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INTRODUCTION:Occlusion of spontaneous portosystemic shunts (SPSSs) in patients with cirrhosis may be required in recurrent or refractory hepatic encephalopathy. We describe a novel method for occlusion of SPSS using endoscopic ultrasound (EUS).METHODS:EUS-guided transgastric shunt obliteration was performed by injecting glue and coils directly into SPSS.RESULTS:EUS-guided transgastric shunt obliteration was performed for 7 patients in 9 sessions. Complete cessation of Doppler flow was achieved in 6/7 cases. Adequate clinical response was observed in 6/7 patients. No procedure-related severe adverse events were seen.DISCUSSION:This novel technique is a potentially effective and efficient method for shunt obliteration.

ObjectivePharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still evolving. Probiotics could be a promising treatment option, but their effectiveness needs to be established. The present study aimed to evaluate the efficacy of a high potency multistrain probiotic in adult patients with NAFLD.MethodsThirty-nine liver biopsy-proven patients with NAFLD were randomised in a double-blind fashion to either lifestyle modifications plus an oral multistrain probiotic (675 billion bacteria daily, n=19) or identical placebo (n=20) for 1 year. Lifestyle modifications included regular exercise for all and control of overweight/obesity (with additional dietary restrictions), hypertension and hyperlipidaemia in those with these risk factors. Primary objective of the study was the histological improvement in NAFLD activity score (NAS) and its components and secondary objectives were improvement in alanine transaminase (ALT) and cytokine profile.ResultsThirty (76.9%) out of 39 patients with NAFLD completed the study with 1 year of follow-up. A repeat liver biopsy at 1 year could be done in 10 patients (52.6%) in probiotic group and five patients (25%) in placebo group. In comparison to baseline, hepatocyte ballooning (p=0.036), lobular inflammation (p=0.003) and NAS score (p=0.007) improved significantly at 1 year in the probiotic group. When compared with placebo, the NAS score improved significantly in the probiotic group (p=0.004), along with improvements in hepatocyte ballooning (p=0.05) and hepatic fibrosis (p=0.018). A significant improvement in levels of ALT (p=0.046), leptin (p=0.006), tumour necrosis factor-α (p=0.016) and endotoxins (p=0.017) was observed in probiotic group in comparison to placebo at 1 year. No significant adverse events were reported in the study.ConclusionPatients with NAFLD managed with lifestyle modifications and multistrain probiotic showed significant improvement in liver histology, ALT and cytokines.Trial registration numberThe clinical trial is registered with CLINICAL TRIAL REGISTRYINDIA (CTRI); http://ctri.nic.in, No. CTRI/2008/091/000074

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious public health concern. Given the paucity of approved therapeutic strategies for this lifestyle disorder, dietary interventions may prove effective. We evaluated the mechanisms of how green jackfruit flour (JF) ameliorates metabolic-dysfunction-associated steatohepatitis (MASH) and halts the progression to hepatocellular carcinoma (HCC). The study used murine models of MASH and MASH-HCC that closely mimic human MASLD. C57Bl/6 male mice were fed with chow or western diet with normal or sugar water for 12 weeks, then randomized to receive either 5 kcal% green jackfruit flour (JF) or an equal volume of placebo flour (PB). JF significantly reduced body weight, liver injury, and insulin resistance, and alleviated obesity, steatosis, inflammation, fibrosis, and tumor development in WDSW or WDSW/CCl 4 mice compared to placebo. Furthermore, JF activated AMPK (AMP-activated protein kinase) and inhibited MAPK (mitogen-activated protein kinase) signaling pathways in MASH and MASH-HCC models, respectively. Sodium propionate treatment, the primary short-chain fatty acid entering the liver from JF’s soluble fiber microbial fermentation, further supported these mechanistic insights. Hence, our findings present strong evidence of JF’s therapeutic potential in attenuating MASH and MASH-HCC, warranting further investigation of JF’s efficacy as a dietary intervention in clinical trials.

PurposeTo evaluate the efficacy and safety of irreversible electroporation (IRE) in the treatment of unresectable hepatocellular carcinoma (HCC).Materials and MethodsA retrospective study was conducted from September 2014 to June 2017. A total of 21 HCCs in 21 patients with cirrhosis were treated with IRE. There were eight subcapsular or exophytic, ten perivascular and three peribiliary tumors. The median tumor size was 26 mm (range 14–40 mm). The technical success of the procedure was recorded. Median follow-up, median time to local recurrence, median local tumor progression-free survival (PFS) and complications were recorded.ResultsTechnical success was achieved in all the patients. The median follow-up was 10 months (range 2–30 months). The median time to local recurrence and local tumor PFS were 4 months (range 3–4 months) and 7 months (range 3–30 months), respectively. The tumor-related factor that was significantly associated with local PFS was the size. Maximum tumor diameter < 25 mm was significantly associated with local tumor PFS (p = 0.045). Other parameters including tumor location, segmental portal vein thrombosis, baseline alpha-fetoprotein level and underlying etiology did not affect local tumor PFS. Complications were noted in nine patients and were classified as grades 1 and 2. No procedure-related mortality was encountered.ConclusionIRE is an effective treatment for ablation of small HCCs. Larger prospective studies with strict selection criteria will establish the safety and efficacy of IRE in the treatment of unresectable HCC in patients who cannot undergo thermal ablation.

The present study evaluated the role of dietary folate modulations in the development of hepatocellular carcinoma (HCC) in a rat model. Male Wistar rats were given diethylnitrosamine (DEN) carcinogen for a period of 18 weeks in addition to different folate modulations. Biochemical parameters were assayed and liver tissues were examined using various histopathological stains viz. Hematoxylin and eosin (H&E), Masson’s trichrome, Immunohistochemistry (IHC) staining for arginase-1 and α-smooth muscle actin (SMA). Serum folate and hepatic folate stores were decreased and increased in folate deficiency (FD) and folate oversupplemented (FO) group respectively. Analysis of serum liver function tests revealed deranged liver functioning in all the groups. H&E staining of rat liver demonstrated vague nodularity from 2nd to 8th week, fibrosis from 10th to 15th week, cirrhosis and HCC from 16th to 18th week. Combining the observations of H&E with IHC for arginase-1, 14 (50%), 11 (39.3%) and 17 (58.6%) rats showed HCC positivity in FN (folate normal), FD and FO diets respectively. IHC for α-SMA depicted increased staining with progression of the disease from fibrosis to cirrhosis in all the dietary groups. Collectively, findings of all the histopathological stains, revealed increase in the number of cirrhotic cases and decrease in the number of HCC cases in FD group, indicating delayed progression of HCC with FD. Moreover, FO led to more number of HCC and reduction in the number of cirrhotic cases, signifying early progression of HCC.

BACKGROUND:Systemic inflammation both in acute liver failure (ALF) and patients with cirrhosis and hepatic encephalopathy (HE) leads to microglial activation and an increase in oxidative stress. Iba-1 has been found to be a highly specific marker expressed in microglial cells in animal models. We studied Iba-1 expression in the brains of patients with ALF and CLF with hepatic encephalopathy and the control patients without any neurological disease.METHODS:Autopsied frontal cortex samples were obtained from 5 patients with ALF due to viral hepatitis (HEV, HBV flare) or toxic liver injury (ATT induced) or mushroom poisoning. 7 patients with cirrhosis and HE and 7 controls were obtained. Expression of Iba-1 mRNA was investigated by real-time PCR using appropriate molecular probes and protein expression was assessed using immunohistochemistry using commercially available polyclonal antibodies and measure the intensity with the help of H-score.RESULTS:Iba-1 immunostaining highlights the microglial cells in the grey matter of the brain in ALF patients (H-score = 2000) as compared to the patients with cirrhosis and HE (H-score = 450) and to controls (H-score = 300). ALF grey matter specifically highlights the microglial nodule, and faint cytoplasmic hue is also noted in the neurons. Gene expression studies show the increased fold change in Iba-1 in ALF (fold change = 4.08, P = 0.11) and in patients with cirrhosis and HE (fold change = 1.1, P = 0.84) patients when compared with controls, though not statistically significant.CONCLUSIONS:These results demonstrated the increased microglial activation as well as the number of microglial cells in the ALF patients that can contribute to neuroinflammation.

BACKGROUND:Background and Aims: Minimal hepatic encephalopathy (MHE) is the mildest form in the spectrum of hepatic encephalopathy that impairs health-related quality of life. PHES remains the gold standard for the diagnosis of this condition. Animal naming test (ANT) is reliable and sensitive tool for diagnosis of MHE and can also predict overt episodes of HE. We compared usefulness of PHES and ANT for the diagnosis of MHE and for the prediction of the development of overt episodes of HE.METHODS:Between July 2017 to June 2018, one hundred and three consecutive patients with liver cirrhosis without overt HE were subjected to PHES and ANT evaluation. MHE was diagnosed when the PHES was ≤−5. Receiver-operating characteristic (ROC) curve was used to determine the optimum cut-off of ANT value for the diagnosis of MHE. The best sensitivity and specificity was found at <14. Patients were followed-up every 3-6 months till October 2018.RESULTS:Thirty-seven (35.9%) patients had MHE as assessed by altered PHES. ANT (<14) was present in 36 (34.95%) patients with MHE with sensitivity of 89.19% and specificity of 95.7%, PPV of 91.67%, NPV of 94.03% and diagnostic accuracy of 93.20%. The area under the curve for diagnosis of MHE was 0.978 (95% CI 0.954–1.0). MHE patients had significantly lower ANT as compared to non MHE patients and controls (10.81 ± 0.324 vs 15.27 ± 0.147 vs 15.78 ± 0.192, respectively, P = 0.01). MHE patients had lower hand grip strength compared to non-MHE patients and the control group (Males: 26 vs 30 vs 38, Females 25 vs 28 vs 28, P > 0.05). PHES significantly correlated with Child-Pugh (r = −0.421, P = 0.001) and model for end-stage liver disease (MELD) (r = −0.345, P = 0.001) scores. ANT correlated with PHES (r = 0.752, P = 0.001) and also with Child-Pugh (r = −0.408, P = 0.001) and MELD (r = −0.318, P = 0.001) scores. During follow-up, 14 patients in MHE group and 4 in non-MHE group developed overt episodes of HE (P = 0.001). Out of 37 patients with abnormal PHES 14 patients developed overt HE on follow up and out of 36 patients with abnormal ANT 14 patients developed overt HE on follow up. 33 patients had both PHES and ANT abnormal. 4 patients had PHES abnormal and ANT normal. 3 patients had PHES normal and ANT abnormal.CONCLUSIONS:ANT is a highly accurate and reliable test for the diagnosis of MHE and prediction of overt episodes of HE in outpatients of cirrhosis as compared to PHES and correlates well with the Child-Pugh and MELD scores.

Background & objective: It has been shown that the combined use of alcohol before radiofrequency ablation (RFA) helps to augment the therapeutic advantage of RFA. The present study was conducted to compare the outcome of treatment with RFA alone and RFA with alcohol as ablative technique in patients with small hepatocellular carcinomas (HCCs), who were not candidates for surgery. Methods: Fifty patients with chronic liver disease and concurrent HCC were enrolled in this prospective study. The patients were treated with either RFA alone (n=25) or RFA combined with alcohol (n=25). Patient outcome was evaluated, and the tumour recurrence and survival of the patients were assessed in the two groups. Results: The survival rates at six months in patients who completed at least six months of follow up were 84 and 80 per cent in patients treated with RFA alone and combination therapy, respectively. During the follow up period, 11 and four patients treated with RFA alone showed local and distant intrahepatic tumour recurrence, respectively. All local recurrences were at one to 18 months of the follow up period. The distant recurrences occurred at 6-36 months of the follow up period. During the follow up period, eight and six patients treated with combination therapy showed local and distant intrahepatic tumour recurrence, respectively. All local recurrences were at 1.5-15 months during the follow up period. The distant intrahepatic recurrences occurred at 6-72 months during the follow up period. Interpretation & conclusions: No significant difference was seen between the survival time of the patients treated with RFA alone and RFA with alcohol as well as in the local recurrences and distant intrahepatic recurrences in RFA compared to RFA and alcohol group patients. Combined use of RFA and alcohol did not improve the local tumour control and survival in patients with HCC compared to RFA alone.