The Story of Ammonia in Liver Disease: An Unraveling Continuum.

Hyperammonemia and liver disease are closely linked. Most of the ammonia in our body is produced by transamination and deamination activities involving amino acid, purine, pyrimidines, and biogenic amines, and from the intestine by bacterial splitting of urea. The only way of excretion from the body is by hepatic conversion of ammonia to urea. Hyperammonemia is associated with widespread toxicities such as cerebral edema, hepatic encephalopathy, immune dysfunction, promoting fibrosis, and carcinogenesis. Over the past two decades, it has been increasingly utilized for prognostication of cirrhosis, acute liver failure as well as acute on chronic liver failure. The laboratory assessment of hyperammonemia has certain limitations, despite which its value in the assessment of various forms of liver disease cannot be negated. It may soon become an important tool to make therapeutic decisions about the use of prophylactic and definitive treatment in various forms of liver disease.

Sarcopenia-related gut microbial changes are associated with the risk of complications in people with cirrhosis.

Background & Aims: Sarcopenia and gut dysbiosis are common in individuals with cirrhosis. However, the association between sarcopenia and microbial alterations, and the subsequent impact on cirrhotic outcomes are poorly understood. This study aimed to identify muscle-dependent microbial changes and related risks of cirrhotic complications. Methods: From September 2018 to December 2020, 89 individuals with cirrhosis and 16 healthy volunteers were prospectively enrolled. Muscle and nutritional status, serum amino acids, and fecal microbiota were analyzed. The association between microbial signatures of sarcopenia and cirrhotic complications was investigated. Results: A decline in muscle mass and strength were associated with gut microbial alterations in individuals with cirrhosis. The greatest microbial dissimilarity was observed between those with sarcopenia (both decline in muscle mass and strength) and those with normal-muscle status (p = 0.035). Individuals with sarcopenia had lower serum levels of alanine, valine, leucine, isoleucine, proline, tryptophan and ornithine. Besides, gut microbial functions associated with amino acid biosynthesis were significantly reduced in individuals with sarcopenia and cirrhosis. Depletion of Dialister, Ruminococcus 2, and Anaerostipes were associated with cirrhotic sarcopenia, and significantly correlated with the serum levels of amino acids. Individuals with coexistent depletion of Ruminococcus 2 and Anaerostipes developed more infectious (44.4% vs. 3.0%) and non-infectious (74.1% vs. 3.0%) complications, and more hospitalizations (54 vs. 3) than those with cirrhosis with good microbial signatures (all p <0.001). In contrast, fecal enrichment of Ruminococcus 2 and Anaerostipes independently decreased the risk of 1-year complications. Conclusions: Sarcopenia-related fecal microbial alterations are associated with cirrhotic complications. These findings may facilitate measures to improve the outcomes of individuals with cirrhosis and sarcopenia by modifying gut microbiota. Impact and implications: The composition and biosynthetic functions of gut microbiota are significantly changed in individuals with sarcopenic cirrhosis. Those with a sarcopenia-related poor microbial signature, in which Ruminococcus 2 and Anaerostipes were both depleted, had significantly more infectious and non-infectious complications, as well as more hospitalizations. These findings highlight the therapeutic potential of modifying the gut microbiota of individuals with sarcopenic cirrhosis to improve their clinical outcomes.

Palliative Care for Patients with End-Stage Liver Disease.

End-stage liver disease (ESLD) is the culmination of progression of chronic liver disease to cirrhosis, decompensation, and chronic liver failure, featuring portal hypertension or hepatocellular failure-related complications. Liver transplantation offers improved long-term survival for these patients but is negatively influenced by donor availability, financial constraints in developing countries, active substance abuse, progression of disease or malignancy on wait-list, sepsis and extrahepatic organ involvement. In this context, palliative care (PC), an interdisciplinary medical practice that aim to prevent and relieve suffering, offers best possible quality of life and is not limited to end-of-life care. It also encompasses achievable goals such as symptom control and aggressive disease-modifying treatments or interventions that beneficially alter the natural course of the disease to offer curative intend. In this narrative review, we discuss the prognostic factors that define disease course in ESLD, various indications and challenges in PC for advanced cirrhosis and management options for major symptom burden in patients with ESLD based on evidence-based best practice.

Incidence and Predictors of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is the commonest type of liver disease worldwide. We aimed to assess the incidence and predictors of liver-related events (LREs) and mortality in NAFLD patients. Methods: NAFLD patients (n = 957) evaluated between January 2000 and November 2021 were included. Patients were categorised as noncirrhosis (NC), compensated cirrhosis (CC) and decompensated cirrhosis (DC), and the incidence of LRE and mortality were estimated and compared. Results: The proportions of NC, CC and DC were 87.8% (n = 840), 8.8% (n = 84) and 3.4% (n = 33), respectively. The median follow-up duration was 3.9 (3.0-5.7) years, and the total cumulative duration was 4633 person-years. The incidence of LRE per 100 person-years was 0.14, 2.72 and 10.24 in patients with NC, CC and DC, respectively. The incidence of mortality was 0.12, 1.05 and 4.24 per 100 person-years, respectively, in the 3 groups. The causes of mortality in the 3 groups were liver related in 1/5 (20%), 3/4 (75%) and 6/9 (66.7%), respectively. Overall, the mortality rate was higher in those with diabetes than those without diabetes (log-rank P value = 0.005). On further analysis, diabetes was associated with poor outcomes only in NC group (log-rank P value = 0.036), and not in CC (log-rank P value = 0.353) or DC groups (log-rank P value = 0.771). On multivariate Cox proportional hazard analysis, age (hazard ratio [HR] 1.070), hypertension (HR 4.361) and DC (HR 15.036) were independent predictors of poor outcomes. Liver stiffness measurement, bilirubin, CC and DC were independent predictors of LRE. Conclusion: In our study of NAFLD from India, the incidence of LRE was found to be similar to that seen in Western studies. In NC NAFLD, diabetes was associated with poor outcomes.

The NAFLD Decompensation Risk Score: External Validation and Comparison to Existing Models to Predict Hepatic Events in a Retrospective Cohort Study.

Background: The NAFLD decompensation risk score (the Iowa Model) was recently developed to identify patients with nonalcoholic fatty liver disease (NAFLD) at highest risk of developing hepatic events using three variables-age, platelet count, and diabetes. Aims: We performed an external validation of the Iowa Model and compared it to existing non-invasive models. Methods: We included 249 patients with NAFLD at Boston Medical Center, Boston, Massachusetts, in the external validation cohort and 949 patients in the combined internal/external validation cohort. The primary outcome was the development of hepatic events (ascites, hepatic encephalopathy, esophageal or gastric varices, or hepatocellular carcinoma). We used Cox proportional hazards to analyze the ability of the Iowa Model to predict hepatic events in the external validation (https://uihc.org/non-alcoholic-fatty-liver-disease-decompensation-risk-score-calculator). We compared the performance of the Iowa Model to the AST-to-platelet ratio index (APRI), NAFLD fibrosis score (NFS), and the FIB-4 index in the combined cohort. Results: The Iowa Model significantly predicted the development of hepatic events with hazard ratio of 2.5 [95% confidence interval (CI) 1.7-3.9, P < 0.001] and area under the receiver operating characteristic curve (AUROC) of 0.87 (CI 0.83-0.91). The AUROC of the Iowa Model (0.88, CI: 0.85-0.92) was comparable to the FIB-4 index (0.87, CI: 0.83-0.91) and higher than NFS (0.66, CI: 0.63-0.69) and APRI (0.76, CI: 0.73-0.79). Conclusions: In an urban, racially and ethnically diverse population, the Iowa Model performed well to identify NAFLD patients at higher risk for liver-related complications. The model provides the individual probability of developing hepatic events and identifies patients in need of early intervention.

Psoas Muscle Index: A Simple and Reliable Method of Sarcopenia Assessment on Computed Tomography Scan in Chronic Liver Disease and its Impact on Mortality.

Objectives: Psoas muscle parameters have been proposed as a simple and quick method for sarcopenia assessment. The aim of this study was to assess sarcopenia in cirrhotics by psoas muscle on computed tomography and its impact on mortality. Methods: One hundred and fifty patients (75 cirrhotics, 75 subjects) were assessed for psoas muscle on CT scan. Psoas muscle index (PMI) was calculated as 'total psoas muscle area/(height of subject)2'. Cut off values for sarcopenia diagnosis were derived from local subjects (n = 75) who did not have cirrhosis/other causes of sarcopenia. Results: Sarcopenia assessed by PMI was seen in 36% (n = 27) of the cirrhotics. Sarcopenia was significantly higher in patients having Child-Pugh C. Ascites, hepatic encephalopathy (HE) and gastro-intestinal bleed were seen in 48%, 18.7% and 24%, respectively. Sarcopenia was significantly associated with ascites and HE (P < 0.05). Out of the 75 cases, 53 cases completed the follow-up period of 1 year. Among the 20 cases who had sarcopenia, 35% (n = 7) succumbed to liver-related illness during 1 year follow-up, and out of the 33 cases without sarcopenia, only 6% (n = 2) died. The association of sarcopenia and 1 year mortality was statistically significant (P = 0.01). Conclusions: The PMI, a simple method for sarcopenia assessment detected sarcopenia in 36% of cirrhotics. Patients with sarcopenia had a significantly higher 1 year mortality rate and appropriate prognostication of such patients is needed.

Recompensation in Cirrhosis: Current Evidence and Future Directions.

The natural history of cirrhosis has usually been conceptualized in the context of progression from compensated cirrhosis to subsequent stages of decompensation. While this unidirectional concept is the most common pathophysiological trajectory, there has been an emerging understanding of a subgroup of patients which undergo recompensation. While literature mostly based on transplant waitlist registries have indicated towards such a population who experience disease regression, the overall literature about this entity remains inexplicit. An effort to generate consensus on defining recompensation has been attempted which comes with its own nuances and limitations. We summarize the available literature on this emerging yet controversial concept of recompensation in cirrhosis and delve into future implications and impact on real-life practice.

Elevated serum levels of glial fibrillary acidic protein are associated with covert hepatic encephalopathy in patients with cirrhosis.

Background & Aims: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. Astrocyte swelling is a major component of hepatic encephalopathy. Thus, we hypothesised that glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes, might facilitate early diagnosis and management. This study aimed to investigate the utility of serum GFAP (sGFAP) levels as a biomarker of CHE. Methods: In this bicentric study, 135 patients with cirrhosis, 21 patients with ongoing harmful alcohol use and cirrhosis, and 15 healthy controls were recruited. CHE was diagnosed using psychometric hepatic encephalopathy score. sGFAP levels were measured using a highly sensitive single-molecule array (SiMoA) immunoassay. Results: In total, 50 (37%) people presented with CHE at study inclusion. Participants with CHE displayed significantly higher sGFAP levels than those without CHE (median sGFAP, 163 pg/ml [IQR 136; 268] vs. 106 pg/ml [IQR 75; 153]; p <0.001) or healthy controls (p <0.001). sGFAP correlated with results in psychometric hepatic encephalopathy score (Spearman's ρ = -0.326, p <0.001), model for end-stage liver disease score (Spearman's ρ = 0.253, p = 0.003), ammonia (Spearman's ρ = 0.453, p = 0.002), and IL-6 serum levels (Spearman's ρ = 0.323, p = 0.006). Additionally, sGFAP levels were independently associated with the presence of CHE in multivariable logistic regression analysis (odds ratio 1.009; 95% CI 1.004-1.015; p <0.001). sGFAP levels did not differ between patients with alcohol-related cirrhosis vs. patients with non-alcohol-related cirrhosis or between patients with ongoing alcohol use vs. patients with discontinued alcohol use.Conclusions: sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker. Impact and implications: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. In this study, we were able to demonstrate that sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker.

Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study.

Background: Liver transplantation (LT) is an effective therapy for acute-on-chronic liver failure (ACLF) but is limited by organ shortages. We aimed to identify an appropriate score for predicting the survival benefit of LT in HBV-related ACLF patients. Methods: Hospitalized patients with acute deterioration of HBV-related chronic liver disease (n = 4577) from the Chinese Group on the Study of Severe Hepatitis B (COSSH) open cohort were enrolled to evaluate the performance of five commonly used scores for predicting the prognosis and transplant survival benefit. The survival benefit rate was calculated to reflect the extended rate of the expected lifetime with vs. without LT. Findings: In total, 368 HBV-ACLF patients received LT. They showed significantly higher 1-year survival than those on the waitlist in both the entire HBV-ACLF cohort (77.2%/52.3%, p < 0.001) and the propensity score matching cohort (77.2%/27.6%, p < 0.001). The area under the receiver operating characteristic curve (AUROC) showed that the COSSH-ACLF II score performed best (AUROC 0.849) at identifying the 1-year risk of death on the waitlist and best (AUROC 0.864) at predicting 1-year outcome post-LT (COSSH-ACLFs/CLIF-C ACLFs/MELDs/MELD-Nas: AUROC 0.835/0.825/0.796/0.781; all p < 0.05). The C-indexes confirmed the high predictive value of COSSH-ACLF IIs. Survival benefit rate analyses showed that patients with COSSH-ACLF IIs 7-10 had a higher 1-year survival benefit rate from LT (39.2%-64.3%) than those with score <7 or >10. These results were prospectively validated. Interpretation: COSSH-ACLF IIs identified the risk of death on the waitlist and accurately predicted post-LT mortality and survival benefit for HBV-ACLF. Patients with COSSH-ACLF IIs 7-10 derived a higher net survival benefit from LT. Funding: This study was supported by the National Natural Science Foundation of China (No. 81830073, No. 81771196) and the National Special Support Program for High-Level Personnel Recruitment (Ten-thousand Talents Program).

Acute Kidney Injury (AKI) at Admission Predicts Mortality in Patients With Severe Alcoholic Hepatitis (SAH).

Background & aims: Severe alcoholic hepatitis (SAH) is a grave condition, and the presence of acute kidney injury (AKI) further jeopardizes patient survival. However, the impact of AKI on survival in SAH has not been assessed from this region of Asia. Materials and methods: This study was conducted on consecutive alcohol-associated liver disease (ALD) patients hospitalized in Gastroenterology Department, SCB Medical College, Cuttack, India, between October 2016 and December 2018. On diagnosis of SAH (mDF score ≥32), demographic, clinical, and laboratory parameters were recorded, and survival was compared between patients with and without AKI (AKIN criteria). In addition, survival was compared among SAH patients defined by other criteria and prognostic models in the presence and absence of AKI. Results: 309 (70.71%) of ALD patients had SAH, and 201 (65%) of them had AKI. SAH patients with AKI had higher total leucocyte count, total bilirubin, serum creatinine, serum urea, INR, MELD (UNOS), MELD (Na+), CTP score, mDF score, Glasgow score, ABIC score, and increased prevalence of acute on chronic liver failure (ACLF) as per EASL-CLIF Consortium criteria (P < 0.001). Further, they had prolonged hospital stay, and increased death during hospitalization, at 28 days as well as 90 days (P < 0.001). Significant differences in survival were also seen in SAH (as per MELD, ABIC, and GAHS criteria) patients above the marked cut offs in respect to AKI. Conclusions: Over two-thirds of ALD patients had SAH, and about two-thirds had AKI. Patients with SAH and AKI had an increased prevalence of ACLF, longer hospital stay, and increased mortality during hospitalization at 28 days and 90 days. Lay summary: SAH is a critical condition, and the presence of AKI negatively affects their survival. Hence, early identification of SAH and AKI, as well as early initiation of treatment, is crucial for better survival. Our study from the coastal part of eastern India is the first to demonstrate the prevalence of SAH among patients with ALD along with the prevalence of AKI among SAH patients in this region. This knowledge will be helpful in managing these patients from this region of world.

Impact of ammonia levels on outcome in clinically stable outpatients with advanced chronic liver disease.

Background & Aims: Ammonia levels predicted hospitalisation in a recent landmark study not accounting for portal hypertension and systemic inflammation severity. We investigated (i) the prognostic value of venous ammonia levels (outcome cohort) for liver-related outcomes while accounting for these factors and (ii) its correlation with key disease-driving mechanisms (biomarker cohort). Methods: (i) The outcome cohort included 549 clinically stable outpatients with evidence of advanced chronic liver disease. (ii) The partly overlapping biomarker cohort comprised 193 individuals, recruited from the prospective Vienna Cirrhosis Study (VICIS: NCT03267615). Results: (i) In the outcome cohort, ammonia increased across clinical stages as well as hepatic venous pressure gradient and United Network for Organ Sharing model for end-stage liver disease (2016) strata and were independently linked with diabetes. Ammonia was associated with liver-related death, even after multivariable adjustment (adjusted hazard ratio [aHR]: 1.05 [95% CI: 1.00-1.10]; p = 0.044). The recently proposed cut-off (≥1.4 × upper limit of normal) was independently predictive of hepatic decompensation (aHR: 2.08 [95% CI: 1.35-3.22]; p <0.001), non-elective liver-related hospitalisation (aHR: 1.86 [95% CI: 1.17-2.95]; p = 0.008), and - in those with decompensated advanced chronic liver disease - acute-on-chronic liver failure (aHR: 1.71 [95% CI: 1.05-2.80]; p = 0.031). (ii) Besides hepatic venous pressure gradient, venous ammonia was correlated with markers of endothelial dysfunction and liver fibrogenesis/matrix remodelling in the biomarker cohort. Conclusions: Venous ammonia predicts hepatic decompensation, non-elective liver-related hospitalisation, acute-on-chronic liver failure, and liver-related death, independently of established prognostic indicators including C-reactive protein and hepatic venous pressure gradient. Although venous ammonia is linked with several key disease-driving mechanisms, its prognostic value is not explained by associated hepatic dysfunction, systemic inflammation, or portal hypertension severity, suggesting direct toxicity. Impact and implications: A recent landmark study linked ammonia levels (a simple blood test) with hospitalisation/death in individuals with clinically stable cirrhosis. Our study extends the prognostic value of venous ammonia to other important liver-related complications. Although venous ammonia is linked with several key disease-driving mechanisms, they do not fully explain its prognostic value. This supports the concept of direct ammonia toxicity and ammonia-lowering drugs as disease-modifying treatment.

Epidemiology and Disease Burden of Alcohol Associated Liver Disease.

Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol consumption. Moreover, the burden of alcohol associated liver disease (ALD) accounts for 5.1% of all disease and injury worldwide. Alcohol use disorder (AUD) affects men more than women globally with significant years of life loss to disability in low, middle and well-developed countries. Precise data on global estimates of alcohol related steatosis, alcohol related hepatitis, and alcohol related cirrhosis have been challenging to obtain. In the United States (US), alcohol related steatosis has been estimated at 4.3% based on NHANES data which has remained stable over 14 years. However, alcohol-related fibrotic liver disease has increased over the same period. In those with AUD, the prevalence of alcohol related hepatitis has been estimated at 10-35%. Globally, the prevalence of alcohol-associated cirrhosis has been estimated at 23.6 million individuals for compensated cirrhosis and 2.46 million for those with decompensated cirrhosis. The contribution of ALD to global mortality and disease burden of liver related deaths is substantial. In 2016 liver disease related to AUD contributed to 50% of the estimated liver disease deaths for age groups 15 years and above. Data from the US report high cost burdens associated with those admitted with alcohol-related liver complications. Finally, the recent COVID-19 pandemic has been associated with marked increase in alcohol consumption worldwide and will likely increase the burden of ALD.

Long-term Outcomes of Stool Transplant in Alcohol-associated Hepatitis-Analysis of Clinical Outcomes, Relapse, Gut Microbiota and Comparisons with Standard Care.

Background: Healthy donor fecal microbiota transplantation (FMT) was preliminarily shown to have clinical benefits in hepatic encephalopathy (HE), severe alcohol-associated hepatitis (SAH), and alcohol use disorder. However, the long-term outcomes of FMT and the gut microbiota (GM) changes in patients with SAH are unknown. Methods: Patients with SAH who underwent FMT (N = 35) or standard of care (SoC, N = 26) from May 2017 to June 2018 were included, and their stored stool samples were analyzed prospectively. Clinical outcomes, including infections, hospitalizations, critical illness, alcohol relapse, and survival, were evaluated. Metagenomic analysis was undertaken to identify the relative abundances (Ras) and significant taxa at baseline and post-therapy (up to three years) among survivors between the two groups. Results: At follow-up, the incidences of ascites, HE, infections, and major hospitalizations were significantly higher in the SoC than in the FMT group (P < 0.05). Alcohol relapse was lower (28.6% versus 53.8%), and the time to relapse was higher in the FMT than in the SoC group (P = 0.04). Three-year survival was higher in the FMT than in the SoC group (65.7% versus 38.5%, P = 0.052). Death due to sepsis was significantly higher in the SoC group (N = 13/16, 81.2%; P = 0.008). GM analysis showed a significant increase in the RA of Bifidobacterium and a reduction in the RA of Acinetobacter in the FMT group. Beyond one to two years, the RA of Porphyromonas was significantly higher and that of Bifidobacterium was lower in the SoC than in the FMT group. Conclusions: In terms of treatment for patients with SAH, healthy donor FMT is associated with significantly lesser ascites, infections, encephalopathy, and alcohol relapse (with a trend toward higher survival rates) than SoC, associated with beneficial GM modulation. Larger controlled studies on FMT are an unmet need.

Deprescribing zolpidem reduces falls and fractures in patients with cirrhosis.

Background & Aims: Benzodiazepines are associated with an increased risk of harm in patients with cirrhosis. However, stopping benzodiazepines must be done with care to avoid withdrawal or other unintended consequences. The impact of deprescribing on patients with cirrhosis is unknown. Methods: We emulated a hypothetical 3-year trial of benzodiazepine deprescription among Medicare enrollees with compensated cirrhosis who lacked other life-limiting diagnoses. All received continuous benzodiazepine prescriptions for the 6-months prior to their diagnosis of cirrhosis. During a 90-day landmark period following their diagnosis of cirrhosis, patients were classified as complete deprescribers (no benzodiazepines dispensed), continuous users, or partial deprescribers. We used inverse probability treatment weighting to compare complete deprescribers to continuous users of traditional benzodiazepines and zolpidem. Outcomes accounted for competing risk of mortality and included incident decompensation (hepatic encephalopathy, ascites, or variceal bleeding), fractures, falls, and alcohol-related hospitalizations. Results: There were 1,651 and 1,463 continuous users of traditional benzodiazepines and zolpidem, respectively, and 728 complete deprescribers. Patients were aged a median of 68 years, 24% had alcohol-related cirrhosis. There was no difference in the risk of death or decompensation for continuous users and deprescribers. Among deprescribers of traditional benzodiazepines, there was no improvement in the risk of falls or fractures. However, compared to continuous zolpidem users, deprescribers had a lower risk of falls (23.2% vs. 31%, p = 0.04) and fractures (21% vs. 29%, p = 0.02). Conclusions: Deprescribing zolpidem reduces the risk of falls and fractures. However, deprescribing benzodiazepines does not improve the risk of decompensation. Efforts to safely address the indications for benzodiazepines such as insomnia and anxiety are urgently needed. Lay summary: Many people with cirrhosis have anxiety, depression, and sleep disorders. Increasingly, patients with cirrhosis are treated with sedating medications called benzodiazepines, including valium, alprazolam ('Xanax'), clonopin, and the sleep-aid zolpidem ('Ambien'), which can cause falls, broken bones, and maybe other brain disorders. For this reason, many researchers are interested in trials of 'deprescribing' (stopping) benzodiazepines. However, no trials have been performed. We used health record data to simulate a trial of deprescribing. We found that stopping benzodiazepines may reduce the chance of falls or broken bones, but it does not improve survival or liver health.

Long-Term Improvement in Liver Function Following Transjugular Intrahepatic Portosystemic Shunt in Patients With Budd-Chiari Syndrome.

Background: Transjugular intrahepatic portosystemic shunt (TIPS) relieves hepatic venous obstruction in Budd-Chiari syndrome (BCS), but the effect on liver function is unclear, particularly outside the immediate post-treatment period. This study aims to evaluate the long-term impact of TIPS on liver function and outcomes in BCS patients. Methods: Twenty patients with BCS who underwent TIPS from 1999 to 2018 were included. Demographic data and clinical data at the time of TIPS procedure, 6 months, 12 months, 2 years, 5 years, and 10 years post-TIPS were collected. Results: There were 13 (13/20, 65%) women and 7 (7/20, 35%) men with a mean age at the time of TIPS of 42.6 ± 12.8 years. The median time from BCS diagnosis to TIPS was 41 (IQR: 4-165) days. The number of patients with severe ascites decreased significantly from 10/17 (58.8%) at the time of TIPS, to 1/16 (7.7%), 1/13 (7.7%), 2/16 (12.5%), 1/14 (7.1%), and 0/8 (0%) at 6 months, 12 months, 2 years, 5 years and 10 years post-TIPS, respectively. 4/20 (20%) patients developed new hepatic encephalopathy post-TIPS procedure. Child-Pugh score significantly decreased from a score of 9.4 ± 1.8 pre-TIPS to 7.6 ± 1.8 at 6 months, 7.4 ± 1.5 at 12 months, 7.3 ± 1.6 at 2 years, 6.8 ± 1.5 at 5 years, and 6.4 ± 0.7 at 10 years post-TIPS. Fifteen (15/20, 75%) patients required TIPS revision including 4 (4/15, 26.7%) within 30 days, 2 (2/15, 13.3% within 1 month to 1 year, and 9 (9/15, 60%) at more than 1 year. Eight (8/20, 40%) patients underwent liver transplantation (LT) at median time of 7.3 (IQR 3.2-12.9) years after TIPS. Conclusion: TIPS placement for BCS results in sustained resolution of symptoms and improved liver function. Despite the frequent need for revisions, the long-term durability of TIPS can forgo the need for LT in the majority of patients.

Gut Microbiome and Alcohol-associated Liver Disease.

Changes in gut microbiota (GM) may be associated with the causation and progression of multiple liver diseases such as metabolic-associated liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune liver disease, and most importantly, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infection, and hepatocellular carcinoma. ALD includes simple steatosis, steatohepatitis, AH, cirrhosis, and acute-on-chronic liver failure. Alcohol consumption is associated with GM changes even before ALD development, and continued alcohol intake results in progressive dysbiosis and development of clinical events such as AH, infection, and HE. The composition and function of GM, specific changes in bacterial communities, and the functional metabolism of GM are affected in the spectrum of ALD, as revealed using high-throughput sequencing. It was reported in preliminary studies that modulation of disrupted GM improves adverse clinical events and ameliorates disease progression in ALD. In this review, we exhaustively discuss the preclinical and clinical studies on GM in ALD and critically discuss GM modulation and its effects based on various human and animal models of ALD.

Gut Barrier and Microbiota in Cirrhosis.

Gut microbiota and their homeostatic functions are central to the maintenance of the intestinal mucosal barrier. The gut barrier functions as a structural, biological, and immunological barrier, preventing local and systemic invasion and inflammation of pathogenic taxa, resulting in the propagation or causation of organ-specific (liver disease) or systemic diseases (sepsis) in the host. In health, commensal bacteria are involved in regulating pathogenic bacteria, sinister bacterial products, and antigens; and help control and kill pathogenic organisms by secreting antimicrobial metabolites. Gut microbiota also participates in the extraction, synthesis, and absorption of nutrient metabolites, maintains intestinal epithelial integrity and regulates the development, homeostasis, and function of innate and adaptive immune cells. Cirrhosis is associated with local and systemic immune, vascular, and inflammatory changes directly or indirectly linked to perturbations in quality and quantity of intestinal microbiota and intestinal mucosal integrity. Dysbiosis and gut barrier dysfunction are directly involved in the pathogenesis of compensated cirrhosis and the type and severity of complications in decompensated cirrhosis, such as bacterial infections, encephalopathy, extrahepatic organ failure, and progression to acute on chronic liver failure. This paper reviews the normal gut barrier, gut barrier dysfunction, and dysbiosis-associated clinical events in patients with cirrhosis. The role of dietary interventions, antibiotics, prebiotics, probiotics, synbiotics, and healthy donor fecal microbiota transplantation (FMT) to modulate the gut microbiota for improving patient outcomes is further discussed.

Impact of Hyponatremia on Morbidity, Mortality, and Resource Utilization in Portal Hypertensive Ascites: A Nationwide Analysis.

Background and aims: Ascites and hyponatremia are important milestones of worsening portal hypertension in those with cirrhosis. The objective of our study was to evaluate the differences in clinical characteristics, resource utilization, and disposition of hospitalized cirrhotic patients with ascites with and without hyponatremia. Methods: The National Inpatient Sample (NIS) database was used to identify all adult hospitalized patients with a diagnosis of cirrhosis and ascites with or without hyponatremia from 2016 to 2017 using ICD-10 codes. Results: During the study period, 10,187 (7.6%) hospitalized patients with cirrhosis had ascites and hyponatremia and 34,555 (24.3%) had ascites but no hyponatremia. Elixhauser comorbidity score, excluding liver disease, was higher in hyponatremic patients (median 21 vs. 12, P < 0.001). Acute kidney injury (50.3% vs. 32.8%, P < 0.001) and sepsis (16.8% vs. 11.8%, P < 0.001) were more common in hyponatremic patients compared to those without hyponatremia. Similarly, acute respiratory failure, coagulopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, acute (on chronic) liver failure, and liver cancer were more common in hyponatremic patients. Hyponatremia patients had a higher number of inpatient procedures, longer (6 days vs. 4 days, P < 0.001) hospital stay, and had higher hospital charges ($97,327 vs. $72,278, P < 0.01) than those without hyponatremia. Inpatient mortality was 38% higher in hyponatremic patients (9.8% vs. 7.1%, P < 0.001) compared to those without hyponatremia. Additionally, hyponatremic patients were less likely to have routine home discharges with self-care. Conclusion: In conclusion, using a large and diverse national cohort of unselected patients, we were able to show that hyponatremia in patients with cirrhosis and ascites is associated with poor clinical outcomes and increased resource utilization.

Encephalopathy in Cirrhosis: Prevention and Management.

Hepatic encephalopathy (HE) is a major neuropsychiatric complication of cirrhosis. The clinical manifestations of HE ranges from mild confusion, disorientation to altered behaviour and coma in advanced stages. HE is an important cause of recurrent admissions in liver cirrhosis patients. HE is the most common cause of altered mentation in a patient of liver cirrhosis. Lactulose and rifaximin are approved treatment options for the treatment of HE. In patients who have localised neurological signs or are not improving with lactulose and rifaximin should be investigated for other causes of altered sensorium.

Rifaximin Vs. Norfloxacin for Spontaneous Bacterial Peritonitis Prophylaxis: A Randomized Controlled Trial.

Background: Spontaneous bacterial peritonitis (SBP) heralds increased mortality in cirrhosis, mandating strategies for prophylaxis. Norfloxacin has been the recommended choice for SBP prevention. However, its use has raised concerns about antibiotic resistance. Rifaximin has been suggested as an alternative. We investigated the efficacy of rifaximin against norfloxacin in primary and secondary prophylaxis of SBP. Methods: In this open-labeled randomized trial, patients with either advanced cirrhosis having ascitic fluid protein levels (<1.5 g/l), Child-Pugh score ≥9 points, serum bilirubin ≥3 mg/dl or impaired renal function (primary prophylaxis group), or those with prior SBP (secondary prophylaxis group) received either norfloxacin (400 mg once daily) or rifaximin (550 mg twice daily). All patients were followed for six months, with the primary endpoint being the development of incident SBP. Results: 142 patients were assessed for eligibility, of which 132 met the enrolment criteria; 12 were lost to follow-up, while 4 discontinued treatment. In patients on primary prophylaxis, occurrence of SBP was similar (14.3% vs. 24.3%, P = 0.5), whereas in secondary prophylaxis SBP recurrence was lower with rifaximin (7% vs. 39% P = 0.004). Rifaximin significantly reduced the odds for SBP development in secondary prophylaxis [OR (95% CI0.14 (0.02-0.73; P = 0.02)]. Patients receiving rifaximin as secondary prophylaxis also had fewer episodes of hepatic encephalopathy (23.1% vs. 51.5%, P = 0.02). 180-day survival between the arms in either group was similar (P = 0.5, P = 0.2). Conclusion: In comparison to norfloxacin, rifaximin significantly reduces incident events of SBP, as well as HE when used as a secondary prophylaxis, whereas for primary prophylaxis both have similar effects (NCT03695705). Clinical trial registration: ClinicalTrials.gov number: NCT03695705.