Type-2 diabetes mellitus is a frequent comorbidity of cirrhosis independently associated with cirrhosis-related complications and mortality. This post hoc analysis of the ANSWER trial database assessed the effects of long-term human albumin (HA) administration on top of the standard medical treatment (SMT) on the clinical outcomes of a subgroup of 85 outpatients with liver cirrhosis, uncomplicated ascites and insulin-treated diabetes mellitus type 2 (ITDM). Compared to patients in the SMT arm, the SMT + HA group showed a better overall survival (86% vs. 57%, p = .016) and lower incidence rates of paracenteses, overt hepatic encephalopathy, bacterial infections, renal dysfunction and electrolyte disorders. Hospital admissions did not differ between the two arms, but the number of days spent in hospital was lower in the SMT + HA group. In conclusion, in a subgroup of ITDM outpatients with decompensated cirrhosis and ascites, long-term HA administration was associated with better survival and a lower incidence of cirrhosis-related complications.

BACKGROUND: The World Health Organization (WHO) reports that Asia and Africa have the highest Chronic Liver Disease (CLD) mortality rate. Cirrhosis, responsible for 22.2 fatalities per 100,000 people, is India\'s 10th most common cause of mortality. The increasing prevalence of chronic liver disease necessitates a study to identify predictive factors for patients who visit the emergency department. Identifying elements that enhance the predictive value of mortality in unstable patients with CLD complications is important in emergency departments. This study aims to determine Clinical and Laboratory Parameters as mortality predictors in adult chronic liver disease patients.
METHODS: The study was conducted at the emergency department of a tertiary healthcare center in Northern India. Patients with chronic liver disease above 18 years of age who satisfied the inclusion criteria were clinically evaluated. Clinical and demographic details were collected, and data was analyzed.
RESULTS: Two hundred thirty-six patients were enrolled. The mean age was 50.77 ± 14.26 years. 78.4% of the participants were men. Abdominal distension, affecting 59.7% of patients, was the most common presenting ailment, followed by melena and hematemesis, affecting 41.9% and 32.6%, respectively. The mean stay in the emergency department was 10.29 ± 8.10 h. Refractory septic shock, the leading cause of mortality, accounts for 69.2% of all deaths, alongside grade 4 hepatic encephalopathy and massive Upper Gastrointestinal (UGI) bleeding, as identified in our study. Factors such as altered mental sensorium, high respiratory rate, low SpO2, increased heart rate, low systolic blood pressure, low diastolic blood pressure, and low Glasgow Coma Scale (GCS) on Emergency Department (ED) arrival are significantly associated with mortality.
CONCLUSIONS: Chronic liver disease, a prevalent condition in India, most commonly seen in middle aged men and lower socioeconomic groups. The parameters independently associated with mortality in our study were presence of altered mental sensorium, Glasgow coma scale, Child Pugh class and need for ICU admission. Understanding the presentation pattern, and mortality predictors can help ED physicians in managing acute events and follow-ups.

Hepatic encephalopathy (HE), a morbid ordeal affecting chronic liver disease patients always insists for the search of a rational, superior & infallible agent beyond the time-proven standards i.e., Lactulose & Rifaximin. In this RCT, we compared the efficacy of intravenous (IV) L-ornithine-L-aspartate(LOLA) versus Oral LOLA in patients with chronic liver disease(CLD) enduring overt Hepatic Encephalopathy(OHE). 40 CLD patients with OHE were randomly assigned IV or oral LOLA in a 1:1 ratio. Patients were graded for HE and monitored for serum ammonia levels from day 1 to day 5. The aim was to compare IV versus oral LOLA efficacy in HE grades improvement and its correlation with ammonia levels. The study was registered with clinical trials registry-India, CTRI/2020/12/029943. Baseline characteristics of patients in both groups were similar. The mean difference in ammonia levels from day 1 to day 5 was 55.4 ± 32.58 µmol/L in the IV LOLA group and 60.75 ± 13.82 µmol/L in the oral LOLA group (p = 0.511). Significant reductions in ammonia levels were observed from day 1 to day 5 within each group (p < 0.001). HE grade & ammonia correlated positively in both groups. LOLA, regardless of administration route, has demonstrated efficacy in OHE.

OBJECTIVE: The effect of transjugular intrahepatic portosystemic shunt (TIPS) plus variceal embolization for treating gastric varices (GVs) remains controversial. This nationwide multicenter cohort study aimed to evaluate whether adding variceal embolization to a small diameter (8-mm) TIPS could reduce the rebleeding incidence in patients with different types of GVs.
METHODS: This retrospective cohort study involved 629 patients who underwent 8-mm TIPS for gastric varices at 7 medical centers. The primary endpoint was all-cause rebleeding, and the secondary endpoints included overt hepatic encephalopathy (OHE) and all-cause mortality.
RESULTS: A total of 629 patients were included. Among them, 429 (68.2%) had gastroesophageal varices type 1 (GOV1), 145 (23.1%) had gastroesophageal varices type 2 (GOV2), and 55 (8.7%) had isolated gastric varices type 1 (IGV1). In the entire cohort, adjunctive embolization reduced rebleeding (6.2% vs 13.6%; P = .005) and OHE (31.0% vs 39.4%; P = .02) compared with TIPS alone. However, no significant differences were found in mortality (12.0% vs 9.7%; P = .42). In patients with GOV2 and IGV1, TIPS plus variceal embolization reduced both rebleeding (GOV2: 7.8% vs 25.1%; P = .01; IGV1: 5.6% vs 30.8%; P = .03) and OHE (GOV2: 31.8% vs 51.5%; P = .008; IGV1: 11.6% vs 38.5%; P = .04). However, in patients with GOV1, adjunctive embolization did not reduce rebleeding (5.9% vs 8.7%; P = .37) or OHE (33.1% vs 35.3%; P = .60).
CONCLUSIONS: Compared with TIPS alone, 8-mm TIPS plus variceal embolization reduced rebleeding and OHE in patients with GOV2 and IGV1. These findings suggest that patients with GOV2 and IGV1, rather than GOV1, could benefit from embolization with TIPS.

BACKGROUND: Diet can affect ammoniagenesis in cirrhosis and hepatic encephalopathy (HE), but the impact of dietary preferences on metabolomics in cirrhosis is unclear. As most Western populations follow meat-based diets, we aimed to determine the impact of substituting a single meat-based meal with an equal protein-containing vegan/vegetarian alternative on ammonia and metabolomics in outpatients with cirrhosis on a meat-based diet.
METHODS: Outpatients with cirrhosis with and without prior HE on a stable Western meat-based diet were randomized 1:1:1 into 3 groups. Patients were given a burger with 20 g protein of meat, vegan, or vegetarian. Blood for metabolomics via liquid chromatography-mass spectrometry and ammonia was drawn at baseline and hourly for 3 hours after meal while patients under observation. Stool microbiome characteristics, changes in ammonia, and metabolomics were compared between/within groups.
RESULTS: Stool microbiome composition was similar at baseline. Serum ammonia increased from baseline in the meat group but not the vegetarian or vegan group. Metabolites of branched chain and acylcarnitines decreased in the meat group compared with the non-meat groups. Alterations in lipid profile (higher sphingomyelins and lower lysophospholipids) were noted in the meat group when compared with the vegan and vegetarian groups.
CONCLUSIONS: Substitution of a single meat-based meal with a non-meat alternatives results in lower ammoniagenesis and altered serum metabolomics centered on branched-chain amino acids, acylcarnitines, lysophospholipids, and sphingomyelins in patients with cirrhosis regardless of HE or stool microbiome. Intermittent meat substitution with vegan or vegetarian alternatives could be helpful in reducing ammonia generation in cirrhosis.

BACKGROUND: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD).
METHODS: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival.
CONCLUSIONS: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care.
BACKGROUND: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation.
BACKGROUND: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

UNASSIGNED: Type C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by 1H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites.
UNASSIGNED: The bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. 1H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/μm2) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy).
UNASSIGNED: The characteristic 1H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity-Callaghan\'s model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema.
UNASSIGNED: dMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.

OBJECTIVE: The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) plus extrahepatic collateral embolisation (TIPS+E) in reducing rebleeding and hepatic encephalopathy (HE) post-TIPS was recently reported in a meta-analysis, but further validation is essential. This study aims to confirm the effectiveness of TIPS+E using real-world data.
METHODS: The multicentre retrospective cohort included 2077 patients with cirrhosis who underwent TIPS±E (TIPS: 631, TIPS+E: 1446) between January 2010 and December 2022. Regression and propensity score matching (PSM) were used to adjust for baseline characteristic differences. After PSM, clinical outcomes, including rebleeding, HE, survival and further decompensation (FDC), were analysed. Baseline data from all patients contributed to the construction of prognostic models.
RESULTS: After PSM, 1136 matched patients (TIPS+E: TIPS=568:568) were included. TIPS+E demonstrated a significant reduction in rebleeding (HR 0.77; 95% CI 0.59 to 0.99; p=0.04), HE (HR 0.82; 95% CI 0.68 to 0.99; p=0.04) and FDC (HR 0.85; 95% CI 0.73 to 0.99; p=0.04), comparing to TIPS. Significantly, TIPS+E also reduced rebleeding, HE and FDC in subgroup of using 8 mm diameter stents and embolising of gastric varices+spontaneous portosystemic shunts (GV+SPSS). However, there were no differences in overall or subgroup survival analysis. Additionally, the random forest models showed higher accuracy and AUROC comparing to other models. Controlling post-TIPS portal pressure gradient (pPPG) within 7 mm HgCONCLUSIONS: Our real-world data validation confirms the high efficacy of TIPS+E in reducing rebleeding and HE, particularly when using 8 mm diameter stents, embolising GV+SPSS and maintaining an optimal pPPG.

BACKGROUND: Proton pump inhibitors (PPI) are frequently used in patients with cirrhosis.
OBJECTIVE: This study aimed to determine whether PPI use is associated with the prognosis of cirrhotic patients.
METHODS: We conducted a multicentre retrospective cohort study involving 1485 patients who had experienced hepatic encephalopathy (HE) from 7 referral centres in Korea. The primary outcome was overall survival and secondary outcomes included the development of cirrhotic complications, including recurrent HE, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS), and gastrointestinal bleeding. Patients treated with PPI with a mean defined daily dose (mDDD) ≥0.5 (high-dose PPI group) were compared to those treated with PPI of an mDDD < 0.5 (No or low-dose PPI group) for each outcome.
RESULTS: Among 1485 patients (median age, 61 years; male, 61%), 232 were assigned to the high-dose PPI group. High-dose PPI use was independently associated with a higher risk of death (adjusted HR [aHR] = 1.71, 95% confidence interval [CI] = 1.38-2.11, p < 0.001). This result was reproducible after propensity score-matching (PSM) (aHR = 1.90, 95% CI = 1.49-2.44, p < 0.001). High-dose PPI use was an independent risk factor of recurrent HE (before PSM: aHR = 2.04, 95% CI = 1.66-2.51, p < 0.001; after PSM: aHR = 2.16, 95% CI = 1.70-2.74, p < 0.001), SBP (before PSM: aHR = 1.87, 95% CI = 1.43-2.43, p < 0.001; after PSM: aHR = 1.76, 95% CI = 1.31-2.36, p = 0.002), HRS (before PSM: aHR = 1.48, 95% CI = 1.02-2.15, p = 0.04; after PSM: aHR = 1.47, 95% CI = 0.95-2.28, p = 0.09), and gastrointestinal bleeding (before PSM: aHR = 1.46, 95% CI = 1.12-1.90, p = 0.006; after PSM: aHR = 1.74, 95% CI = 1.28-2.37, p < 0.001).
CONCLUSIONS: The use of high-dose PPI was independently associated with increased risks of mortality and cirrhotic complications.

UNASSIGNED: Hyperammonemia and hepatotoxicity are well-known complications of valproic acid (VPA) poisoning. The objective of this study is to evaluate the potential role of carnitine in mitigating the adverse effects of acute VPA toxicity in mice.
UNASSIGNED: 54 male mice (25-30 g) were randomly assigned to one of three categories, including acute, sub-acute, and chronic poisoning. Each category contained 3 groups, each consisting of 6 mice (Group 1: control, Group 2: VPA treated, and Group 3: VPA + carnitine treated). The animals were sacrificed 24 hours after the initial injection, and their blood, liver, and brain samples were compared between groups of each category regarding liver function biomarkers, oxidative stress markers, ammonia level, and liver histopathologic changes using one-way ANOVA followed by Tukey\'s multiple comparison test.
UNASSIGNED: The administration of VPA increased the serum level of aspartate aminotransferase (AST) (p=0.003) and alanine aminotransferase (ALT) (p=0.001), as well as serum, and brain level of ammonia (p=0.0001 for both) in the intervention group. Elevated levels of lipid peroxidation and oxidative stress (p=0.0001 for both) in the liver tissue, decreased liver glutathione (p=0.0001) and ferric ion-reducing antioxidant power (FRAP) (p=0.0001), and histopathologic changes in the form of moderate to severe inflammation were observed. Administration of VPA + carnitine reduced AST (p=0.05) and ALT (p=0.01), increased the FRAP, reduced free oxygen radicals and liver lipid peroxidation (p=0.0001 for all), and decreased tissue damage in the form of moderate inflammation. The administration of carnitine was ineffective in reducing brain or plasma ammonia levels in acute VPA-treated animals (p = 0.0115).
UNASSIGNED: Although the administration of carnitine has been suggested as a protective remedy in cases of VPA toxicity, according to the present study, it did not have an antidotal effect and did not prevent encephalopathy or liver injury in acute VPA toxicity.