Prevalence of Acute on Chronic Liver Failure in Autoimmune Hepatitis, Treatment Response and Mortality Burden Assessment: A Region-Predominant Systematic Review and Meta-Analysis.

Acute-on-chronic liver failure (ACLF) is a global health problem. Little scientific evidence exists on its prevalence in autoimmune hepatitis. Treatment response and mortality outcomes have also been reported differently. The study was conducted to estimate the overall prevalence of ACLF among patients with autoimmune hepatitis (AIH) and determine the associated treatment response and mortality. We scrutinized wide literature in Scopus, PubMed, Embase, Web of Science, and Cochrane, and assessed published articles completely, studies performed and reported from around the globe, until December 07, 2023, according to the PROSPERO registered protocol (CRD42023412176). Studies (retrospective and prospective cohort study type) that stated the ACLF development among established AIH cases were considered. Features of the study, duration of follow-up, and numeric patient information were retrieved from the studies included. The research paper quality was checked for risk of bias. Random effect meta-analysis with metaregression and subsection scrutinies were performed with R. The main outcome was the collective prevalence of ACLF in the AIH patients, whereas treatment response and mortality in AIH-associated ACLF were secondary outcomes. Six studies were involved with confirmed diagnoses in 985 AIH patients for the data synthesis. The pooled prevalence of ACLF in the explored patients was 12% (95% CI: 8-17) ( P =0.01). Heterogeneity was found to be high in the present meta-analysis ( I2 =72%; P < 0.01). For the secondary endpoint analysis, the pooled prevalence of complete remission at 1-year follow-up was 71% (0.52; 0.85), and mortality from the ACLF-AIH patient population was 32% (95% CI: 18-50). Sensitivity analysis showed no influence on the overall estimations of the pooled prevalence of ACLF by omitting studies one by one. One in 10 AIH patients likely present with ACLF. The response to treatment is seen in two-thirds of patients, and mortality is high.

Capsule endoscopy for small bowel bleed: Current update.

Small intestine, hitherto an obscure area for endoscopists before 2000, is now easily evaluated non-invasively using capsule endoscopy and invasively by device-assisted enteroscopies. Major advances in understanding the causes and management of small bowel diseases have been in obscure gastrointestinal (GI) bleed, currently re-named as small bowel bleed, after the discovery of capsule endoscopy. The current article is a narrative review of the technology of capsule endoscopy, its advantages and limitations, future perspective and Indian studies on its utility in patients with small bowel bleed. Till date, eight large series reporting 2319 patients with obscure GI bleed (1554 overt and 765 occult) undergoing capsule endoscopy have been reported from India. Overall yield of capsule endoscopy to detect lesions in these studies varied from 43.5% to 90%. The major causes detected in various studies for small bowel bleed include vascular malformation, portal hypertensive enteropathy, ulcer, stricture, tumor, polyps, etc. Hookworm can cause both occult as well as overt small bowel bleed as shown mainly from India. Capsule endoscopy has also been quite safe in patients with small bowel bleed as despite 0.6% to 15% retention of imaging capsule in Indian studies, development of clinically evident small bowel obstruction has rarely been reported. The major limitations of capsule endoscopy include lack of maneuvrability and therapeutic capability. Research is in progress to overcome some of the limitations of the current capsule endoscopy system. It is concluded that discovery of capsule endoscopy has brought a new paradigm in GI endoscopy and explored a hitherto unexplored area of GI tract, i.e. small bowel that continued to be a black box for the endoscopists.

Novel application of lumen-apposing metal stent for management of malignant recto-sigmoid stricture with fistula.

Video 1Demonstration of novel application of lumen-apposing metal stent for management of a malignant recto-sigmoid junction stricture with fistula.

Magnetic resonance elastography (MRE) outperforms acoustic force radiation impulse (ARFI) in predicting oesophageal varices in obese NAFLD cirrhosis.

PURPOSE: Liver stiffness measurement (LSM) by transient elastography has been shown to underperform in high-risk varices (HRVs) prediction in obese non-alcoholic fatty liver disease (NAFLD) compensated cirrhosis (CC). LSM by magnetic resonance elastography (MRE) and acoustic force radiation impulse (ARFI) has been shown to be useful in prediction of oesophageal varices (EVs), but has limited evidence in obese NAFLD-CC. METHODS: Obese patients with NAFLD-CC who underwent MRE and ARFI for LSM and endoscopy for screening of varices were enrolled. Performance of MRE and ARFI for predicting EVs or HRVs was evaluated using area under receiver operating characteristics (AUROC) curves and regression analyses were performed for predictor variables. RESULTS: One hundred eight patients [mean age 54.7 ± 9.6 years, median BMI, 28.5 (26.4-30.0) kg/m2. 72.2% diabetics, 45.4% hypertensive] were enrolled. Fifty-two (48.1%) had no varices, while 29 (26.8%) and 27 (25%) had low-risk varices (LRVs) and HRVs, respectively. MRE-LSM was higher in patients with LRVs (p = 0.01) or HRVs (p = 0.001) against those without varices. ARFI-LSM did not differ significantly between those without and with LRVs or HRVs (p > 0.05 for all). There was a low correlation between ARFI-LSM and MRE-LSM in the overall cohort (r = 0.19). Only platelet count (PC) [0.98 (0.97-0.99)] and MRE-LSM [1.8 (1.26-2.79)] were predictors of HRVs. At a cut-off of 4.75, MRE showed a sensitivity of 96.3%. Model combining MRE-LSM with PC had a diagnostic AUROC of 0.77 and 0.76 for EVs and HRVs. CONCLUSION: In obese NAFLD-CC, MRE-LSM is significantly higher in patients with varices. MRE combined with PC predicts EVs and HRVs with better accuracy than ARFI.

Definitive Role of Contrast-enhanced Endoscopic Ultrasound (EUS) in the Diagnosis of Hepatocellular Carcinoma With Non-diagnostic Cross-sectional Imaging: A Case Report.

The diagnosis of hepatocellular carcinoma is usually centered around cross-sectional imaging (CSI) modalities. However, in some instances focal hepatic lesions may be missed on CSI. Endoscopic ultrasound (EUS) has an evolving role in hepatology and have been shown to be useful in diagnosing focal lesions with advantages of tissue acquisition. We report a case hepatitis B-related cirrhosis presenting with acute decompensation, wherein EUS was used to identify HCC and perform tissue acquisition as CSI was non-diagnostic.

Efficacy and safety of transjugular intrahepatic portosystemic shunt in patients with hepatocellular carcinoma-A systematic review and meta-analysis.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) and cirrhosis can present with features of severe portal hypertension, which can be worsened further by portal vein tumoral thrombosis (PVTT). Due to the technical difficulties and short survival of these patients, HCC was traditionally considered a relative contra-indication for transjugular intrahepatic portosystemic shunt (TIPS). However, there is an increasing body of evidence, mainly from China, supporting the use of TIPS in HCC. The present study aimed at analyzing the efficacy and safety of TIPS in patients with HCC. METHODS: From 2000 through May 2023, MEDLINE, Embase and Scopus were searched for studies analyzing the outcome of TIPS in HCC. Technical and clinical success, adverse events (AE) and mortality were the main outcomes assessed. With the use of a random effects model, the event rates were combined. RESULTS: Total 19 studies with 1498 patients were included in the final analysis. The pooled technical and clinical success rates with TIPS in HCC were 98.8% (98.0-99.7) and 94.1% (91.2-97.0), respectively. After TIPS, ascites was controlled in 89.2% (85.1-93.3) of the cases, while rebleeding was observed in 17.2% (9.4-25.0) of cases on follow-up. The pooled incidence of overall AE, serious AE and post-TIPS hepatic encephalopathy (HE) was 5.2% (2.5-7.9), 0.1% (0.0-0.4) and 25.1% (18.7-31.5), respectively. On follow-up, 11.9% (7.8-15.9) of the patients developed shunt dysfunction requiring re-intervention. CONCLUSION: The present analysis supports the feasibility, safety and efficacy of TIPS in the management of portal hypertension in patients with HCC.

Determinants, profile and outcomes of hepatitis A virus-associated severe acute liver injury in adults.

BACKGROUND AND OBJECTIVES: Hepatitis A virus (HAV)-related hepatitis is witnessing an epidemiological transition with increasing trends in adults. While uncomplicated hepatitis remains common, evidence suggests it to be a growing cause for acute liver failure (ALF). In between the two extremes exists severe acute liver injury (s-ALI) which has a propensity to transition to ALF. We aimed at describing the clinical profile of patients with HAV-related s-ALI and identifying potential predictors of progression to ALF. METHODS: This was a single-center retrospective analysis of adult patients admitted with HAV-related s-ALI between April 2022 and December 2023. Demographic and laboratory parameters were compared between patients with only s-ALI and those with ALF. Predictors of progression from s-ALI to ALF were identified using logistic regression. RESULTS: Forty-three patients satisfied criteria of s-ALI, of which 33 (76.7%) had only s-ALI, while 10 (23.3%) had ALF. Patients with s-ALI had lesser leukocytosis (6.3 ± 3 vs. 13.2 ± 4.8), less incidence of acute kidney injury (9.1% vs. 40%) and lower model for end-stage liver disease (MELD) (20 [18-24.5] vs. 31.5 [26-42]), arterial lactate (2.1 [1.3-3.1] vs. 6.3 [5.2-8.0]), arterial ammonia (94 [72-118] vs. 299 [188-573]), procalcitonin (0.5 [0.28-1.25] vs. 3.2 [1.2-6.1]) and ferritin (482 [213-1633] vs. 5186 [1341-11,053]) compared to HAV-ALF (p < 0.05 for all). Three patients (9.09%) with s-ALI progressed to ALF of whom one (3%) died. Baseline ammonia levels (unadjusted odds ratio [OR] 1.03 [1.01-1.06]) and leukocyte count (OR 1.00 [1.00-1.01]) tended to be associated with ALF progression, although none was significant after multi-variable adjustment. Ammonia levels had an area under receiver operating curve of 0.816 (0.64-0.93) (p = 0.009) (cut-off of 144 µmol/L). Additional comorbidities did not impact overall outcomes. CONCLUSION: HAV presents as s-ALI in young adults, with almost one in 10 progressing to ALF. Baseline ammonia may be an important predictor of progression even in s-ALI, but mandates larger well-designed studies.

Alcoholic Liver Disease/Non-Alcoholic Fatty Liver Disease Index for Classification of Patients with Steatotic Liver Disease.

Background: Steatotic liver disease (SLD) encompasses metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (AALD) at extremes as well as an overlap group termed MASLD with increased alcohol intake (Met-ALD). The Alcoholic Liver Disease/Non-Alcoholic Fatty Liver Disease Index (ANI) was proposed to differentiate ALD from non-alcoholic fatty liver disease (NAFLD). We analysed the performance of the ANI in differentiating within the SLD spectrum. Methods: In a cross-sectional study at a tertiary care center, 202 adults (>18 years) who were prospectively diagnosed with SLD defined by magnetic resonance imaging-proton density fat fraction >6.4% were enrolled. Alcohol consumption (AC) was recorded according to thresholds for significant AC: 140-350 g/week (or 20-50 g/day) for females and 210-420 g/week (or 30-60 g/day) for males. The ANI was calculated, and area under the receiver operating characteristic curve (AUROC) was generated. Results: Of 202 patients (47 years [interquartile range, IQR, 38 to 55], 23.75% females, 77% obese, 42.1% diabetic, 38.1% hypertensive, 28.7% statin use), 40.5% were ever-alcohol consumers; 120 (59%), 50 (24.7%), and 32 (15.8%) were MASLD (ANI, -3.7 [IQR, -7 to -1.6]; Met-ALD, - 1.45 [IQR, -2.4 to 0.28]; and AALD, 0.71 [IQR, -1.3 to 4.8], respectively; P<0.05 for all). The AUROC of the ANI for MASLD and AALD was 0.79 (0.72 to 0.84; cut-off <-3.5) and 0.80 (0.74 to 0.86; cut-off >-1.49), respectively. The ANI outperformed aspartate transaminase/alanine transaminase (AST/ALT) ratio (AUROC=0.75 [0.69 to 0.81]) and gamma glutamyl transpeptidase (GGT) (AUROC=0.74 [0.67 to 0.80]). Addition of GGT did not improve model performance (AUCdiff=0.004; P=0.33). Conclusion: AC is common in MASLD. The ANI distinguishes MASLD and AALD, with individual cut-offs within the intermediate zone indicating Met-ALD. ANI also outperforms AST/ALT ratio or GGT.

Current status of etiology and outcomes of acute liver failure in India-A multicentre study from tertiary centres.

BACKGROUND AND AIMS: Acute liver failure (ALF) is a medical emergency and liver transplantation (LT) may be required as definitive therapy. The etiology varies across geographical locations and is mostly viral dominant in India. We aimed at evaluating the spectrum, impact of interventions (plasma exchange [PLEx], continuous renal replacement therapy [CRRT]) and outcomes of ALF in India in recent times. METHODS: A multicentre retrospective study across four major tertiary care centres. RESULTS: As many as 183 ALF patients (median age, 23 years; females, 43.1%; model for end-stage liver disease [MELD], 32.7) from January 2021 to December 2023 were included. Nineteen per cent had infection and 40.4% of patients satisfied King's College criteria (KCC) at admission. Most common cause for ALF was hepatitis A virus (HAV) (44.2%) followed by rodenticide poisoning (10.3%). Approximately 35% of patients each received either PLEx or CRRT. The 7, 14 and 21-day transplant-free survival probability was 65.5%, 60.1%, and 57.3%, respectively. Only 3.8% of patients underwent liver transplantation. On multivariable Cox regression analysis, hemoglobin (HR, 0.74 [0.63-0.87]), lactate (HR, 1.14 [1.03-1.26]), advanced hepatic encephalopathy (HE) (HR, 4.87 [1.89-12.5]) and fulfilling KCC [HR, 10.04 [4.57-22.06]) at admission were the independent predictors of mortality. A model including KCC + lactate + HE ≥ 3 with or without hemoglobin had an AUROC of 0.81-0.84 to predict mortality. In those who underwent PLEx, advanced HE (HR, 4.13 [1.75-9.7]), procalcitonin (HR, 1.18 [1.07-1.30]) and KCC (HR, 4.6 [1.6-13.1), while for those who received CRRT, lactate (HR, 1.37 [1.22-1.54]) and KCC (HR, 6.4 [2.5-15.8]) independently predicted mortality. CONCLUSIONS: Hepatitis A virus is currently the most common cause for ALF in India, emphasizing the need for universal vaccination programmes. Spontaneous survival in tertiary care centres is 57%. LT rates were low.

Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials. METHODS: We obtained individual patient data (IPD) from 9 eligible randomized trials comparing treatment regimens (different androgen deprivation therapy [ADT] strategies or ADT plus docetaxel in the control or research arms) in mHSPC. rPFS was defined as the time from random assignment to radiographic progression or death from any cause whichever occurred first; cPFS was defined as the time from random assignment to the date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. We implemented a two-stage meta-analytic validation model where conditions of patient-level and trial-level surrogacy had to be met. We then computed the surrogate threshold effect (STE). RESULTS: IPD from 6,390 patients randomly assigned from 1994 to 2012 from 13 units were pooled for a stratified analysis. The median OS, rPFS, and cPFS were 4.3 (95% CI, 4.2 to 4.5), 2.4 (95% CI, 2.3 to 2.5), and 2.3 years (95% CI, 2.2 to 2.4), respectively. The STEs were 0.80 and 0.81 for rPFS and cPFS end points, respectively. CONCLUSION: Both rPFS and cPFS appear to be promising surrogate end points for OS. The STE of 0.80 or higher makes it viable for either rPFS or cPFS to be used as the primary end point that is surrogate for OS in phase III mHSPC trials with testosterone suppression alone as the backbone therapy and would expedite trial conduct.

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

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

Prophylactic Lactulose Therapy in Patients with Cirrhosis and Upper Gastrointestinal Bleeding: A Meta-analysis of Randomized Trials.

BACKGROUND AND AIMS: Lactulose is the first-line drug for both treatment and secondary prophylaxis for overt hepatic encephalopathy (HE). The use of lactulose for the primary prophylaxis of HE in patients with cirrhosis and acute upper gastrointestinal bleeding (AUGIB) has been debated. Hence, we conducted this meta-analysis to assess the role of lactulose in HE prophylaxis in patients with cirrhosis and AUGIB. METHODS: A comprehensive search of literature from inception to December 2022 was performed of three databases for randomized studies comparing lactulose and placebo in patients with cirrhosis and AUGIB. Risk ratios (RR) with 95% confidence intervals were calculated for all the dichotomous outcomes. RESULTS: A total of five studies were included in the final analysis, out of which three studies had a low risk of bias, and two had a moderate risk of bias. Lactulose therapy was associated with a significantly lower risk of OHE compared to placebo, with a RR of 0.38 (0.23-0.62) and a number needed to treat of 6. There was no difference in the risk of mortality between the groups, with a RR of 0.71 (0.29-1.76). The pooled incidence rates of overall adverse events (AEs) and diarrhea with the use of lactulose therapy were 53.2% (42.2- 64.2) and 34.7% (17.7-51.7), but a majority did not require drug discontinuation. The certainty of the evidence was moderate to low. CONCLUSIONS: Prophylactic lactulose reduces the incidence of HE after AUGIB but has no effect on mortality. Diarrhea and abdominal discomfort are common AEs but do not need drug discontinuation.

Effects of non-invasive vagus nerve stimulation on clinical symptoms and molecular biomarkers in Parkinson's disease.

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson's disease (PD) patients. In a subgroup of patients, we measured selected neurotrophins, inflammatory markers and markers of oxidative stress in serum. Thirty-three PD patients with freezing of gait (FOG) were randomized to either active nVNS or sham nVNS. After baseline assessments, patients were instructed to deliver six 2 min stimulations (12 min/day) of the active nVNS/sham nVNS device for 1 month at home. Patients were then re-assessed. After a one-month washout period, they were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters (speed, stance time and step length) were observed with active nVNS. While serum tumor necrosis factor- α decreased, glutathione and brain-derived neurotrophic factor levels increased significantly (p < 0.05) after active nVNS treatment. Here we present the first evidence of the efficacy and safety of nVNS in the treatment of gait in PD patients, and propose that nVNS can be used as an adjunctive therapy in the management of PD patients, especially those suffering from FOG. Clinical trial registration: identifier ISRCTN14797144.