Transjugular intrahepatic portosystemic shunt: A promising therapy for recompensation in cirrhotic patients.

This is a retrospective study focused on recompensation after transjugular intrahepatic portosystemic shunt (TIPS) procedure. The authors confirmed TIPS could be a treatment for recompensation of patients with cirrhosis according to Baveno VII. The paper identified age and post-TIPS portal pressure gradient as independent predictors of recompensation in patients with decompensated cirrhosis after TIPS. These results need to be validated in a larger prospective cohort.

[Liver cirrhosis as a multisystem disease]. / Die Leberzirrhose als Multisystemerkrankung.

In recent years, the pathophysiological concept of decompensated liver cirrhosis has undergone significant changes. Until a few years ago, the focus of pathophysiological considerations was on the hyperdynamic circulation resulting from portal hypertension. In recent years, emerging data suggests that increased bacterial translocation leading to systemic inflammation plays an important role in patients with decompensated liver cirrhosis. This inflammation affects a variety of extrahepatic organs. Nowadays, liver cirrhosis is considered not only a condition confined to the liver but rather an inflammatory-triggered multisystem disease. The existing inflammation serves as the common pathophysiological explanation for the diverse impact of liver cirrhosis on several extrahepatic organs. It plays a significant role in the development of conditions such as hepatorenal syndrome, cirrhotic cardiomyopathy, hepatopulmonary syndrome, hepatic encephalopathy, and even in the emergence of cirrhosis-associated relative adrenal insufficiency. These new pathophysiological insights hold clinical significance as they influence the prophylaxis and treatment of patients with decompensated liver cirrhosis.

Efficacy of long-term albumin therapy in the treatment of decompensated cirrhosis.

BACKGROUND AND AIMS: Decompensated liver cirrhosis has a poor prognosis, with a median overall survival of two to four years, which is worse than for many oncological disorders. These patients are highly susceptible to infections due to increased systemic inflammation leading to kidney failure and death. The aim was to study the efficacy of albumin in reducing episodes of decompensation, preventing bacterial infection, kidney dysfunction and mortality. METHOD: Study involved patients with Child B or C cirrhosis with an albumin level below 3.0 g/dL, who were administered 20% human albumin weekly with standard medical treatment (SMT) for three months or till serum albumin levels were 4.0 g/dL (whichever is earlier) and compared with age and sex-matched controls who received only SMT. The primary end-point was six-month mortality and the secondary end-points were reduction in infections, kidney dysfunction, ascites recurrence, hepatic encephalopathy (HE), gastrointestinal (GI) bleed and complications of cirrhosis. RESULTS: From September 2021 to January 2023, 88 cases and 86 controls were taken and followed up for six months. Overall, six-month survival was not statistically significant between groups (95.1% vs. 91.9%; p = 0·330). The incidence of recurrence of ascites (34.09% vs. 59.3%, p < 0.001), kidney dysfunction (6.8% vs. 24.4%, p < 0.001), HE (15.9% vs, 37.2%, p = 0.015), spontaneous bacterial peritonitis (SBP) (3.4% vs 17.4%, p = 0.002) and non-SBP infections (7.9% vs. 18.6%, p = 0.038) were significantly less in cases as compared with controls; however, GI bleed (14.8% vs. 17.4%, p = 0.632) was not statistically significant. CONCLUSION: Long-term human albumin acts as a disease-modifying treatment in patients with decompensated cirrhosis.

PHES scores have limited impact on the risk of overt HE in patients with minimal HE.

BACKGROUND: Minimal hepatic encephalopathy, defined by the portosystemic hepatic encephalopathy score (PHES), is associated with a higher risk of subsequent OHE. It remains unclear if there is a stepwise increase in OHE risk with worse PHES results. METHODS: In this multicenter study, patients with minimal hepatic encephalopathy, as defined by abnormal PHES, were followed for OHE development. RESULTS: In all, 207 patients were included. There was no stepwise increase in OHE risk with worse PHES results. CONCLUSIONS: Abnormal PHES is associated with a higher OHE risk, but we found no stepwise increase in OHE risk with worse PHES results below the established cutoff.

Overview of acute liver failure in India.

Acute liver failure (ALF) is an infrequent, but serious complication subsequent to severe acute liver injury (sALI) due to various hepatotoxic agents such as hepatotropic virus(es) and drugs such as anti-tubercular medications, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and anti-cancer and anti-epileptic therapy and due to metabolic and autoimmune disease flares. ALF after sALI presents with encephalopathy associated with prolonged international normalized ratio (INR). Mortality in ALF is high and ranges between 50% and 80%. Due to severe liver damage, multiple sequels consequent to hepatic dysfunction result in complications such as hyperammonemia that culminates in encephalopathy associated with cerebral edema; innate immune paralysis resulting in increased frequency of infections and endotoxemia causing decrease in systemic vascular resistance (SVR) and tissue hypoperfusion and damage-associated molecular patterns (DAMPs) released from damaged hepatic parenchyma inducing pro-inflammatory cytokine storm, which may cause other organ dysfunctions. Certain etiologies such as hepatitis E virus and hepatitis A virus-related ALF or paracetamol-ALF (hyper-acute presentation) have better survival than remaining causes. In addition, if etiology-specific treatment (antivirals for ALF related to hepatitis B virus (HBV) or Herpes simplex virus (HSV) or N-acetylcysteine for paracetamol) is available, then the outcome with treatment is better. About half of the patients can be salvaged with medical therapy. All patients need intensive care and organ support to provide time for the liver to regenerate. Various prognostic models to predict high probability of mortality have been described, which should be used to select patient early during the disease for liver transplantation, which is associated with high long-term survival in these sick patients. The Indian National Association for Study of the Liver (INASL) recommends the ALF-Early Dynamic (ALFED) model as a preferred prognostic model in the Indian scenario, where hepatitis viruses are a dominant etiology of ALF and occur on a naïve liver with good regenerative capacity.

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.

Natural history of clinical outcomes and hepatic decompensation in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: The natural progression of hepatic decompensation in metabolic dysfunction-associated steatotic liver disease (MASLD) is not well-characterised. We aimed to describe it by conducting a retrospective analysis. METHODS: This longitudinal, retrospective analysis of well-characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver-related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured. RESULTS: Of the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow-up of 3.2 years. Ascites was the most common first liver-related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver-related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy-three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years. CONCLUSION: The most common first liver-related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years.

Clinical risk factors for portal hypertension-related complications in systemic therapy for hepatocellular carcinoma.

BACKGROUND: During systemic therapy, the management of portal hypertension (PH)-related complications is vital. This study aimed to clarify factors associated with the incidence and exacerbation of PH-related complications, including the usefulness of contrast-enhanced computed tomography (CECT) in the management of PH-related complications during systemic therapy. METHODS: A total of 669 patients who received systemic therapy as first-line treatment (443 patients for sorafenib, 131 for lenvatinib, and 90 for atezolizumab/bevacizumab [ATZ/BEV]) were enrolled in this retrospective study. Additionally, the lower esophageal intramural vessel diameters (EIV) on CECT and endoscopic findings in 358 patients were compared. RESULTS: The cutoff values of the EIV diameter on CECT were 3.1 mm for small, 5.1 mm for medium, and 7.6 mm for large varices, demonstrating high concordance with the endoscopic findings. esophageal varices (EV) bleeding predictors include EIV ≥ 3.1 mm and portal vein tumor thrombosis (PVTT). In patients without EV before systemic therapy, factors associated with EV exacerbation after 3 months were EIV ≥ 1.9 mm and ATZ/BEV use. Predictors of hepatic encephalopathy (HE) include the ammonia level or portosystemic shunt diameter ≥ 6.8 mm. The incidence of HE within 2 weeks was significantly higher (18%) in patients with an ammonia level ≥ 73 µmol/L and a portosystemic shunt ≥ 6.8 mm. The exacerbating factors for ascites after 3 months were PVTT and low albumin levels. CONCLUSIONS: Careful management is warranted for patients with risk factors for exacerbation of PH-related complications; moreover, the effective use of CECT is clinically important.

Prognostic markers in hepatitis A-related pediatric acute liver failure and validation of the Peds-hepatitis A virus prognostic model.

OBJECTIVES: Hepatitis A virus (HAV) is the commonest cause for pediatric acute liver failure (PALF) in India. The objective of the study was to identify the predictors of mortality and to evaluate the utility of Peds-HAV model in a cohort of non-LT HAV-PALF. METHODS: The study included HAV-related PALF from two non-transplant centers. The predictors of outcome were identified by univariate analysis followed by Cox regression analysis. The prognostic accuracy of Peds-HAV model, King's College Hospital (KCH) criteria and pediatric end-stage liver disease score (PELD) were evaluated. RESULTS: As many as 140 children with PALF were included, of whom 96 (68.6%) children had HAV-PALF. On Cox regression analysis, international normalized ratio (INR) (p < 0.001), jaundice to encephalopathy (JE) interval (p < 0.001) and hepatic encephalopathy (HE) grade 3/4 (p = 0.01) were independent predictors of mortality. The mortality rates were 0% (0/42), 14.3% (3/21), 60% (9/15) and 94.4% (17/18) when none, 1, 2 or 3 criteria of the Peds-HAV were met, respectively. Peds-HAV model at a listing cut-off of  ≥ 2 criteria predicted death with 89.7% sensitivity and 89.6% specificity. In contrast, KCH criteria had a lower sensitivity of 62.1%. PELD score had a sensitivity of 89.7% and specificity of 85.1% at a cut-off of 30. The overall prognostic accuracy of Peds-HAV model (89.6%) was higher than those of KCH (83.3%) and PELD (86.5%). CONCLUSION: INR, HE grade and JE interval were independent predictors of mortality. The study provides an external validation of Peds-HAV model as a prognostic score in HAV-PALF. CLINICAL TRIAL REGISTRY NUMBER: Not applicable as this is a retrospective study.

Critical care management of acute liver failure.

The management of acute liver failure (ALF) in modern hepatology intensive care units (ICU) has improved patient outcomes. Critical care management of hepatic encephalopathy, cerebral edema, fluid and electrolytes; prevention of infections and organ support are central to improved outcomes of ALF. In particular, the pathogenesis of encephalopathy is multifactorial, with ammonia, elevated intra-cranial pressure and systemic inflammation playing a central role. Although ALF remains associated with high mortality, the availability of supportive care, including organ failure support such as plasma exchange, timely mechanical ventilation or continuous renal replacement therapy, either conservatively manages patients with ALF or offers bridging therapy until liver transplantation. Thus, appropriate critical care management has improved the likelihood of patient recovery in ALF. ICU care interventions such as monitoring of cerebral edema, fluid status assessment and interventions for sepsis prevention, nutritional support and management of electrolytes can salvage a substantial proportion of patients. In this review, we discuss the key aspects of critical care management of ALF.

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.