Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial.

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/DESIGN: 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. DISCUSSION: 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. ETHICS AND DISSEMINATION: 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. TRIAL REGISTRATION: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

Bayesian network-based survival prediction model for patients having undergone post-transjugular intrahepatic portosystemic shunt for portal hypertension.

BACKGROUND: Portal hypertension (PHT), primarily induced by cirrhosis, manifests severe symptoms impacting patient survival. Although transjugular intrahepatic portosystemic shunt (TIPS) is a critical intervention for managing PHT, it carries risks like hepatic encephalopathy, thus affecting patient survival prognosis. To our knowledge, existing prognostic models for post-TIPS survival in patients with PHT fail to account for the interplay among and collective impact of various prognostic factors on outcomes. Consequently, the development of an innovative modeling approach is essential to address this limitation. AIM: To develop and validate a Bayesian network (BN)-based survival prediction model for patients with cirrhosis-induced PHT having undergone TIPS. METHODS: The clinical data of 393 patients with cirrhosis-induced PHT who underwent TIPS surgery at the Second Affiliated Hospital of Chongqing Medical University between January 2015 and May 2022 were retrospectively analyzed. Variables were selected using Cox and least absolute shrinkage and selection operator regression methods, and a BN-based model was established and evaluated to predict survival in patients having undergone TIPS surgery for PHT. RESULTS: Variable selection revealed the following as key factors impacting survival: age, ascites, hypertension, indications for TIPS, postoperative portal vein pressure (post-PVP), aspartate aminotransferase, alkaline phosphatase, total bilirubin, prealbumin, the Child-Pugh grade, and the model for end-stage liver disease (MELD) score. Based on the above-mentioned variables, a BN-based 2-year survival prognostic prediction model was constructed, which identified the following factors to be directly linked to the survival time: age, ascites, indications for TIPS, concurrent hypertension, post-PVP, the Child-Pugh grade, and the MELD score. The Bayesian information criterion was 3589.04, and 10-fold cross-validation indicated an average log-likelihood loss of 5.55 with a standard deviation of 0.16. The model's accuracy, precision, recall, and F1 score were 0.90, 0.92, 0.97, and 0.95 respectively, with the area under the receiver operating characteristic curve being 0.72. CONCLUSION: This study successfully developed a BN-based survival prediction model with good predictive capabilities. It offers valuable insights for treatment strategies and prognostic evaluations in patients having undergone TIPS surgery for PHT.

Pathophysiology of Hepatic Encephalopathy: A Framework for Clinicians.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that is observed primarily in patients with liver disease. The pathophysiology is complex and involves many factors including ammonia toxicity, dysregulation of central nervous system activity, and excess inflammatory cytokines. Symptoms of HE range from subclinical to debilitating. HE can be difficult to treat and represents a large burden to patients, their caregivers, and the health-care system because of associated resource utilization. This review article provides an overview of the current understanding of the pathophysiology behind HE and where the current research and treatments are pointing toward.

Minimal Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) is a pervasive frequent complication of cirrhosis of any etiology. The diagnosis of MHE is difficult as the standard neurologic examination is essentially within normal limits. None of the symptoms and signs of overt HE is present in a patient with MHE, such as confusion, disorientation, or asterixis. Progress has been made in diagnostic tools for detection of attention and cognitive deficits at the point of care of MHE. The development of MHE significantly impacts quality of life and activities of daily life in affected patients including driving motor vehicles and machine operation.

Hepatic Encephalopathy: Clinical Manifestations.

Hepatic encephalopathy (HE) can occur as a complication of chronic liver disease as well as acute liver failure. HE is associated with significantly increased morbidity and worse patient outcomes. The clinical manifestation of HE ranges from early less-severe presentations that may only be accurately detected on dedicated psychomotor diagnostic testing to overt alterations in cognition and mental status to the most severe form of coma. Greater awareness of the clinical manifestations of HE across the spectrum of symptom severity is critical for early identification and timely initiation of appropriate therapy to improve patient outcomes.

Social Impact of Hepatic Encephalopathy.

Hepatic encephalopathy is a medical condition that stems from liver dysfunction, leading to the accumulation of toxins in the bloodstream. This can result in cognitive impairments, mood changes, and motor dysfunction. Its social impact includes challenges in employment, relationships, and daily functioning for affected individuals. Stigma and misunderstanding around the condition can further exacerbate the difficulties faced by both patients and their caregivers. Efforts to raise awareness, improve medical management, and provide support systems can help mitigate the social impact of hepatic encephalopathy.

The Health Care Burden of Hepatic Encephalopathy.

Hepatic encephalopathy-a common and debilitating complication of cirrhosis-results in major health care burden on both patients and caregivers through direct and indirect costs. In addition to risk of falls, inability to work and drive, patients with hepatic encephalopathy often require hospital admission (and often readmission), and many require subacute care following hospitalization. The costs and psychological impact of liver transplantation often ensue. As the prevalence of chronic liver disease increases throughout the United States, the health care burden of hepatic encephalopathy will continue to grow.

Interventional Radiology Management of Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a clinically severe and devastating complication of decompensated liver disease affecting mortality, quality of life for patients and families, hospital admission rates, and overall health-care costs globally. Depending on the cause of HE, several medical treatment options have been developed and become available. In some refractory HE, such as spontaneous portosystemic shunt-related HE (SPSS-HE) or posttransjugular intrahepatic portosystemic shunt HE (post-TIPS HE), advanced interventional radiology (IR) procedures have been used, and shown to be effective in these conditions. This review presents 2 effective IR procedures for managing SPSS-HE and post-TIPS HE.

Preventing Readmissions for Hepatic Encephalopathy.

Hepatic encephalopathy is a strong predictor of hospital readmissions in patients with advanced liver disease. The frequent recurrence of hepatic encephalopathy and subsequent readmissions may lead to nonreversible organ dysfunction, resulting in a significant decrease of patient quality of life and increase of health care burden costs for patients and facilities. Many of these readmissions for hepatic encephalopathy are preventable. Multidisciplinary patient-centered care throughout the continuum is essential in the management of hepatic encephalopathy. Understanding the patient's daily functions and limitations in the outpatient setting is key to correctly identifying the cause of hospital admission.

Ammonia is associated with liver-related complications and predicts mortality in acute-on-chronic liver failure patients.

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients.

High-dose proton pump inhibitor treatment is associated with a higher mortality in cirrhotic patients: A multicentre study.

BACKGROUND: Proton pump inhibitors (PPI) are frequently used in patients with cirrhosis. AIMS: 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.

Disparity Among African Americans in Transjugular Intrahepatic Portosystemic Shunt Procedure: A National Inpatient Sample Analysis from 2015 to 2020.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure used to alleviate patients with chronic liver cirrhosis and portal hypertension. Racial disparities were present in TIPS where numerous studies suggested African American patients experience higher in-hospital mortality rates. However, the incidence of post-TIPS surgical complications, such as HE, has yet to be examined among African Americans. Therefore, this study aimed to provide a comprehensive examination of the disparities in TIPS procedures among African American patients. METHODS: The study compared African American and Caucasian patients who underwent TIPS procedures in the National Inpatient Sample (NIS) database from the last quarter of 2015-2020 after ICD-10 change. Preoperative variables, including demographics, comorbidities, primary payer status, and hospital characteristics, were examined and multivariable analysis was used to assess outcomes correcting preoperative variables with p < 0.1. RESULTS: Compared to Caucasians, African Americans had higher in-hospital mortality (16.18 vs 8.22%, aOR 1.781, p < 0.01), hepatic encephalopathy (33.09 vs 27.44%, aOR 1.300, p = 0.05), and acute kidney injury (45.59 vs 29.60%, aOR 2.019, p < 0.01). Using the generalized linear model, African Americans have longer length of stay (11.04 ± 0.77 days vs 8.54 ± 0.16 days, p < 0.01). CONCLUSION: Despite a higher prevalence of cirrhosis, African Americans continue to have marked underrepresentation in TIPS procedures in recent years. Their underrepresentation, in conjunction with higher mortality, morbidity, and increased comorbidity conditions, could imply disparity in accessing care. This finding underscores the necessity for improved access to diagnostic and therapeutic services for African Americans with liver cirrhosis.

Evaluation of potential hepatic recompensation criteria in patients with PBC and decompensated cirrhosis.

BACKGROUND: Aetiological therapy improves liver function and may enable hepatic recompensation in decompensated cirrhosis. AIMS: We explored the potential for recompensation in patients with decompensated primary biliary cholangitis (PBC) - considering a biochemical response to ursodeoxycholic acid (UDCA) according to Paris-II criteria as a surrogate for successful aetiological treatment. METHODS: Patients with PBC were retrospectively included at the time of first decompensation. Recompensation was defined as (i) resolution of ascites and hepatic encephalopathy (HE) despite discontinuation of diuretic/HE therapy, (ii) absence of variceal bleeding and (iii) sustained liver function improvement. RESULTS: In total, 42 patients with PBC with decompensated cirrhosis (age: 63.5 [IQR: 51.9-69.2] years; 88.1% female; MELD-Na: 13.5 [IQR: 11.0-15.0]) were included and followed for 41.9 (IQR: 11.0-70.9) months after decompensation. Seven patients (16.7%) achieved recompensation. Lower MELD-Na (subdistribution hazard ratio [SHR]: 0.90; p = 0.047), bilirubin (SHR per mg/dL: 0.44; p = 0.005) and alkaline phosphatase (SHR per 10 U/L: 0.67; p = 0.001) at decompensation, as well as variceal bleeding as decompensating event (SHR: 4.37; p = 0.069), were linked to a higher probability of recompensation. Overall, 33 patients were treated with UDCA for ≥1 year and 12 (36%) achieved Paris-II response criteria. Recompensation occurred in 5/12 (41.7%) and in 2/21 (9.5%) patients with vs. without UDCA response at 1 year, respectively. Recompensation was linked to a numerically improved transplant-free survival (HR: 0.46; p = 0.335). Nonetheless, 4/7 recompensated patients presented with liver-related complications after developing hepatic malignancy and/or portal vein thrombosis and 2 eventually died. CONCLUSIONS: Patients with PBC and decompensated cirrhosis may achieve hepatic recompensation under UDCA therapy. However, since liver-related complications still occur after recompensation, patients should remain under close follow-up.

Prevalence and impact on the outcome of myosteatosis in patients with cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Myosteatosis in cirrhotic patients has been evaluated in limited studies with conflicting results and no systematic review or meta-analysis have been performed in this setting. METHODS: We searched for all articles published until June 2023 to evaluate the prevalence of myosteatosis in cirrhosis and chronic liver disease. RESULTS: Seventeen studies focused on cirrhosis and five studies in patients with chronic liver disease were included: the overall pooled prevalence of myosteatosis was 46% [95% Confidence Interval (CI) 36-57%] and 33% (95% CI 15-59%), respectively (p = 0.35). Among the studies with cirrhosis, the prevalence of myosteatosis was higher in those using the body mass index-based definition of myosteatosis (56%), than gender-based (36%) or other criteria (21%) (p < 0.01); was higher in women than in men (61% vs 45%), in Child-Pugh class C than A or B (57% vs 49% vs 50%), in non-alcoholic fatty liver disease (NAFLD)- than viral-associated cirrhosis (57% vs 43%), but these differences were not statistically significant (p > 0.05). Cirrhotic patients with myosteatosis, compared to those without myosteatosis, had more frequently a previous history of hepatic encephalopathy (32% vs 15%, p = 0.04), less frequently a previous history of variceal bleeding (46% vs 65%, p < 0.01), were more likely to suffer from diabetes mellitus (27% vs 18%, p < 0.01), while they had higher mortality rates (40% vs 14%, p = 0.02). CONCLUSION: Myosteatosis is highly prevalent in patients with cirrhosis, particularly in those with NAFLD-associated cirrhosis. Myosteatosis is associated with hepatic encephalopathy, while it seems to have a negative impact on the outcome.

The assessment and management of cirrhotic patients with encephalopathy.

Hepatic encephalopathy (HE) is a debilitating complication associated with both acute and chronic liver injury. It is associated with a greater risk of death than any other significant hepatic decompensation event. It manifests as a wide spectrum of neuropsychological abnormalities ranging from subtle impairments in higher cognitive function, to confusion and coma. The pathophysiological role of ammonia in the development of HE is well known, but there is increasing recognition that the gut microbiome, gut-derived systemic inflammation and development of infection can serve as drivers of HE in patients with cirrhosis. The development of HE portents to the severity of cirrhosis and the prognosis is poor without liver transplantation. A referral for liver transplantation should therefore be considered early in those who are eligible. This review covers the pragmatic assessment of HE in patients with cirrhosis, as well as the current evidence base for the best practice management of HE in such patients.

Advanced chronic renal disease is an independent risk factor for inpatient mortality following transjugular intrahepatic portosystemic shunt procedure.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure used to alleviate portal hypertension in patients with decompensated liver cirrhosis. However, the risks and outcomes associated with TIPS in patients with advanced chronic kidney disease (CKD) remain uncertain. This study aimed to investigate the perioperative outcomes of TIPS procedures in patients with advanced CKD using the National Inpatient Sample (NIS) database, a comprehensive all-payer inpatient database in the US. METHODS: The study identified patients who underwent TIPS procedures in the NIS database from Q4 2015 to 2020. Patients with advanced CKD were identified using specific ICD-10-CM codes, and they were compared to patients without CKD. Preoperative variables, including demographics, indications for TIPS, comorbidities, APR-DRG subclass, primary payer status, and hospital characteristics, were noted. Perioperative outcomes were examined by multivariable logistic regression. RESULTS: A total of 248 patients with advanced CKD and 5511 patients without CKD undergoing TIPS procedures were identified in the NIS database. Compared to non-CKD, patients with advanced CKD had higher mortality (13.70% vs. 8.60%, aOR = 1.56, P  = 0.03), acute kidney injury (51.21% vs. 29.34, aOR = 1.46, P  < 0.01), transfer out (25.00% vs. 12.84%, aOR = 1.88, P  < 0.01), and length of stay over 7 days (64.11% vs. 38.97%, aOR = 2.34, P  < 0.01). However, there was no difference in hepatic encephalopathy (31.85% vs. 27.19%, aOR = 1.12, P  = 0.42). CONCLUSION: Advanced CKD patients undergoing TIPS are at higher risk of mortality and AKI compared to patients without CKD; HE was mildly elevated but NS. Long-term prognosis of patients with advanced CKD who had TIPS is needed in future studies.

Severe hepatic encephalopathy with mechanical ventilation may inform waitlist priority in acute liver failure: A UNOS database analysis.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF. METHODS: We studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002-2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30-day waitlist mortality (Competing risk), and post-LT mortality (Cox-proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30-day waitlist mortality. RESULTS: About 3212 adults with ALF were waitlisted, for hepatotoxicity (41%), viral (12%) and unspecified (36%) etiologies. The median number of organ failures was three (interquartile range 1-3). Having ≥3 organ failures (vs. ≤2) was associated with a sub hazard ratio (HR) of 2.7 (95%CI 2.2-3.4)) and a HR of 1.5 (95%CI 1.1-2.5)) for waitlist and post-LT mortality, respectively. LCA identified neurologic and respiratory failure as most impactful on 30-day waitlist mortality. The odds ratios for both organ failures (vs. neither) were higher for mortality 4.5 (95% CI 3.4-5.9) and lower for delisting for spontaneous survival .5 (95%CI .4-.7) and LT .6 (95%CI .5-.7). CONCLUSION: Cumulative organ failure, especially neurologic and respiratory failure, significantly impacts waitlist and post-LT mortality in patients with ALF and may inform risk-prioritized allocation of organs.

Risks of Proton Pump Inhibitors in Patients with Cirrhosis: Please Peruse the Indications.

The use of proton pump inhibitor (PPI) in cirrhotic patients can be associated with increased risks of long-term mortality, decompensation, hepatic encephalopathy, spontaneous bacterial peritonitis, and infection, but not with short-term mortality. Ensure clear indications at lowest effective dose of is mandatory for the use of PPI among cirrhotic patients.