[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.

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.

Sensory ataxic polyneuropathy unmasking late-onset urea cycle defect.

A 63-year-old man with type 2 diabetes mellitus, alcohol consumption in moderation, and three episodes of hepatic encephalopathy presented with symmetrical lower limb distal weakness, sensory ataxia, thickened palpable nerves, mood disturbances for seven years, and a family history of schizophreniform disorders. Nerve conduction studies showed demyelinating sensorimotor polyradiculoneuropathy. CSF analysis showed mild albumino-cytological dissociation. MRI brain and lumbosacral plexus showed thickened fifth cranial nerves and lumbosacral roots. He was treated with steroids for a provisional diagnosis of chronic inflammatory polyneuropathy and became encephalopathic. EEG showed triphasic waves. Serum ammonia was 201 micrograms/dL. Further evaluation suggested ornithine transcarbamylase (OTC) deficiency. The patient underwent hemodialysis with a low protein diet, rifaximin, and sodium benzoate, with subsequent recovery.

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.

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.

Hepatic Encephalopathy-A Guide to Laboratory Testing.

Hepatic encephalopathy (HE) remains both a clinical diagnosis and one of exclusion. Laboratory testing is largely focused on identifying precipitating factors. Ammonia levels in the blood can be helpful for the diagnosis of HE but are not required for confirmation. More recent literature is lending support to the prognostic capabilities of ammonia in cirrhosis, both in predicting future HE events and in determining outcomes in hospitalized patients. Accurate ammonia testing requires strict protocols to avoid common pitfalls in the measurement of this labile analyte. Future studies investigating the utility of other laboratory testing to diagnose, stage, or predict HE are encouraged.

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.

Association of low serum 25-Hydroxy vitamin D [25(OH) d] with hepatic encephalopathy in patients with decompensated liver cirrhosis.

BACKGROUND AND STUDY AIMS: The mechanism of hepatic encephalopathy is complex and has not been conclusively established. Recent studies support lower serum 25-Hydroxy Vitamin D [25(OH) D] levels in patients with hepatic encephalopathy. This study aimed to evaluate the association between serum 25(OH) D and hepatic encephalopathy in patients with decompensated cirrhosis of liver. PATIENTS AND METHODS: A total of 70 cirrhosis patients (35 cases of hepatic encephalopathy and 35 patients without encephalopathy as control, mean age 53.07 ± 12.99 years, 67 % male) were recruited for this study. Assessment of the severity of cirrhosis was done by using a model for end-stage liver disease(MELD) and Child Turcotte Pugh (CTP) scores, and assessment of the severity of hepatic encephalopathy was done according to West Haven criteria. Serum 25 (OH) D level was measured by Chemiluminescent Microparticle Immuno Assay(CMIA). RESULTS: The mean serum 25(OH) D level among hepatic encephalopathy patients was significantly lower in comparison to the control group without encephalopathy (18.76 ± 8.84 nmol/L vs 31.19 ± 13.9 nmol/L, P<0.0001). 91.4 % of hepatic encephalopathy patients had moderate to severe 25(OH)D deficiency as compared to 51.4 % in the control group. There was a significant correlation observed between the severity of the 25 (OH) D deficiency and the severity of liver disease (r =  - 0.35, P = 0.002). No statistically significant difference in serum 25(OH) D levels was found among patients with different hepatic encephalopathy grades (P = 0.416). CONCLUSION: A significant association was found between a low serum 25(OH) D leveland hepatic encephalopathy. It requires further large-scale multicenter studies to establish it as a risk factor and predictor of hepatic encephalopathy.

Neurofilament light chain but not glial fibrillary acidic protein is a potential biomarker of overt hepatic encephalopathy in patients with cirrhosis.

INTRODUCTION AND OBJECTIVES: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis and may cause cerebral damage. Neurodegenerative diseases can induce the release of neuroproteins like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in body fluids, including blood plasma. We investigated whether NfL and GFAP could serve as potential diagnostic plasma biomarkers for overt HE (oHE). MATERIALS AND METHODS: We included 85 patients from three prospective cohorts with different stages of liver disease and HE severity. The following patients were included: 1) 34 patients with primary sclerosing cholangitis (PSC) with compensated disease; 2) 17 patients with advanced liver disease without oHE before elective transjugular intrahepatic portosystemic shunt (TIPS) placement; 3) 17 intensive care unit (ICU) patients with oHE and 17 ICU patients without cirrhosis or oHE. Plasma NfL and GFAP were measured using single molecule assays. RESULTS: ICU oHE patients had higher NfL concentrations compared to pre-TIPS patients or ICU controls (p < 0.05, each). Median GFAP concentrations were equal in the ICU oHE and pre-TIPS patients or ICU controls. Plasma NfL and GFAP concentrations correlated with Model for End-Stage Liver Disease (MELD) scores (R = 0.58 and R = 0.40, p < 0.001, each). CONCLUSIONS: Plasma NfL deserves further evaluation as potential diagnostic biomarker for oHE and correlates with the MELD score.

Pediatric acute liver failure: Current perspective in etiology and management.

Pediatric acute liver failure (PALF) is a catastrophic clinical condition with very high morbidity and mortality without early detection and intervention. It is characterized by the acute onset of massive hepatocellular injury that releases circulating inflammatory mediators, resulting in metabolic disturbances, coagulopathy, hepatic encephalopathy and multi-organ failure. The etiological spectrum is dominated by hepatotropic viruses, drug-induced liver injury, metabolic and genetic disorders and immune-mediated diseases. Unlike adults, indeterminate causes for acute liver failure constitute a considerable proportion of cases of acute liver failure in children in the west. The heterogeneity of age and etiology in PALF has led to difficulties in developing prognostic scoring. The recent guidelines emphasize prompt identification of PALF, age-appropriate evaluation for hepatic encephalopathy and laboratory evaluation with careful monitoring. Current therapy focuses on supporting the failing liver and other organs, pending either spontaneous recovery or liver transplantation. Targeted therapy is available for a select group of etiologies. Liver transplantation can be lifesaving and a plan for the same should be organized, whenever indicated. The aim of this review is to define PALF, understand its etiopathogenesis, address the challenges encountered during the management and update the latest advances in liver transplantation and non-transplant treatment options in PALF.

Hepatic encephalopathy: a neurologist's perspective.

Liver disease is increasingly common, estimated to affect over 25% of the world's population. Failure of the liver to maintain a normal metabolic milieu leads to impaired brain function (hepatic encephalopathy), and conditions that cause liver disease can themselves predispose to neurological disease. As neurologists' involvement with the acute take increases, it is important that we are familiar with the neurological complications of liver disease, their investigation and management, and to know which other neurological diseases occur in this patient population. In this article, we review the causes, presentation and treatment of hepatic encephalopathy, and discuss important differential diagnoses in patients with liver disease who present with neurological disturbance.

Regression-based Chinese norms of number connection test A and digit symbol test for diagnosing minimal hepatic encephalopathy.

Number connection test A (NCT-A) and digit symbol test (DST), the preferential neuropsychological tests to detect minimal hepatic encephalopathy (MHE) in China, haven't been standardized in Chinese population. We aimed to establish the norms based on a multi-center cross-sectional study and to detect MHE in cirrhotic patients. NCT-A and DST were administered to 648 healthy controls and 1665 cirrhotic patients. The regression-based procedure was applied to develop demographically adjusted norms for NCT-A and DST based on healthy controls. Age, gender, education, and age by education interaction were all predictors of DST, while age, gender, and education by gender interaction were predictors of log10 NCT-A. The predictive equations for expected scores of NCT-A and DST were established, and Z-scores were calculated. The norm for NCT-A was set as Z ≤ 1.64, while the norm for DST was set as Z ≥ - 1.64. Cirrhotic patients with concurrent abnormal NCT-A and DST results were diagnosed with MHE. The prevalence of MHE was 8.89% in cirrhotic patients, and only worse Child-Pugh classification (P = 0.002, OR = 2.389) was demonstrated to be the risk factor for MHE. The regression-based normative data of NCT-A and DST have been developed to detect MHE in China. A significant proportion of Chinese cirrhotic patients suffered from MHE, especially those with worse Child-Pugh classification.

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.

Undiagnosed Cirrhosis and Hepatic Encephalopathy in a National Cohort of Veterans With Dementia.

Importance: Dementia and hepatic encephalopathy (HE) are challenging to distinguish clinically. Undiagnosed cirrhosis in a patient with dementia can lead to missed opportunities to treat HE. Objective: To examine the prevalence and risk factors of undiagnosed cirrhosis and therefore possible HE in veterans with dementia. Design, Setting, and Participants: A retrospective cohort study was conducted between 2009 and 2019 using data from the Veterans Health Administration (VHA) and 2 separate validation cohorts from the Richmond Veterans Affairs Medical Center. Data analysis was conducted from May 20 to October 15, 2023. Participants included 177 422 US veterans with a diagnosis of dementia at 2 or more clinic visits, no prior diagnosis of cirrhosis, and with sufficient laboratory test results to calculate the Fibrosis-4 (FIB-4) score. Exposures: Demographic and clinical characteristics. Main Outcomes and Measures: An FIB-4 score (>2.67 suggestive of advanced fibrosis and >3.25 suggestive of cirrhosis), capped at age 65 years even for those above this cutoff who were included in the analysis. Results: Among 177 422 veterans (97.1% men; 80.7% White; mean (SD) age, 78.35 [10.97] years) 5.3% (n = 9373) had an FIB-4 score greater than 3.25 and 10.3% (n = 18 390) had an FIB-4 score greater than 2.67. In multivariable logistic regression models, FIB-4 greater than 3.25 was associated with older age (odds ratio [OR], 1.07; 95% CI, 1.06-1.09), male gender (OR, 1.43; 95% CI, 1.26-1.61), congestive heart failure (OR, 1.48; 95% CI, 1.43-1.54), viral hepatitis (OR, 1.79; 95% CI, 1.66-1.91), Alcohol Use Disorders Identification Test score (OR, 1.56; 95% CI, 1.44-1.68), and chronic kidney disease (OR, 1.11; 95% CI, 1.04-1.17), and inversely associated with White race (OR, 0.79; 95% CI, 0.73-0.85), diabetes (OR, 0.78; 95% CI, 0.73-0.84), hyperlipidemia (OR, 0.84; 95% CI, 0.79-0.89), stroke (OR, 0.85; 95% CI, 0.79-0.91), tobacco use disorder (OR, 0.78; 95% CI, 0.70-0.87), and rural residence (OR, 0.92; 95% CI, 0.87-0.97). Similar findings were associated with the FIB-4 greater than 2.67 threshold. These codes were associated with cirrhosis on local validation. A local validation cohort of patients with dementia showed a similar percentage of high FIB-4 scores (4.4%-11.2%). Conclusions and Relevance: The findings of this cohort study suggest that clinicians encountering patients with dementia should be encouraged to screen for cirrhosis using the FIB-4 score to uncover reversible factors associated with cognitive impairment, such as HE, to enhance outcomes.

Diagnostic Performance of the ICD-10 Code K76.82 for Hepatic Encephalopathy in Patients With Cirrhosis.

INTRODUCTION: Hepatic encephalopathy (HE) is prevalent and is associated with increased morbidity and mortality among patients with cirrhosis. On October 1, 2022, a new, specific International Classification of Diseases-10 code for HE, K76.82, was introduced. We aimed to analyze the diagnostic accuracy of K76.82. METHODS: Diagnostic performance of K76.82 for HE (sensitivity, specificity, positive predictive ratio, and negative predictive ratio) was evaluated in 2 large health systems compared with lactulose, rifaximin, and K72.90. RESULTS: A total of 2,483 patients were analyzed. The combination term "lactulose or rifaximin" showed the highest sensitivity of >98% while K76.82 demonstrated a specificity of >87% in all cohorts. DISCUSSION: Although K76.82 is promising, the combination term "lactulose or rifaximin" identified patients with HE more accurately.

Minimal hepatic encephalopathy is associated with a higher risk of overt hepatic encephalopathy and poorer survival.

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) is a frequent complication in patients with liver cirrhosis. Its impact on predicting the development of overt hepatic encephalopathy (OHE) and survival has not been studied in large multicenter studies. METHODS: Data from patients recruited at eight centers across Europe and the United States were analyzed. MHE was detected using the psychometric hepatic encephalopathy score (PHES). A subset was also tested with the simplified animal naming test (S-ANT1). Patients were followed for OHE development and death/liver transplantation (LTx). RESULTS: A total of 1462 patients with a median model of end-stage liver disease of 11 were included (Child-Pugh (CP) stages: A 47%/B 41%/C 12%). Median follow-up time was 19 months, during which 336 (23%) patients developed an OHE episode and 464 (32%) reached the composite end point of death/LTx (369 deaths, 95 LTx). In multivariable analyses, MHE (defined by PHES) was associated with the development of OHE (subdistribution hazard ratio 1.74, p < 0.001) and poorer LTx-free survival (hazard ratio 1.53, p < 0.001) in the total cohort as well as in the subgroup of patients without a history of OHE. In subgroup analyses, MHE (defined by PHES) was associated with OHE development in patients with CP B, whereas there was no association in patients with CP A or C. In the subgroup of patients with available S-ANT1, MHE (defined by S-ANT1) was independently associated with OHE development. Combined testing (PHES+S-ANT1) was superior to single testing for predicting OHE and poorer LTx-free survival. CONCLUSIONS: This large multicenter study demonstrates that screening for MHE is a useful tool for predicting OHE and poorer survival.

QuickStroop Predicts Time to Development of Overt Hepatic Encephalopathy and Related Hospitalizations in Patients With Cirrhosis.

Cirrhosis-related neurocognitive impairment caused by covert or minimal hepatic encephalopathy (CHE) affects psychosocial function, increases risk of overt hepatic encephalopathy (OHE) development, and worsens survival.1,2 However, detection in clinical practice is challenging.2 One modality used for screening and prediction of outcomes related to cirrhosis is the EncephalApp Stroop, but it can require up to 10 minutes. Furthermore, the assessment comprises of distinct stages of difficulty, with an easier "Off" stage and a more challenging "On" stage.3 To alleviate these concerns, QuickStroop, which takes <1 minute, was developed. This uses only the first 2 runs of the Off stage of the EncephalApp Stroop, where number signs presented in red, green, or blue need to be matched quickly to their respective colors.4 A prior study showed these versions were comparable cross-sectionally to diagnose CHE.4 However, the utility of QuickStroop to predict cirrhosis-related outcomes is unclear.5-7 Our aim was to determine the ability of QuickStroop to determine time to development of OHE and OHE-related hospitalizations, all-cause hospitalizations, and death in outpatients with cirrhosis.