeding Complications of Portal Hypertension.

In portal hypertension, acute variceal bleed is the cause of 2/3rd of all upper gastrointestinal bleeding episodes. It is a life-threatening emergency in patients with cirrhosis. Nonselective beta-blockers by decreasing the hepatic venous pressure gradient are the mainstay of medical therapy for the prevention of variceal bleeding and rebleeding. Evaluation of the severity of bleed, hemodynamic resuscitation, prophylactic antibiotic, and intravenous splanchnic vasoconstrictors should precede the endoscopy procedure. Endoscopic band ligation is the recommended endotherapy. Rescue transjugular intrahepatic port-systemic shunt (TIPS) is recommended for variceal bleed refractory to endotherapy. In patients with a high risk of failure of combined pharmacologic and endoscopic therapy, pre-emptive TIPS may improve the outcome. For gastric varices, "Sarin classification" is universally applied as it is simple and has therapeutic implication. For IGV1 and GOV2, injection cyanoacrylate glue is considered the endotherapy of choice. Endoscopic ultrasound is a useful modality in the management of gastric varices.

Midodrine plus propranolol versus propranolol alone in preventing first bleed in patients with cirrhosis and severe ascites: a randomized controlled trial.

BACKGROUND: Propranolol, a non-selective beta-blocker, commonly used to prevent variceal bleed, but might precipitate circulatory dysfunction in severe ascites. Midodrine, an alpha-1 adrenergic agonist improves renal perfusion and systemic hemodynamics. Addition of midodrine might facilitate higher maximum tolerated dose (MTD) of propranolol, thereby less risk of variceal bleed in cirrhosis patients with severe ascites. METHODS: 140 patients with cirrhosis and severe/refractory ascites were randomized- propranolol and midodrine (Gr.A,n = 70) or propranolol alone (Gr.B,n = 70). Primary outcome was incidence of bleed at 1 year. Secondary outcomes included ascites control, achievement of target heart rate (THR), HVPG response and adverse effects. RESULTS: Baseline characteristics were comparable between two groups. Cumulative incidence of bleed at 1 year was lower in Gr.A than B (8.5%vs.27.1%,p-0.043). The MTD of propranolol was higher in Gr.A (96.67 ± 36.6 mg vs. 76.52 ± 24.4 mg; p-0.01) and more patients achieved THR (84.2%vs.55.7%,p-0.034). Significantly higher proportion of patients in Gr.A had complete resolution of ascites [17.1%vs.11.4%,p-0.014), diuretic tolerance (80%vs.60%,p-0.047) at higher doses(p-0.02) and lesser need for paracentesis. Patients in Gr.A also had greater reduction in variceal grade (75.7%vs.55.7%;p-0.01), plasma renin activity (54.4% from baseline) (p = 0.02). Mean HVPG reduction was greater in Gr.A than B [4.38 ± 2.81 mmHg(23.5%) vs. 2.61 ± 2.87 mmHg(14.5%),p-0.045]. Complications like post-paracentesis circulatory dysfunction and spontaneous bacterial peritonitis on follow-up were higher in Gr.B than A (22.8%vs.51.4%,p = 0.013 and 10%vs.15.7%, p = 0.03, respectively). CONCLUSION: Addition of midodrine facilitates effective use of propranolol in higher doses and greater HVPG reduction, thereby preventing first variceal bleed, reduced paracentesis requirements with fewer ascites- related complications in patients with cirrhosis with severe/refractory ascites.

Safety and Efficacy of Endoscopic Retrograde Cholangio-Pancreatography in Patients of Liver Cirrhosis: A Case-Control Study.

Background With the improvement in noninvasive diagnostic imaging modalities, Endoscopic Retrograde Cholangio-Pancreatography (ERCP) has evolved into a primarily therapeutic procedure. Besides being efficacious and one of the most commonly done procedures, ERCP is also associated with a high risk of complications. However, there is a lack of studies analyzing the safety and success of ERCP in patients with liver cirrhosis. We retrospectively evaluated the outcome of ERCP in patients with cirrhosis of the liver compared to non-cirrhotic patients using the database from our institute. Methods Patients with liver cirrhosis who underwent ERCP from January 2010 to March 2020 were analyzed. This was a matched case-control study in which one cirrhotic patient undergoing ERCP was age and gender-matched randomly to one non-cirrhotic patient. We compared adverse events and the success rate of ERCP between cirrhotic patients and non-cirrhotic patients. The primary outcome of the study was analyzing the prevalence of procedure-related adverse events and their independent risk factors in patients of cirrhosis compared to the non-cirrhotic population. Results Two hundred patients were analyzed in both groups. Choledocholithiasis was the most common reason for ERCP in both groups. Mean Child-Turcotte-Pugh (CTP) score and Model for End-stage Liver Disease (MELD) score in the cirrhosis group were 9.16 ±1.78 and 19.09 ±7.06 respectively. Patients in the cirrhosis group had a significantly higher frequency of complications compared to the controls: 41 (20.5 %) versus 15 (7.5%), p < 0.01. Bleeding was the most common adverse event in both groups: 19 (9.5%) vs 6(3%). High International Normalised Ratio (INR), low platelets, and cholangitis at presentation were independently predictive of post-ERCP complications. Despite a similar technical success rate, the clinical success rate was lower in the cirrhotic than in the noncirrhotic group (83.9% versus 97.9%, p=0.006). Conclusion The prevalence of complications following ERCP was nearly three-fold higher in patients with cirrhosis than in non-cirrhotic patients. These events were related primarily to cholangitis, coagulopathy, and the advanced status of chronic liver disease.

Collateral Impact on Patients of Liver Diseases in the Second COVID-19 Wave: A Retrospective Cohort Study.

Background The second wave of the COVID-19 pandemic in India started in April 2021. This necessitated a change in focus from chronic ailments. This wave lasted till May 2021. Its impact on liver disease patients without COVID-19 infection has not been analyzed. Methods Records of liver disease patients from the Institute database admitted from April to May 2021 were compared with that from April to May 2019 i.e., prior to the pandemic. The primary outcome was a comparison of in-hospital mortality rates. Secondary outcomes were a comparison of 30 and 90-day readmission rates and liver transplantation rates. Results Seven hundred and seventy-one patients in April-May 2019 (group 1) and 545 patients in April-May 2021 (group 2) were analyzed. Patients in group 2 were sicker with higher PT (INR), urea, creatinine, CTP, and MELD score and low serum sodium, albumin, and platelet count with a higher prevalence of variceal bleed, hepatic encephalopathy, and acute kidney injury. There was higher mortality in group 2 (128/545; 23.5%) than group 1 (124/ 771;16.1%), OR 1.6, 95% CI 1.2 - 2.1, p<0.01. 30 day readmission rate was numerically higher in group1; 18.3% vs 16.9%, p=0.5. The 31-90 day readmission rate was higher in group 1; 29.4% vs 16.9%, p<0.01. There was no significant difference in the number of patients undergoing liver transplantation in two groups, 19 in group 1 and 14 in group 2 (p=0.90). Conclusion The second wave of the COVID-19 pandemic had a significant collateral impact on liver disease patients even without causing infection in them. Patients were sicker at the time of admission with higher mortality.

Diagnostic adequacy and safety of endoscopic ultrasound-guided fine-needle aspiration in patients with lymphadenopathy in a large cohort.

BACKGROUND AND STUDY AIMS: The role of endoscopic-ultrasound (EUS) guided fine-needle aspiration (FNA) in patients with lymphadenopathy in terms of diagnostic adequacy and safety in large population is not well defined. The aim of this study was to evaluate diagnostic adequacy and safety of EUS-FNA in patients with lymphadenopathy. PATIENTS AND METHODS: Retrospective study from October 2010 to September 2015 at tertiary care center in Delhi-NCR. We analyzed data from 1005 EUS- FNAs of lymph nodes. RESULTS: The study cohort comprised 1005 lymph nodes in 865 patients; 68 % were males, mean age was 50 ±â€Š14 years. Indications of FNA were to look for etiology of pyrexia of unknown origin or staging of malignancy mainly. FNA was taken from mediastinal nodes (n = 528, 52.5 %) and intra-abdominal nodes (n = 477, 47.5 %). Median size of nodes at long axis and short axis was 17 (12 - 25.7) and 10 (8 - 15) mm respectively. Adequate material by FNA was obtained in 92.8 % cases. The cytopathologic diagnosis were malignancy in 153 (15.2 %), granulomatous change in 452 (42 %), and reactive lymphadenopathy in 328 (35.6 %). There was statistically significant difference seen between groups with pathological and reactive lymph nodes regarding size at long and short axis, hypoechoic nature, well defined borders and presence of necrosis and calcification. Procedure-related adverse effects were encountered in 6 patients (0.8 %). Four patients had mild mucosal bleeding in chronic liver disease patients and two had mild hepatic encephalopathy related to sedation. CONCLUSION: EUS-FNA of lymph nodes has good diagnostic adequacy and safety.

Acute viral hepatitis e is associated with the development of myocarditis.

Myocarditis, an inflammatory disease of heart muscle, is an important cause of dilated cardiomyopathy worldwide. Viral infection is an important cause of myocarditis. This condition presents with various symptoms, ranging from minimally symptomatic cases to fatal arrhythmia and cardiogenic shock, and may develop chronic myocarditis and dilated cardiomyopathy in some patients. We report the case of a 26-year-old patient with acute viral hepatitis E who developed symptomatic myocarditis. As far as we could search, this is probably the 3rd case report of this rare association.

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. Due to the rapid advancements in the knowledge and available information, a consortium of members from countries across Asia Pacific, "APASL ACLF Research Consortium (AARC)," was formed in 2012. A large cohort of retrospective and prospective data of ACLF patients was collated and followed up in this data base. The current ACLF definition was reassessed based on the new AARC data base. These initiatives were concluded on a 2-day meeting in February 2014 at New Delhi and led to the development of the final AARC consensus. Only those statements which were based on the evidence and were unanimously recommended were accepted. These statements were circulated again to all the experts and subsequently presented at the annual conference of the APASL at Brisbane, on March 14, 2014. The suggestions from the delegates were analyzed by the expert panel, and the modifications in the consensus were made. The final consensus and guidelines document was prepared. After detailed deliberations and data analysis, the original proposed definition was found to withstand the test of time and identify a homogenous group of patients presenting with liver failure. Based on the AARC data, liver failure grading, and its impact on the "Golden therapeutic Window," extra-hepatic organ failure and development of sepsis were analyzed. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals, and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information are presented here.

Management of acute kidney injury in cirrhosis.

Acute kidney injury (AKI) is a relatively frequent problem, occurring in approximately 20 % of hospitalized patients with cirrhosis. Although serum creatinine (S Cr) is the most commonly used method to determine AKI because of easy availability and low cost, practically it underestimates the extent of kidney injury in patients with chronic liver disease. AKI is defined as an abrupt rise in S Cr of 0.3 mg/dl or more (>26.4 mmol/l) or an increase of 150 % or more (1.5-fold) from baseline. The cause of AKI in cirrhosis is multifactorial and is unique in terms of pathogenesis. The most common causes of AKI in cirrhosis can be subdivided into either functional or structural. The functional group includes volume-responsive (prerenal azotemia) and volume-unresponsive states (hepatorenal syndrome). Volume responsive is the most common type of AKI due to frequent use of diuretics, large volume abdominal paracentesis and gastrointestinal bleeding in patients with liver disease. The structural causes include acute tubular necrosis, tubulointerstitial and glomerular diseases. Patients with decompensated cirrhosis are in a vasodilatory state leading to a decrease in effective arterial blood volume, predisposing to AKI. Therefore, management of AKI depends on the underlying cause, and therapy should be directed toward removal of the cause. The outcome in cirrhosis when patients are on dialysis is very dismal. Every effort should be made to prevent AKI.