Therapeutic plasma exchange provides native liver survival benefit in children with acute liver failure: A propensity score-matched analysis.

OBJECTIVES: This study aimed to evaluate the safety and efficacy of therapeutic plasma exchange (TPE) in pediatric acute liver failure (PALF). METHODS: All children aged 2-18 years with PALF were included. The intervention cohort included a subset of PALF patients undergoing complete three sessions of TPE, whereas the matching controls were derived by propensity score matching from the patient cohort who did not receive any TPE. Propensity matching was performed based on the international normalized ratio (INR), grade of hepatic encephalopathy (HE), age, bilirubin, and ammonia levels. The primary outcome measure was native liver survival (NLS) in the two arms on day 28. RESULTS: Of the total cohort of 403 patients with PALF, 65 patients who received TPE and 65 propensity-matched controls were included in analysis. The 2 groups were well balanced with comparable baseline parameters. On day 4, patients in the TPE group had significantly lower INR (P = 0.001), lower bilirubin (P = 0.008), and higher mean arterial pressure (MAP) (P = 0.033) than controls. The NLS was 46.15% in the TPE arm and 26.15% in the control arm. The overall survival (OS) was 50.8% in the TPE arm and 35.4% in the control arm. Kaplan-Meier survival analysis showed a significantly higher NLS in patients receiving TPE than controls (P = 0.001). On subgroup analysis, NLS benefit was predominantly seen in hepatitis A-related and indeterminate PALF. CONCLUSION: TPE improved NLS and OS in a propensity-matched cohort of patients with PALF. Patients receiving TPE had lower INR and bilirubin levels and higher MAP on day 4.

Early Versus Standard Initiation of Terlipressin for Acute Kidney Injury in ACLF: A Randomized Controlled Trial (eTerli Study).

BACKGROUND AND AIMS: Terlipressin infusion is effective in hepatorenal syndrome (HRS-AKI). However, its efficacy for HRS-AKI resolution in acute-on-chronic liver failure (ACLF) patients has been suboptimal. Progression of AKI is rapid in ACLF. We investigated whether early initiation of terlipressin(eTerli) can improve response rates. METHODS: Consecutive ACLF patients with stage II/III AKI despite albumin resuscitation (40 g) were randomized to receive terlipressin at 2 mg/24 h plus albumin at 12 h (ET, n = 35) or at 48 h as standard therapy (ST, n = 35). (June 22, 2020 to June 10, 2022). The primary end-point was AKI reversal by day7. RESULTS: Baseline parameters including AKI stage and ACLF-AARC scores in two arms were comparable. Full AKI response at day 7 was higher in ET [24/35 (68.6%)] than ST arm [11/35 (31.4%; P 0.03]. Day3 AKI response was also higher in ET arm [11/35 (31.4%) vs. 4/35 (11.4%), P 0.04]. Using ST compared to ET [HR 4.3; P 0.026] and day 3 serum creatinine > 1.6 mg/dl [HR 9.1; AUROC-0.866; P < 0.001] predicted HRS-AKI non-response at day 7. ET patients showed greater improvement in ACLF grade, mean arterial pressure, and urine output at day 3, and required lower albumin within 7 days than ET arm (149.1 ± 41.8 g vs. 177.5 ± 40.3 g, P 0.006) and had lower 28-day mortality: 40% vs. 65.7%, P 0.031]. Early use of terlipressin than ST [HR 2.079; P 0.038], baseline HE [HR 2.929; P 0.018], and AKI persistence at day 3 [HR 1.369; P 0.011] predicted 28-day mortality. Fifteen (21.4%) patients had treatment related adverse effects, none was life threatening. CONCLUSION: In ACLF patients, early initiation of terlipressin for AKI persisting after 12 h of volume expansion with albumin helps in reduced short-term mortality and early AKI reversal with regression of ACLF stage. These results indicate need for change in current practice for terlipressin usage in HRS-AKI.

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

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

High prevalence of MAFLD in general population: A large cross-sectional study calls for concerted public health action.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) is a relatively new term with limited studies done in South Asian population. AIM: To determine prevalence and clinico-epidemiological characteristics of MAFLD in general population. METHODS: A cross-sectional study was conducted in randomly selected regions across Delhi, India. Data were collected on socio-demographic particulars, health status and lifestyle factors. Anthropometric measurements, transient elastography, and laboratory investigations were carried out. RESULTS: Altogether 6146 participants (mean age: 43.1 ± 13.9 years, 48.1% males) were included. The prevalence of MAFLD was 56.4% (n = 3468), of which lean MAFLD constituted 11.3%. Higher age (OR: 2.47; 95% CI: 2.21-2.76), low education level (OR: 1.23; 95% CI: 1.09-1.39), upper socio-economic class (OR: 1.32; 95% CI: 1.17-1.49), and low physical activity (OR: 1.15; 95% CI: 1.03-1.28) were more common in MAFLD. The association of female sex with MAFLD differed in age groups <40 years (OR: 0.64 and 95% CI: 0.55-0.75) and >40 years (OR: 1.40 and 95% CI: 1.22-1.62) in both magnitude and direction (p < 0.001). Liver fibrosis was present in 23% of the study population (32.2% among MAFLD group). Advanced liver fibrosis was three times more common in MAFLD group (6.2% vs 1.8%, p < 0.001). Obesity and fibrosis had a statistically significant relationship and 75.8% of the individuals with advanced stages of fibrosis had obesity. CONCLUSION: Nearly half of study population was found to have MAFLD. Advanced hepatic fibrosis was three times more common in these subjects. Aggressive public health measures are urgently required to raise awareness and introduce interventional strategies.

Severity of Acute Portal Hypertension Determines the Clinical Outcomes in Severe Alcoholic Hepatitis.

BACKGROUND: Severe alcohol-associated hepatitis (SAH) presenting as acute-on-chronic liver failure (ACLF) has high mortality. Severe hepatic inflammation and ongoing hepatocellular cell death lead to rapid rise in portal pressure, a hyperdynamic circulation that might precipitate infections and organ failures. METHODS: Consecutive SAH patients were classified based on baseline HVPG measurement as 6to < 12 mmHg, 12to < 20 mmHg, and ≥ 20 mmHg. We analyzed portal hypertension severity in relation to fibrosis stage, ACLF at presentation, response to prednisolone, severity scores(MELD and Maddrey's Discriminant Function, mDF), and 90-day mortality. RESULTS: Of 819 SAH patients (94.6% ACLF, 85.4% histological cirrhosis, median MELD and mDF scores 25 and 66, respectively), 250(30.5%) had HVPG ≥ 20 mmHg. Patients with HVPG ≥ 20 mmHg more often had large esophageal varices (25.2%vs.13.2%; p-0.001), higher baseline MELD (27.1 ± 5.6vs.25.3 ± 5.2; p-0.001), and mDF(76.1 ± 16vs.68.4 ± 15.1; p-0.01) scores. No patient without ACLF had HVPG ≥ 20 mmHg. Moreover, during hospital course these patients had higher incidence of variceal bleed (17.2%vs.8.8%; p-0.001), acute kidney injury (36.4%vs.25.3%; p-0.001), and spontaneous bacterial peritonitis (6.4%vs.3.5%; p-0.05). Of 412(50.3%) eligible patients treated with prednisolone, 69.2% showed response at day 7(Lille's score < 0.45). 90-day mortality was 27.6%; and baseline MELD > 25.5[HR 1.78], HVPG ≥ 20 mmHg [HR 1.86], the presence of HE[HR 1.63], and prednisolone ineligibility due to sepsis[HR 1.27] were independent predictors. Mortality was unrelated to varices grade, variceal bleed, and histological cirrhosis. Repeat HVPG performed in 114(19.2%) patients after a median of 5.2 months showed significant decrease (3.6 mmHg; p-0.001) which correlated with improvement in MELD score(13points; p-0.05). CONCLUSION: Development of ACLF and complications in SAH are likely a result of acute rise in HVPG. "High-risk" SAH are SAH patients with HVPG ≥ 20 mmHg in the presence of ascites. Understanding the drivers for acute rise in portal pressure in SAH ACLF might help introduction of newer therapies.

Real-Time Shear Wave Elastography for Determining the Ideal Site of Liver Biopsy in Diffuse Liver Disease.

Objectives The objective of the study was to identify accurate site of liver biopsy under ultrasound and elastography guidance and compare the shear wave elastography (SWE) and transient elastography (TE) diagnostic accuracy with histopathological correlation. Methods This was a prospective single-center study where patients scheduled for nonfocal liver biopsy were divided into two groups (group U: ultrasound; group E elastography) by sequential nonrandom selection of patients. Elastography was performed before the biopsy and biopsies from the maximum stiffness segment were taken. Results There was no significant difference of intersegmental liver stiffness with mean velocity; however, biopsy segment velocities show significant difference with mean liver stiffness suggestive of heterogenous distribution of fibrosis. The rho ( r ; Spearman's correlation) value between biopsy segments and mean velocities shows excellent correlation. The diagnostic performance of TE was good for fibrosis stages F2, F3, and F4, while SWE was fair for the diagnosis of fibrosis stages F1 and F2 and fairly equal for the diagnosis stages F2 and F3. Area under the curve (AUC) values in differentiating mild (F1) or no fibrosis from significant fibrosis (≥F2) were 95.5 with cutoff value of at least 1.94 m/s. Conclusions The diagnostic performance of SWE is comparable with TE in liver fibrosis staging and monitoring. Fibrosis is heterogeneously distributed in different segments of the right lobe liver. Therefore, elastography at the time of biopsy may help in defining the accurate site for biopsy and improve histopathological yield in detecting liver fibrosis in patients with chronic liver disease. Advances in Knowledge Elastography-guided biopsy is helpful to determine the ideal site of biopsy.

Long Term HBsAg Responses to Peg-Interferon Alpha-2b in HBeAg Negative Chronic Hepatitis B Patients Developing Clinical Relapse after Stopping Long-Term Nucleos(t)ide Analogue Therapy.

Background and aims: A high proportion of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients develop clinical relapse after stopping long-term nucleotide analogues (NAs). The aim of this study was to assess the efficacy of pegylated interferon (PEG-IFN) alpha 2b in inducing hepatitis B surface antigen (HBsAg) loss in such patients. Methods: NAs were stopped in 118 HBeAg-negative CHB patients fulfilling the Asian Pacific Association for the Study of Liver (APASL) 2015 criteria for stopping NAs; they had received NAs for a median interquartile range (IQR) of 60 (48-84) months. Results: Overall, 82 of 118 (69.5%) patients developed clinical relapse after stopping NAs; 44 within 12 months (and treated with PEG-IFN alpha 2b 1.5 mcg/kg weekly subcutaneous injections for 48 weeks); and 38 after 12 months [and treated with tenofovir alafenamide fumarate (TAF) 25 mg daily] of follow-up. The decision to treat with either PEG-IFN or TAF was not a time-bound decision but was due to logistical problems.During the median IQR follow-up of 48 (43.5-52.5) months after the start of PEG-IFN, 14 of 44 (31.8%) patients developed clinical relapse after stopping PEG-IFN and were started on TAF. At the last follow-up visit, HBsAg was found to be negative in 7/44 (15.9%) of patients receiving PEG-IFN.Among 38 patients treated with TAF for clinical relapse, during the median IQR follow-up of 18 (12-30) months after start of TAF, no patient became HBsAg negative.36 patients did not develop clinical relapse during the follow-up, and after a median IQR follow-up of 60 (60-60) months after stopping NAs, HBsAg negative was found in 1/36 (2.8%) of patient at the last follow-up. Conclusions: Among patients with HBeAg-negative chronic hepatitis B who developed clinical relapse after stopping long-term NAs therapy and were subsequently treated with PEG-IFN alpha 2b, 15.9% achieved HBsAg loss on long-term follow-up.

Combined hepatocellular cholangiocarcinoma in hepatectomy specimens: A clinicopathologic analysis.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon form of primary liver carcinoma. It is heterogenous in terms of morphology, immunohistochemistry, radiology, and clinical features; making it a challenging entity for diagnosis. Aims: The purpose of the present study was to evaluate clinicopathological characteristics of patients with cHCC-CCA. Settings and Design: Retrospective observational study. Materials and Methods: The patients diagnosed with cHCC-CC were identified from hepatic surgical specimens and were evaluated. Statistical Analysis: Survival was estimated as per Kaplan-Meier method. Results: Out of six patients, five had undergone resection while one had liver transplant. Five were male and one was female and the mean age was 52 years. Tumor markers revealed raised serum alfa-fetoprotein and CA19.9 in four and three patients, respectively. Five of the liver specimens were cirrhotic. Diagnosis was predominantly based on tumor morphology. All cases were of Allen and Lisa type B and cHCC-CCA as per WHO (2019) classification. Stem cell features <5% were noted in two cases. Immunohistochemistry for programmed death 1/programmed death ligand 1 (PD1/PDL1) was negative in both the hepatocellular and cholangiocellular components in all six cases. Mismatch repair (MMR) protein expression was retained in two and deficient in four cases. The median follow-up after surgery was 21.3 months (range, 5-46.2 months). Five patients had intrahepatic and/or extrahepatic recurrence on follow-up after surgery. The median recurrence-free survival was estimated at 13.1 months (95% CI 5.67-20.6). Three patients had received salvage treatment. The median overall survival was estimated at 20 months (95% CI 0-45.3). Conclusions: The present study highlights the role of morphology in the diagnosis of cHCC-CCA. The choice of locoregional and/or systemic therapy after surgery may be individualized based on the clinicopathological characteristics.

e-GLR Score Predicts Early Graft Loss in Adult Live-Donor Liver Transplantation.

Objective: This study aimed to analyze risk factors and develop a predictive model for early allograft loss due to early graft dysfunction (EGD) in adult live-donor liver transplantation (LDLT). Methods: Data of patients who underwent LDLT from 2011 to 2019 were reviewed for EGD, associated factors, and outcomes. A homogeneous group of 387 patients was analyzed: random cohort A (n = 274) for primary analysis and random cohort B (n = 113) for validation. Results: Of 274 recipients, 92 (33.6%) developed EGD. The risk of graft loss within 90 days was 29.3% and 7.1% in those with and without EGD, respectively (P < 0.001). Multivariate logistic regression analysis determined donor age (P = 0.045), estimated (e) graft weight (P = 0.001), and the model for end-stage liver disease (MELD) score (0.001) as independent predictors of early graft loss due to EGD. Regression coefficients of these factors were employed to formulate the risk model: Predicted (P) early graft loss risk (e-GLR) score = 10 × [(donor age × 0.052) + (e-Graft weight × 1.681) + (MELD × 0.145)] - 8.606 (e-Graft weight = 0, if e-Graft weight ≥640 g and e-Graft weight = 1, and if e-Graft weight < 640 g). Internal cross-validation revealed a high predictive value (C-statistic = 0.858). Conclusions: Our novel risk score can efficiently predict early allograft loss following graft dysfunction, which enables donor-recipient matching, evaluation, and prognostication simply and reliably in adult LDLT.

Tolerance of standard dose albumin infused over 6 hrs for treatment of spontaneous bacterial peritonitis-A randomized controlled trial.

BACKGROUND AND AIMS: Twenty per cent albumin (1.5 g/kg at diagnosis and 1 g/kg on day three, infused over six-hour duration) is recommended particularly in high-risk spontaneous bacterial peritonitis (SBP). Whether reduced dose albumin infusion is as effective as the standard dose albumin infusion is not clear. The aim of this study was to compare standard dose albumin infusion with reduced dose albumin infusion in acute kidney injury (AKI) development or progression in patients with cirrhosis and high-risk SBP. METHODS: Sixty-three patients were randomized to the standard dose albumin arm (n = 31) and reduced dose albumin arm (n = 32, 0.75 g/kg at diagnosis and 0.5 g/kg 48 h later). The albumin was infused over six-hour duration in both groups. When the patient developed respiratory distress, the albumin infusion was stopped and that dose (i.e. of day one or day three) was not restarted and no attempt was made to finish the whole dose of that day. However, the next dose was started at the pre-calculated infusion rate if there was no evidence of respiratory distress at the start of next infusion. RESULTS: All 31 patients in standard dose and two (6.25%) in the reduced dose group developed symptomatic circulatory overload (p < 0.001), with infusions being stopped prematurely. The actual albumin dose received on day one was similar in both groups and only slightly higher in the standard dose group on day three. Resolution of SBP, progression of AKI to higher stage, in-hospital mortality and 28 days' mortality were similar in both groups. CONCLUSIONS: For treatment of SBP, standard dose albumin infusion (1.5 g/kg at diagnosis and 1 g/kg 48 hours later) infused over six hours is not tolerated by Indian patients. The effectiveness of standard dose albumin infused over more prolonged periods, as compared to reduced dose albumin, should be evaluated in further studies. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT04273373 .

Non-resolution of acute kidney injury in the first week portends the development of chronic kidney disease in critically ill patients with cirrhosis.

BACKGROUND: Renal tubular epithelial cells (RTECs) cause maladaptive repair and perpetuate renal fibrosis. AIM: To evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) and RTEC as risk factors for non-resolution of acute kidney injury (AKI-NR) at day seven and chronic kidney disease (CKD) in critically ill patients with cirrhosis. METHODS: We performed urinary NGAL and microscopy at enrolment and day 7 in all patients. We assessed 17 renal injury, endothelial injury and repair markers, genes for mitochondrial biogenesis by qRT-PCR in RTEC, and post-mortem renal biopsies for understanding mechanisms of AKI non-resolution (n = 30). RESULTS: We enrolled 310 patients, aged 48.1 ± 11.6 years, 87% male, 90% alcoholic. Of these, 36% had RTEC at enrolment, and 53% had AKI-NR on day 7. On mean follow-up of 136 days (range 43-365), 150 (48.3%) developed CKD. The presence of RTEC or granular casts, NGAL and AKI-NR were independent predictors of CKD development on competing risk analysis. Higher MCP-1, renal endothelial injury, decrease in tubular repair markers and failure of mitochondrial biogenesis in RTEC were seen in patients with AKI-NR compared with AKI-R (p < 0.05). Renal biopsies showed infiltration with monocyte-macrophage, increased α-SMA, and tubulointerstitial fibrosis. CONCLUSION: Almost two-thirds of critically ill patients with cirrhosis have AKI, which resolves in only one-half at day seven and predicts the development of CKD. Higher NGAL, RTEC, or granular casts were independent predictors of AKI-NR and CKD development. Enhanced tubular and endothelial injury, decreased repair, monocyte-macrophage infiltration and mitochondrial dysfunction in RTEC are associated with AKI non-resolution and risk of renal fibrosis.

Podoplanin-positive dilated lymphatic vessels in duodenum associates with three-month mortality in patients with cirrhosis.

Dilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis. Here, we studied LVs in duodenal (D2)-biopsies of liver cirrhosis patients and investigated the prognostic role of a LV marker, podoplanin (PDPN), in predicting the mortality of patients with cirrhosis. A prospective, single-center cohort study was performed in liver cirrhosis patients (n = 31) and matched healthy controls (n = 9). D2-biopsies were obtained during endoscopy procedure, immunostained with PDPN, and scored based on 1) intensity and 2) density of positively-stained LVs per high power field. Gut and systemic inflammation were estimated by quantifying duodenal CD3+ intraepithelial lymphocytes (IELs), CD68+ macrophages, and serum TNF-α and IL-6 levels, respectively. Gut permeability and inflammation as assessed by quantifying gene expression of TJP1, OCLN, TNF-α, and IL-6 in D2-biopsies. Gene expression of LV markers, PDPN (8-fold), and LYVE1 (3-fold) was enhanced in D2-biopsies of cirrhosis patients compared to control (p < 0.0001). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, p < 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). PDPN score positively and significantly correlated with the number of IELs (r = 0.33), serum TNF-α (r = 0.35), and IL-6 (r = 0.48) levels, while inversely correlated with TJP1 expression (r = -0.46, p < 0.05 each). In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61; 1.08-29.109; p = 0.04). The area under the curve for the PDPN score was 84.2, and cutoff value for predicting mortality was ≥6.5 with 100% sensitivity and 75% specificity. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. PDPN score correlates with enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis.

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.

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

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

Etiologic fractions in patients of hepatocellular carcinoma in India with and without a background of cirrhosis: a multi-centric study.

BACKGROUND: Hepatocellular cancer (HCC) typically arises in the background of cirrhosis. The epidemiology of HCC has changed in recent years due to availability of newer antivirals, changing life-styles and greater possibility for early detection. We undertook a multicentric national sentinel surveillance for liver cirrhosis and HCC to assess the attributable risk factors for the development of HCC, both with and without a background of cirrhosis. METHODS: Data from January 2017 till August 2022 from hospital-based records of eleven participating centers were included. Diagnosed cases of cirrhosis [radiological (multiphase and/or histopathological] and HCC [as per AASLD 2018] were included. History of significant alcohol intake was elicited by AUDIT-C questionnaire. RESULTS: Altogether 5798 enrolled patients were assessed, of which 2664 patients had HCC. The mean age was 58.2 ± 11.7 years and 84.3% (n = 2247) were males. Diabetes was found in over a third of those with HCC (n = 1032;39.5%). The most common etiology of HCC was NAFLD (n = 927;35.5%) followed by viral hepatitis B and C and harmful levels of alcohol. Among those with HCC, 27.9% (n = 744) had no cirrhosis. Higher proportion of cirrhotic HCC patients had alcohol as an etiological factor as compared to non-cirrhotic (17.5 vs. 4.7%, p ≤ 0.001). NAFLD was an etiological factor for a higher proportion of non-cirrhotic HCC patients as compared to cirrhotic HCC (48.2 vs. 30.6%, p ≤0.001). Diabetics more commonly had non-cirrhotic HCC (50.5 vs. 35.2%). The following factors were associated with an occurrence of cirrhotic HCC: male gender (OR 1.372 and 95% CI 1.070-1.759), age above 60 years (OR 1.409 and 95% CI 1.176-1.689), HBV (OR 1.164 and 95% CI 0.928-1.460), HCV (OR 1.228 and 95 CI 0.964-1.565) and harmful consumption of alcohol (OR 3.472 and 95% CI 2.388-5.047). The adjusted odds of non-cirrhotic patients having NAFLD was 1.553 (95% CI 1.290-1.869). CONCLUSION: This large multi-centric study demonstrates that NAFLD is the most important risk factor for development of both cirrhotic and non-cirrhotic HCC in India and has overtaken viral hepatitis. Awareness campaigns and large-scale screening are required to reduce the high burden of NAFLD-related HCC in India.

Post-transjugular Intrahepatic Portosystemic Shunt Hepatic Encephalopathy: Sarcopenia Adds Insult to Injury.

BACKGROUND: Hepatic encephalopathy, which is a serious complication, and sarcopenia are undesirable consequences in cirrhosis. Transjugular intrahepatic portosystemic shunt increases the risk of hepatic encephalopathy. We investigated the effect of sarcopenia on the incidence of post-transjugular intrahepatic portosystemic shunt hepatic encephalopathy. METHODS: Clinical data of patients who underwent transjugular intrahepatic portosystemic shunt were extracted retrospectively. Computed tomography images at L3 level of scans performed prior to transjugular intrahepatic portosystemic shunt were analyzed to assess skeletal muscle index-expressed as skeletal muscle area (cm2)/ height (m2). RESULTS: Of 210 patients who underwent transjugular intrahepatic portosystemic shunt, complete information was available in 79 [male: 68 (86%); age: 50.5 ± 11.2 years; Child-Turcotte-Pugh score: 8.81 ± 1.23; etiology-alcohol: 44 (56%), non-alcoholic steatohepatitis: 16 (20%), others: 19 (24%); transjugular intrahepatic portosystemic shunt indication-ascites: 56 (71%); bleed: 23 (29%); sarcopenics: 42 (53%)]. Post-transjugular intrahepatic portosystemic shunt hepatic encephalopathy developed in 29 (37%) patients. In patients who developed hepatic encephalopathy, both serum ammonia [177.6 ± 82.5 vs. 115.5 ± 40.5 µg/dL, P =.008] and prevalence of sarcopenia [69% vs. 44%; P =.02; odds ratio (95% CI): 2.8 (1.08-7.4), P =.02] were higher, with sarcopenics having 3 times higher risk of hepatic encephalopathy and 8 times higher risk of multiple episode of hepatic encephalopathy [31% vs. 5.4%; odds ratio (95% CI): 8.2 (1.68- 40.5), P =.009]. In multivariate analysis, age [odds ratio (95% CI): 1.05 (1.001-1.11), P =.047], serum albumin [odds ratio (95% CI): 0.162 (0.05-0.56), P =.004], and skeletal muscle index [odds ratio (95% CI): 0.925 (0.89-0.99), P =.017] were independently associated with post-transjugular intrahepatic portosystemic shunt hepatic encephalopathy. CONCLUSIONS: Sarcopenia is present in nearly half of the cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt, which increases the risk of a single episode of hepatic encephalopathy by 3-fold and that of multiple episodes of hepatic encephalopathy by 8-fold after transjugular intrahepatic portosystemic shunt procedure. Increased skeletal muscle index is associated with decreased risk of hepatic encephalopathy.

Study of Adherence to Medication in Pediatric Liver Diseases ("SAMPLD" Study) in Indian Children.

Background/objectives: Adherence to medication(s) is an essential component of holistic management in any chronic disease including in post liver transplant (LT) patients. Thus, this study aimed to assess adherence to medications in Indian pediatric liver disease patients (including post LT recipients) and to identify variables affecting its occurrence. Methods: A cross-sectional study was conducted among pediatric (<18 years of age) subjects with Wilson disease (WD) and autoimmune liver disease (AILD) along with post LT recipients from May 2021 to October 2021. Structured tools using prevalidated questionnaires (Medication adherence measure and the Child & Adolescent Adherence to Medication Questionnaire) were used to collect data related to nonadherence prevalence (based on missed and late doses) and factors influencing the adherence. Results: A total of 152 children were included in the study (WD 39.5%, AILD 32.9%, and post LT 27.6%). Prevalence of missed and late dose nonadherence (at a cut-off of ≥20%) was 12.5% and 16.4%, respectively. Older age (odd's ratio/O.R 1.185), stay in a rural area (O.R 5.08), and barriers like bad taste of medication (O.R 4.728) and hard to remember the medication (O.R 7.180) were independently associated with nonadherence (P < 0.05). Conclusions: Overall, nonadherence was seen in 12-16%, i.e., around one-sixth of the patients, with least nonadherence seen in post LT recipients (0-2.4%). Older age of the patient, rural place of stay and personal barriers like hard to remember/forgetfulness and bad medication taste were identified as factors independently leading to nonadherence.

Tadalafil improves erectile dysfunction and quality of life in men with cirrhosis: a randomized double blind placebo controlled trial.

BACKGROUND AND AIMS: Patients with cirrhosis have high prevalence of erectile dysfunction (ED). The aim of this study was to study the efficacy and safety of tadalafil for ED in patients with cirrhosis. METHODS: 140 cirrhotic males with ED were randomized into tadalafil 10 mg daily (n = 70) or placebo (n = 70) for 12 weeks. ED was diagnosed if erectile function (EF) domain score was < 25 in International Index of Erectile Function (IIEF) questionnaire. The erectile function domain consists of six questions concerning erection frequency, erection firmness, frequency of partner penetration, frequency of maintaining erection after penetration, ability to maintain erection to completion of intercourse and confidence in achieving and maintaining erection. Primary outcome was proportion of patients having an increase in > 5 points in EF domain of the IIEF. Generalized Anxiety Disorder 7 (GAD-7) questionnaire was used for screening and severity measuring of GAD. The presence of depression was screened using the Patient Health Questionnaire (PHQ-9) and the assessment of health related quality of life was done using the Short Form (36) Health Survey. RESULTS: At the end of 12 weeks, more patients in tadalafil group achieved > 5 points increase in the EF domain of the IIEF when compared with the placebo group [44(62.9%) vs. 21(30%), p < 0.001]. At the end of 12 weeks, patients receiving tadalafil had significantly more change in scores on the erectile function domain, orgasmic function domain, intercourse satisfaction domain, overall satisfaction domain, erection vaginal penetration rates and successful intercourse; significantly more decline in the GAD-7 and PHQ-9 scores; significantly more improvement in scores of five of the eight domains of SF-36 (general health perception, vitality score, social functioning, role emotional and mental health) and the mental component summary rates when compared with placebo. The development of side effects and the changes in HVPG were not significantly different between the two groups. CONCLUSIONS: Tadalafil therapy may enhance erectile function, improve anxiety, depression and quality of life; and is well tolerated by men with cirrhosis (CTP score < 10) and ED. However, further larger and long-term studies are needed to confirm these results and look for rarer side effects of using tadalafil in patients with cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT03566914; first posted date: June 25, 2018.

Low-dose continuous terlipressin infusion is effective and safer than intravenous bolus injections in reducing portal pressure and control of acute variceal bleeding.

BACKGROUND AND AIMS: Continuous infusion of terlipressin is better tolerated, and equally effective at lower doses than intravenous boluses in type 1 hepatorenal syndrome. This approach in cirrhosis patients with acute esophageal variceal bleed was investigated by comparing the efficacy and adverse events of continuous versus bolus administration of terlipressin. METHODS: One hundred ten consecutive cirrhosis patients with acute esophageal variceal bleed (AEVB) were randomized to receive either terlipressin as bolus (BOL, n = 55), 2 mg every 4 h, or, continuous infusion (CONI, n = 55), 4 mg/24 h for 5 days. Hepatic venous pressure gradient (HVPG) was measured at baseline, 12 and 24 h and response to terlipressin was defined as > 10% decline from baseline. RESULTS: Baseline demographics, model for end-stage liver disease (MELD) and HVPG were comparable between groups. The primary objective of HVPG response at 24 h was achieved in significantly more patients in CONI than BOL group {47/55(85.4%) vs. 32/55(58.2%), p = 0.002}. Early HVPG response at 12 h was also higher in CONI group (71.5 vs. 49.1%, p < 0.01). Median dose of terlipressin was significantly lower {4.25 ± 1.26 mg vs. 7.42 ± 1.42 mg/24 h, p < 0.001)} and adverse events were fewer {20/55(36.3%) vs. 31/55(56.4%), p = 0.03} in the CONI than BOL group. Significantly higher incidence of very early rebleed was noted in BOL group {8/55 (14.5%) vs. 1/55, (1.8%), p = 0.03}. Baseline HVPG (OR 1.90, 95% CI = 1.25-2.89, p = 0.002) and MELD (OR 1.18, 95% CI = 0.99-1.41, p = 0.05) were predictors of rebleed. CONCLUSION: "HVPG-tailored" continuous terlipressin infusion is more effective than bolus administration in reducing HVPG at a lower dose with fewer adverse events in cirrhotic patients. CLINICAL TRIAL IDENTIFIER: NCT02695862.

Fecal microbiota transplantation compared with prednisolone in severe alcoholic hepatitis patients: a randomized trial.

BACKGROUND: Severe alcoholic hepatitis (SAH) has high 90-day mortality. Prednisolone therapy has shown modest survival benefits over placebo at 28 but not 90 days. Fecal microbial transplantation (FMT) has shown promise in these patients. We compared the efficacy and safety of the two therapies in SAH patients. METHODS: Steroid eligible SAH patients were randomized in an open-label study to prednisolone (n = 60) 40 mg/day for 28 days (assessed at day-7 for continuation) or healthy donor FMT (n = 60) through naso-duodenal tube, daily for seven days. Primary outcome of study was day-90 survival. RESULTS: Patients in prednisolone and FMT arms were comparable at baseline (discriminant function score 65 ± 16.2 and 68 ± 14, MELD score 17.1 and 16.5, respectively). Of 120 patients, 112 [prednisolone-57; FMT-55] completed trial. As per intention-to-treat analysis, 90-day survival was achieved by 56.6% (34/60) patients in prednisolone and 75% (45/60) in FMT group (p = 0.044, FMT HR = 0.528, 95%CI 0.279-0.998). Secondary outcome of 28-day survival [78.33% (47/60) and 88.33% (53/60) (p = 0.243, FMT HR = 0.535, 95%CI 0.213-1.34)] with comparable severity scores over time between both arms. Infections accounted for 11 (19.3%) and 2 (3.6%) deaths in prednisolone and FMT groups, respectively (p = 0.01). Path-tracing showed a slow establishment of microbiota and alpha diversity (Shannon index) improvement by day-28 (p = 0.029). FMT resulted in 23 new taxa by day-28, reduction from baseline in pathogenic taxa [Campylobacter (19-fold, p = 0.035), anaerobes (Parcubacteria, Weisella and Leuconostocaceae)], and increase of Alphaproteobacteria [~ sevenfold, p = 0.047] and Thaumarcheota (known ammonia oxidizer, p = 0.06). Lachnospiraceae (p = 0.008), Prevotella and Viellonella communities in gut favored survival (p < 0.05). CONCLUSION: In severe alcoholic hepatitis, FMT is safe and improves 90-day survival and reduces infections by favorably modulating microbial communities. It can be a useful alternative to prednisolone therapy.