Impact of educational interventions on hepatitis B and C awareness among school students of Delhi NCR, India.

BACKGROUND: Viral hepatitis, particularly B and C, is a major cause of liver cirrhosis and cancer, leading to about 1.4 million deaths annually. Alarmingly, less than 20% of those with hepatitis are aware of their status, with only 6.3% receiving treatment. School children can play a pivotal role in raising awareness and preventing the spread of infections. This intervention study focuses on understanding and enhancing the knowledge, attitudes, and practices related to Hepatitis B and C, among school children in Delhi NCR to foster dialogue and awareness. METHODS: An intervention study was conducted in selected schools across Delhi NCR between September and October 2022 to assess baseline knowledge, attitudes, and practices related to Hepatitis B and C. Three of seven schools were randomly selected by probability sampling, representing 9-12 grade students, and 901 students participated. Following this, an educational interventional program was conducted using educational material, interactive sessions, and audiovisual aids. Post-intervention assessments were done to measure the impact on knowledge improvement. RESULTS: The study is expected to provide insights into the current level of awareness regarding Hepatitis B and C. Furthermore, the intervention's effectiveness was analysed using the pre-formed questionnaire. The average pre-test knowledge score was 8.9 ± 3.2, while the post-test average was 15.6 ± 4.4, indicating a substantial increase of 6.7 ± 4.7 points (+ 75.2%). There was a positive correlation of 0.240 between pre and post-test scores. Attitude change before and after the session showed a positive percentage change of + 38.0% with a correlation of 0.351. The study indicated substantial improvements in knowledge about hepatitis B and C, notably regarding awareness about transmission methods and risk factors. CONCLUSION: This interventional study seeks to bridge the knowledge gap among school children regarding Hepatitis B and C in Delhi NCR, fostering a proactive approach towards prevention, detection, and treatment. The considerable rise in awareness and favourable changes in perspectives post-intervention say that specific health education initiatives are pivotal in raising awareness and comprehension of infectious diseases, ultimately contributing to improving community health.

Clinical and Genomic Perspective of SARS CoV-2 Infection in Liver Disease Patients: A Single-Centre Retrospective Study.

The limited literature on the clinical course of COVID-19 among patients with underlying liver disease (LD) is available from India. The present study aimed to evaluate the clinical and mutational profile of SARS-CoV-2 among LD cases. This was a retrospective study including admitted LD cases in whom SARS-CoV-2 RT-PCR testing was performed. Complete demographic and clinical details were retrieved from Hospital Information System. Detailed mutational analysis was performed by comparing LD COVID-19 positive study group, i.e. LD-CoV(+) with COVID-19 positive outpatients without any underlying LD as control, i.e. NLD-CoV(+). Out of 232 enrolled LD cases, 137 (59.1%) were LD-CoV(+). LD cases with existing co-morbidities were affected more (P = 0.002) and had 2.29 times (OR 2.29, CI 95%, 1.25-4.29) higher odds of succumbing to COVID-19 (P = 0.006). On multivariate regression analysis, ascites (P = 0.05), severe COVID-19 pneumonia (P = 0.046), and an increased levels of bilirubin (P = 0.005) and alkaline phosphatase (P = 0.003) were found to be associated with adverse outcome in LD-CoV(+).On mutational analysis, we found certain differences between LD- and NLD-CoV(+) infected with Delta [LD- and NLD-CoV (+ /D)] and Omicron [LD- and NLD-CoV(+/O)]. More mutations were shared between LD- and NLD-CoV(+/O) compared to LD- and NLD-CoV(+/D). There were differences in prevalence of indel mutations specific to LD-CoV ( +) for both Delta and Omicron. Moreover, we also reported an interesting genic bias between LD- and NLD-CoV( +) in harbouring deleterious/tolerated mutations. To conclude, LD cases with comorbidities were affected more and had higher odds of mortality due to COVID-19. The definite difference between LD- and NLD-CoV(+) groups with respect to frequency of harboured mutations and an inherent genic bias between them is of noteworthy importance.

Granulocyte colony stimulating factor improves Prednisolone responsiveness and 90-day survival in steroid eligible severe Alcohol associated Hepatitis: The GPreAH Study a randomized trial.

BACKGROUND: Severe alcohol-associated-hepatitis(SAH) carries high one-month mortality. Corticosteroids provide a modest 28 day but not 90-day survival benefit, due to development of infections and organ failures. Granulocyte colony stimulating factor(GCSF) has shown promise in SAH patients by its immunomodulatory and regenerative capabilities. We studied the safety and efficacy of combination(GCSF+Prednisolone, GPred) therapy in management of steroid eligible SAH patients. METHODS: Steroid eligible patients with SAH(mDF scores 32- 90) were randomized to receive Prednisolone(GrA, n=42), GPred(GrB, n=42) or GCSF alone(GrC, n=42). GCSF was given as 150-300mcg/day for 7 days followed by every third day for a maximum of 12 doses in one month. Prednisolone 40mg/day was given for 7-days and continued for 28days in responders(Lille score<0.45). RESULTS: Baseline characteristics of patient groups were comparable. On intention-to-treat analysis, the primary endpoint of 90-day survival was achieved in 64.3%(27/42) in Prednisolone, 88.1%(37/42) in GPred and 78.6%(33/42) in GCSF group respectively (p =0.03, Prednisolone vs. GPred). The 28-day survival was not different between the groups [85.7%, 95.2% and 85.7% respectively(p=0.27)]. GPred group had more responders by day-7 (71.4% vs. 92.9% vs. 76.2%,p=0.037) and had greater reduction in mDF (-7.33±4.78, -24.59±3.7,-14.59±3.41,p=0.011), and MELDNa (-1.69±1.26,-7.02±1.24, -3.05±0.83, p=0.002) by day-90. Prednisolone-only group had higher incidence of new infections(35.7%, 19%, 7.1% respectively, p<0.002). Acute kidney injury (33.3%, 7.1%, 11.9%, p=0.002), hepatic encephalopathy (35.7%,9.5%,26.2%,p=<0.001) and rehospitalizations (59.5%, 14.3%, 30.9%, p=<0.01) were lower in GPred group. CONCLUSION: Addition of GCSF to prednisolone improves steroid responsiveness and 90-day survival with fewer infections and new onset complications in SAH patients.

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.

Impact of coagulopathy assessment with thromboelastography and thromboelastometry on transfusion requirements in critically ill cirrhosis with nonvariceal bleeding: A prospective observational study.

Background: Viscoelastic tests are now routinely used for coagulopathy correction in patients with cirrhosis. Thromboelastography (TEG®) and rotational thromboelastometry (RoTEM®) are the most widely studied tests in this population. However, they have not been compared with each other in critically ill patients with liver disease presenting with nonvariceal bleed. Hence, we aimed to compare these tests for coagulopathy correction in patients with liver disease presenting with nonvariceal bleeding. Methods: Sixty adult patients with liver cirrhosis presented to the liver intensive care unit, presenting with a nonvariceal upper gastrointestinal (GI) bleed (diagnosed by doing upper GI endoscopy which revealed bleeding from a nonvariceal source) oral or nasal bleed were enrolled. The patients were allocated to the TEG® group (Group T) or RoTEM® group (Group R) depending on the immediate availability of the viscoelastic test. Coagulopathy correction was done in each group as per established protocols and the results were compared. Results: There was a significant difference in the fresh frozen plasma (FFP) transfusion between the groups. The TEG® group received more FFP when compared to the RoTEM® group (P = 0.001). Conclusion: RoTEM®-based coagulopathy correction leads to lesser use of blood products with similar control of bleeding when compared to TEG, in critically ill patients with cirrhosis.

Treatment Response and Survival with Chemotherapy for Unresectable, Nonmetastatic Cholangiocarcinoma.

Background and objectives: Limited studies have dwelt upon the treatment of unresectable, nonmetastatic cholangiocarcinoma as a separate entity. Hence, the management protocols are not clearly defined for this subgroup of patients. We aimed to analyze patients treated for unresectable, nonmetastatic cholangiocarcinoma. Materials and methods: We analyzed the treatment of patients with unresectable, nonmetastatic cholangiocarcinoma retrospectively. Results: A total of 162 cases of cholangiocarcinoma were reported to our center from 2016 to 2019, out of which 54 were unresectable and nonmetastatic. Thirty patients opted for treatment and were the subjects of this study. Of 30 patients, 24 had hyperbilirubinemia, out of which 10 received chemotherapy after biliary drainage procedure. Out of 30 patients, a total of 16 patients had received chemotherapy, while 14 did not. Gemcitabine/Cisplatin was the first-line chemotherapy administered to 9 patients, whereas 5 received Gemcitabine/Capecitabine and 2 received single-agent gemcitabine. Partial response was documented in 6 patients, and 4 patients had stable disease. The median overall survival was 12.04 months in patients who had received chemotherapy and 6.02 months in those who did not receive chemotherapy (p = 0.005). The median progression-free survival was 6.53 months for patients who had received chemotherapy. The aHR for mortality with chemotherapy compared with no chemotherapy was 0.353 (95% CI: 0.154-0.807). Conclusion: The study data demonstrate that gemcitabine combined with cisplatin- or capecitabine-based chemotherapy prolongs survival in patients with unresectable and nonmetastatic cholangiocarcinoma. In patients with cholangiocarcinoma associated with jaundice, biliary drainage procedure enables giving chemotherapy. Hyperbilirubinemia persisting despite drainage procedures portends poor prognosis and represents an unmet need. How to cite this article: Gupta A, Sahai P, Prasad M, et al. Treatment Response and Survival with Chemotherapy for Unresectable, Nonmetastatic Cholangiocarcinoma. Euroasian J Hepato-Gastroenterol 2024;14(1):5-8.

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.

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.

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.

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.

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.