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.

Infection, inflammation and hepatic encephalopathy from a clinical perspective.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

Performance of EncephalApp Stroop Test in Cirrhotic Patients for Evaluating Covert Hepatic Encephalopathy.

BACKGROUND: Covert hepatic encephalopathy (HE) is the mildest HE spectrum that is difficult to detect, but associated with significant decrease in quality of life. Currently, there is no gold standard to detect covert HE. EncephalApp Stroop Test as a newer diagnostic tool is easier, faster and its ease of availability in various health institutions is expected to be applied in Indonesia for covert HE detection. This study aimed to validate and test the reliability and diagnostic ability of EncephalApp Stroop Test to diagnose covert HE, compared to the Psychometric Hepatic Encephalopathy Score (PHES) and critical flicker frequency (CFF). METHODS: This study is a cross-sectional test, conducted from August to September 2018, targeted at patient with cirrhosis in Jakarta, to obtain Area Under The Curve (AUC), sensitivity, specificity, cut-off point, predictive value, likelihood ratio, and post-test probability of the EncephalApp Stroop Test, compared to PHES and CFF. The Validity and reliability tests were done before diagnostic study. Translation of the EncephalApp Stroop Test were first carried out using WHO protocol. All patients first underwent a Mini Mental State Examination and Ishihara Test to rule out color blindness. RESULTS: Thirty subjects participated in validity and reliability tests, and eighty in diagnostic tests. The translated application showed excellent internal consistency (Chronbach's Alpha of 0.942) and correlation coefficient of 0.82. The diagnostic study showed OnTime + OffTime as the best parameter (AUC: 0.897 (95% CI: 82.9% - 96.5%); sensitivity: 88.6%; specificity: 80%; positive predictive value (PPV): 0.77; negative predictive value (NPV): 0.9; positive likelihood ratio (LK+): 4.4; negative likelihood ratio (LK-): 1.4; positive post-test probability: 0,775; negative post-test probability: 0,1; and cut-off point ≥ 188.8 seconds. CONCLUSION: The EncephalApp Stroop Test is valid and reliable, with good AUC value, sensitivity, specificity, PPV, NPV and likelihood ratio in diagnosing covert hepatic encephalopathy in patients with cirrhosis in Indonesia.

Proposal for new sleep disorder criteria in patients with chronic liver disease: Influence of liver-related complications.

AIM: Sleep disorder is common in patients with chronic liver disease (CLD). Liver-related silent complications, including muscle cramps, covert hepatic encephalopathy (HE), and sarcopenia, often reduce the quality of life of patients with CLD and have been reported to cause sleep disorders. In this study, we clarified the prevalence of liver-related complications associated with sleep disorders in patients with CLD. METHODS: We conducted a multicenter cohort study of 271 patients with CLD. The Athens Insomnia Scale, muscle cramps questionnaires, and Stroop test were used to assess insomnia, muscle cramps, and covert HE, respectively. In addition, sarcopenia, dynapenia, and myopenia were diagnosed according to the guidelines of the Japan Society of Hepatology. RESULTS: In total, 136 patients (50.2%) had sleep disorders. Serum albumin and hemoglobin levels and prothrombin time activity were significantly lower in patients with sleep disorders than in those without sleep disorders. On univariate and multivariate analyses adjusted with inverse probability weighting, muscle cramps, covert HE, and dynapenia were associated with a sleep disorder. Sleep disorder was categorized as follows: cramp, covert HE, dynapenia, multiple complications, and others. In total, 106 of 136 patients (77.9%) with sleep disorder had at least one liver-related complication, whereas 75 patients had multiple liver-related complications. CONCLUSION: Sleep disorder in patients with CLD was classified into four categories (muscle cramp, covert HE, dynapenia, and others). Questionnaire for sleep disorder might be an easy primary step for surveillance of high-risk patients with silent complications associated CLD.

Proposal of Stroop test cut-off values as screening for neuropsychological impairments in cirrhosis: A Japanese multicenter study.

AIM: Despite its relevant clinical impact and high prevalence, covert hepatic encephalopathy (HE) still remains underdiagnosed. As patients with liver cirrhosis tend to be older in Japan, more suitable tests for the elderly and cut-off values based on this attribute are needed. Recently, a Stroop test has been developed and validated for the screening and diagnosis of covert HE in the United States. The present study aims to establish the cut-off values of the Stroop test to screen covert HE. METHODS: This study was a prospective multicenter cross-sectional endeavor. We undertook a survey of 311 cirrhotic patients, administering the number connection test (NCT)-A and -B and the Stroop-off and -on test. RESULTS: We determined the cut-off values of Stroop test results for cirrhotic patients in a variety of age ranges. The cut-off value of the Stroop test was strongly correlated with age. There was a significant correlation between the results of NCT-B and age, and Stroop-on test results showed a correlation with serum albumin (Alb) levels. Serum Alb ≤3.2 g/dl could have the potential to be an objective biomarker of covert HE. In addition, stepwise logistic regression analysis revealed a relationship between the results of the Stroop-on test and plasma ammonia levels. CONCLUSIONS: We established the cut-off values of Stroop test results and confirmed the efficacy of the Stroop test as a simple tool for assessing cognitive alterations. The Stroop test could be suitable as a necessary minimum for the diagnosis of covert HE.

Liver Transplant Is Associated with Sustained Improvement in Tandem Gait and Risk of Falls.

BACKGROUND: Cirrhosis is associated with poor health-related quality of life (HRQOL), cognitive dysfunction (CD), and lack of coordination leading to falls. Tandem gait (TG; heel-toe) can be used to assess coordination. The impact and relationship between CD, TG and falls pre-/post-liver transplant (LT) is unclear. We aimed to determine the impact of LT on CD, abnormal TG, and HRQOL in cirrhosis. METHODS: We analyzed patients who underwent complete neurological examination, cognitive testing by psychometric hepatic encephalopathy score (PHES), and HRQOL assessment using sickness impact profile (SIP). All patients were followed for 1 post-LT visit at 6 or 12 months post-LT for clinical course and falls. Change in CD, TD, and falls pre-/post-LT were compared. RESULTS: Off 131 recruited, 61 patients completed all visits. Majority were men (84%), with HCV etiology (34%). Pre-LT: Abnormal TG trended towards increased falls (OR 3.3, P = 0.08). Forty-nine % had abnormal TG, 61% had CD, 32.7% had CD + abnormal TG, 62% had prior OHE, and 14.7% had falls. Abnormal and normal TG patients had similar ages, BMI, sex, education level, and MELD scores. Abnormal TG group had higher prior overt HE (P = 0.03) and worse physical SIP score (P = 0.008). Post-LT: There was sustained improvement in CD, HRQOL, falls, and TG post-LT more at 12 than 6 months in all patients. Patients who had abnormal TG pre-LT continued to have a worse PHES (P = 0.0064) and physical SIP score (P = 0.008) compared to normal pre-LT TG patients. CONCLUSION: After LT, there is a sustained improvement in coordination measured via tandem gait, accompanied by a lower rate of falls.

Combined Scores from the EncephalApp Stroop Test, Number Connection Test B, and Serial Dotting Test Accurately Identify Patients With Covert Hepatic Encephalopathy.

BACKGROUND & AIMS: The EncephalApp Stroop test is a high-sensitivity but low-specificity test that has been used to identify patients with covert hepatic encephalopathy (CHE). We aimed to develop a new strategy to detect CHE, combining EncephalApp Stroop test score with scores from subtests of the psychometric hepatic encephalopathy scoring system (PHES). METHODS: We performed a survey of 569 adult volunteers (229 men) in 9 communities in Shanghai, China, administering the EncephalApp Stroop test to determine the range of scores in the general population. Data from the standard PHES, including the number connection test-A, number connection test-B (NCT-B), line tracing test, serial dotting test (SDT), and digit symbol test, were used as the reference standard for diagnosis of CHE. A combination of the EncephalApp Stroop with subtests of the PHES was used to establish a new strategy for CHE diagnosis. We validated our findings using data from 160 patients with cirrhosis from 5 centers China. RESULTS: We determined the range of EncephalApp Stroop test scores for the volunteers of different decades of age, education levels, and sexes. Age, education level, and sex were independently associated with EncephalApp Stroop test scores. A combination of scores from the EncephalApp Stroop test, the NCT-B, and the SDT identified patients with CHE with the highest level of accuracy, when the standard PHES was used as the reference standard. A combination of scores of 187 sec for the EncephalApp Stroop test and below -1 for the NCT-B or below -1 for the SDT identified patients with CHE with an area under the curve (AUC) of 0.86, 81.0% sensitivity, and 91.9% specificity, and 87.5% accuracy. In the validation cohort, these cutoff scores identified patients with CHE with an AUC of 0.88, 97.1% sensitivity, 79.3% specificity, and 86.9% accuracy. The average time to calculate this score was 374±140 sec, compared 424±115 sec for the entire PHES. CONCLUSION: Scores from the EncephalApp Stroop test, NCT-B, and SDT identify patients with CHE with approximately 87% accuracy, and in a much shorter time than the standard PHES. This score combination could be a valid and convenient method for identifying patients with CHE. chictr.org.cn number, ChiCTR-EDC-17012007, ChiCTR1800019954.

Utility of the EncephalApp Stroop Test for covert hepatic encephalopathy screening in Chinese cirrhotic patients.

BACKGROUND AND AIM: Considering the large size of the potential population and limitations of common detection methods, covert hepatic encephalopathy (CHE) is difficult to screen for routinely. The present study aims to explore EncephalApp Stroop Test as a smartphone-based CHE screening tool in China. METHODS: A multicenter, single-visit study was carried out. The cutoff of the Chinese EncephalApp translation was determined by using Chinese standardized psychometric hepatic encephalopathy score (PHES) in cirrhotic patients as the gold standard. Indicators reflecting time required and number of tests on subtask on (naming the color of pound signs) and off (naming the color of the word in discordant coloring) were recorded, with the feedback from investigators and patients. RESULTS: One hundred forty-four patients were included; 58 (40.28%) patients were diagnosed with CHE by PHES. The cutoff of > 97.34 s for off time and > 186.63 s for on time + off time had the maximum area under the curve values (0.77) in all patients. Furthermore, with the cutoff of 186.63 s, on time + off time has the highest sensitivity (0.86). However, the specificity was unsatisfactory (0.59). Age and alcoholic hepatitis (odds ratio = 1.05 and 3.12, both P < 0.05) were positively correlated with the risk of CHE. The experience with electronic devices and education duration were negatively correlated (odds ratio = 0.21 and 0.92, both P < 0.05). Compared with PHES, EncephalApp represented 38% time saving. Furthermore, it was superior to PHES regarding accessibility, convenience, and acceptability by administrators (all P < 0.05). CONCLUSIONS: The EncephalApp Stroop Test is an efficient screening tool for CHE in Chinese cirrhotic patients.

Updating the neuropsychological test system in Japan for the elderly and in a modern touch screen tablet society by resetting the cut-off values.

AIM: Covert hepatic encephalopathy is frequently seen in cirrhotic patients. This condition can be diagnosed by a computerized neuropsychological test system (NPT); however, NPT has not been updated for approximately two decades in Japan. The aim of this study is to update the NPT to be more suitable for both the elderly and modern society by resetting of cut-off values. METHODS: We enrolled 367 healthy subjects aged between 40 and 79 years old between 2003 and 2010. The NPT consists of the following eight tests: number connection tests (NCT)-A and -B, a figure position test, a digit symbol test, a block design test, and reaction time tests (RTT)-A, -B, and -C. All subjects were classified into eight groups (5-year quartile ranges from 40 to 79 years old), and the cut-off value for each test was compared to the former cut-off value (NPT version 1). RESULTS: In all eight tests, most of the cut-off values were different from those in NPT version 1. The difference was minimal in RTT-A, RTT-B, and RTT-C. However, the difference was evident in the NCT-A, NCT-B, digit symbol test, and block design test. In particular, a 57.8-s decrease in the cut-off value was seen in the 65-69-year-old group for the NCT-B test (71.3 s vs. 129.1 s). CONCLUSIONS: We updated the NPT by covering subjects aged 40-79 years and resetting the cut-off values. Thus, the updated NPT is an elderly and modern subject-compliant application. This update may improve the diagnostic ability of covert hepatic encephalopathy in contemporary cirrhotic patients.

Cognitive reserve is a resilience factor for cognitive dysfunction in hepatic encephalopathy.

Cognitive Reserve (CR) modulates symptoms of brain disease. The aim of this study was: to evaluate the effect of CR on cognition in cirrhosis and on the mismatch between cognitive and neurophysiologic assessment of hepatic encephalopathy (HE). Eighty-two outpatient patients with cirrhosis without overt HE were studied [73% males; age: 62 (54-68) (median, interq. range) yrs.; education: 8 (6-13) yrs.]. The Psychometric Hepatic Encephalopathy Score (PHES) was used as cognitive measure of HE. The spectral analysis of the electroencephalogram (EEG) was used as neurophysiologic measure of HE. The CR was assessed by the CR Index (CRI), which was measured by the CRI questionnaire (CRIq) ( http://cri.psy.unipd.it ). The PHES was altered in 28% of patients and the EEG in 41%. Altered PHES was related to the severity of cirrhosis as assessed by Child-Pugh classification (R = 0.31, p < 0.005). Patients with maintained PHES had higher CRI than those with altered PHES (CRI = 100 ± 20 vs. 88 ± 12 vs., p < 0.01), but not the ones with normal EEG compared to those with abnormal EEG (CRI = 96 ± 17 vs. 98 ± 17 vs. p: n.s.).The PHES, but not the EEG, was found to be related to the CRI (r = 0.35, p < 0.01). The mismatch between cognitive and neurophysiologic evaluation of non-overt HE (the ratio between PHES and the mean dominant frequency -MDF- of the EEG i.e., cognitive performance normalized by EEG speed) was found to be correlated to the CRI (r = 0.36, p < 0.005). CR is a resilience factor for cognitive dysfunction in cirrhosis, and is easily measurable by CRIq.

Effects of obstructive sleep apnea on sleep quality, cognition, and driving performance in patients with cirrhosis.

BACKGROUND & AIMS: In patients with cirrhosis, sleep disturbances are assumed to result from hepatic encephalopathy (HE). The effects of obstructive sleep apnea (OSA) on cognition, sleep parameters, or driving in patients with cirrhosis are unclear. METHODS: We performed a cross-sectional and prospective study of 118 subjects. Subjects were assigned to 1 of 4 groups: those with OSA and cirrhosis (without hepatic encephalopathy or ascites, n = 34), those with cirrhosis only (n = 30), those with OSA only (n = 29), and those without OSA or cirrhosis (controls, n = 25). None of the OSA patients were receiving continuous positive airway pressure (CPAP) therapy. Subjects underwent cognitive testing (paper-pencil tests for psychomotor speed and attention, as well as executive function tests), sleep assessment (daytime sleepiness and night-time sleep quality), and a monotonous driving simulation (worsening lane deviations over time indicated poor performance). We also tested patients with OSA, with cirrhosis (n = 10) and without cirrhosis (n = 7), before and after CPAP therapy. RESULTS: Daytime sleepiness and sleep quality were worse in subjects in the OSA groups (with or without cirrhosis) than subjects with cirrhosis alone or controls. Of subjects with only OSA, 36% had impaired psychomotor speed and attention, compared with more than 60% of subjects in both cirrhosis groups. In contrast, executive function was uniformly worse in subjects with OSA, with or without cirrhosis, than groups without OSA. Simulator performance (lane deviations) worsened over time in both OSA groups. CPAP therapy significantly increased executive function and sleep quality, and reduced simulator lane deviations and sleepiness, in OSA subjects with and without cirrhosis. After CPAP therapy, performance on the paper-pencil test improved significantly only in subjects with OSA without cirrhosis. CONCLUSIONS: OSA should be considered in evaluating sleep impairment in patients with cirrhosis. In patients with cirrhosis and OSA, psychomotor speed and attention issues likely are related to cirrhosis, whereas executive function and simulator performance are affected by OSA. CPAP therapy improves executive function and simulator performance in patients with OSA, regardless of cirrhosis.

Covert and Overt Hepatic Encephalopathy: Diagnosis and Management.

Hepatic encephalopathy (HE) is part of a spectrum of neurocognitive changes in cirrhosis. HE is divided into 2 broad categories based on severity: covert hepatic encephalopathy (CHE) and overt hepatic encephalopathy (OHE). CHE has a significant impact on a patient's quality of life, driving performance, and recently has been associated with increased hospitalizations and death. Likewise, OHE is associated with increased rates of hospitalizations and mortality, and poor quality of life. Given its significant burden on patients, care takers, and the health care system, early diagnosis and management are imperative. In addition, focus also should be directed on patient and family member education on the disease progression and adherence to medications. Treatment strategies include the use of nonabsorbable disaccharides, antibiotics (ie, rifaximin), and, potentially, probiotics. Other therapies currently under further investigation include L-ornithine-L-aspartate, ornithine phenylacetate, glycerol phenylbutyrate, molecular adsorbent recirculating system, and albumin infusion.

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.

Short-latency reaction time and accuracy are impaired in patients with cirrhosis: An international multicenter retrospective study.

AIM: The inability to quickly react to an external event can lead to an increased risk for accidents (e.g., falls, car crashes) in patients with cirrhosis. The aim of this study was to determine whether a novel clinically feasible measure of simple reaction time (SRT) and reaction accuracy (RA)-a go/no-go task occurring within 400 ms-could differentiate patients with cirrhosis from controls. METHODS: This retrospective study included 160 patients with cirrhosis and 160 controls assessed between January 2010 and October 2022. SRT and RA were evaluated using a ruler drop paradigm and compared using propensity score matching. Factors distinguishing patients with cirrhosis from controls were assessed using logistic regression and receiver operating characteristics curve (ROC) analyses. RESULTS: Propensity score matching identified 112 participants in each group with comparable baseline characteristics. As compared with controls, patients with cirrhosis exhibited significantly prolonged SRT (200 vs. 174 ms; P < 0.001) and diminished total RA (63% vs. 73%; P < 0.001). After adjustment for confounding factors, SRT and RA independently identified patients with cirrhosis. ROC analyses showed that SRT more effectively identified patients with cirrhosis than did the number-connection test/trail-making test-B (area under the curve, 0.87 vs. 0.60; P < 0.001). CONCLUSIONS: Patients with cirrhosis demonstrated impairments in short-latency cognitive function. Given that SRT and RA are associated with balance, falls, and response to perturbation, these parameters may present a task-specific method to identify patients with cirrhosis at high risk of falls and motor vehicle crashes. Geriatr Gerontol Int 2024; 24: 25-31.

Proton pump inhibitor use and risk of hepatic encephalopathy: A multicentre study.

Background & Aims: Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting, and data from multicentre studies are scarce. The aim of this study was to dissect the potential association between PPI use and minimal (MHE) and overt HE (OHE). Methods: Data from patients with cirrhosis recruited at seven centres across Europe and the US were analysed. MHE was defined by the psychometric hepatic encephalopathy score (PHES). PPI use was recorded on the day of testing with PHES. Patients were followed for OHE development and death/liver transplantation. Results: A total of 1,160 patients with a median MELD of 11 were included (Child-Pugh stages: A 49%/B 39%/C 11%). PPI use was noted in 58% of patients. Median follow-up time was 18.1 months, during which 230 (20%) developed an OHE episode, and 224 (19%) reached the composite endpoint of death/liver transplantation. In multivariable analyses, PPI use was neither associated with the presence of MHE at baseline nor OHE development during follow-up. These findings were consistent in subgroup analyses of patients with Child-Pugh A or B cirrhosis and after excluding patients with a history of OHE. PPI use was also not associated with a higher risk of OHE, neither in patients with an indication for treatment nor in patients without an indication. Conclusions: PPI use is not associated with a higher risk of HE in patients with cirrhosis. Based on these findings, at present, a prescription should not be prohibited in case of a generally accepted indication. Impact and implications: Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting. In this study, PPI use was not associated with a higher risk of minimal HE at baseline or overt HE during follow-up in patients with cirrhosis. Based on these findings, prescription of a PPI for a generally accepted indication should not be prohibited in patients with cirrhosis.

Vitamin D deficiency stratifies the risk of covert and overt hepatic encephalopathy in patients with cirrhosis: A retrospective cohort study.

BACKGROUNDS & AIMS: This study aimed to investigate the association between vitamin D deficiency and covert hepatic encephalopathy (CHE), overt hepatic encephalopathy (OHE) occurrence, and mortality in patients with cirrhosis. METHODS: This retrospective study reviewed 679 patients with cirrhosis. Vitamin D deficiency was defined as serum 25-hydorxyvitamin D (25-OHD) levels < 20 ng/mL. The associations between 25-OHD and CHE, OHE occurrence, and mortality were assessed using logistic regression, Fine-Gray competing risk regression, and Cox proportional hazards regression models, respectively. RESULTS: Of 428 eligible patients, 75% had vitamin D deficiency and 23% had CHE. The prevalence of CHE was higher in patients with vitamin D deficiency than in those without vitamin D deficiency (28% vs. 13%, p = 0.002). During the median follow-up period of 2.3 years, 14% of the patients developed OHE and 27% died. Patients with vitamin D deficiency had a higher incidence of OHE (p = 0.002) and mortality (p = 0.006) than those without vitamin D deficiency. After adjustment for potential covariates, multivariate analyses showed that 25-OHE was associated with CHE (odds ratio, 0.95; 95% confidence interval [CI], 0.91-0.99; p = 0.023), OHE occurrence (sub-distribution hazard ratio, 0.92; 95% CI, 0.86-0.98; p = 0.013) and mortality (hazard ratio, 0.96; 95% CI, 0.93-0.99; p = 0.020) in patients with cirrhosis. CONCLUSIONS: Vitamin D deficiency is highly prevalent and is associated with CHE, OHE, and mortality in patients with cirrhosis. Evaluation of vitamin D is essential to predict the outcomes of patients with cirrhosis.

Cognitive dysfunction is associated with poor socioeconomic status in patients with cirrhosis: an international multicenter study.

BACKGROUND & AIMS: In patients with cirrhosis, cognitive dysfunction most often results from covert hepatic encephalopathy (HE). These patients are not tested routinely for cognitive dysfunction despite single-center evidence that it could be associated with poor socioeconomic status (SES). We investigated the association between SES and cognition in a multicenter study of cirrhosis. METHODS: In a cross-sectional study, 236 cirrhotic patients from 3 centers (84 subjects from Virginia, 102 from Ohio, and 50 from Rome, Italy; age 57.7 ± 8.6 y; 14% with prior overt HE) were given recommended cognitive tests and a validated SES questionnaire that included questions about employment, personal and family income, and overall financial security. Comparisons were made among centers and between subjects who were employed or not. Regression analysis was performed using employment and personal income as outcomes. RESULTS: Only 37% of subjects had been employed in the past year. Subjects had substantial financial insecurity-their yearly personal income ranged from $16,000 to $24,999, and their family income ranged from $25,000 to $49,999. They would be able to maintain a residence for only 3 to 6 months if their income stopped, and their current liquid assets were $500 to $4999 (<$500 if debt was subtracted). Cognition and SES were worst in Ohio and best in Virginia. Cognition correlated with personal and family income, within and between centers. On regression analysis, cognitive performance (digit symbol, lures, and line tracing) was associated with personal yearly income, after controlling for demographics, country, employment, and overt HE. Unemployed subjects had a higher rate of overt HE, worse cognition, and lower personal income than employed subjects. On regression analysis, performance on digit symbol, line tracing, inhibitory control test lures, and serial dotting tests remained associated with employment, similar to income. CONCLUSIONS: In an international multicenter study of patients with cirrhosis, socioeconomic condition, based on employment and personal income, was associated strongly with cognitive performance, independent of age, education, and country.

Hepatic Encephalopathy: Diagnostic Tools and Management Strategies.

Hepatic encephalopathy (HE) is brain dysfunction secondary to liver insufficiency or portosystemic shunting. HE is a major burden on patients and caregivers, impairs quality of life and is associated with higher mortality. Overt HE is a clinical diagnosis while Covert HE, needs specialized diagnostic strategies. Mainstay of treatment of HE is nonabsorbable disaccharides such as lactulose as well as rifaximin; however, investigational therapies are discussed in this review. Better tools are needed to prognosticate which patients will go on to develop HE but microbiome and metabolomic-driven strategies are promising. Here we review methods to prevent the HE development and admissions.

Covert hepatic encephalopathy is associated with aggressive disease progression and poor survival in patients with cirrhosis.

OBJECTIVES: Covert hepatic encephalopathy (CHE) negatively affects the health-related quality of life and increases the risk of overt HE (OHE) in patients with liver cirrhosis. However, the impact of CHE on long-term patient outcomes remains controversial. This study aimed to explore the association between CHE and disease progression and survival among cirrhotic patients. METHODS: This was a single-center prospective study that enrolled 132 hospitalized patients with cirrhosis, with an average follow-up period of 45.02 ± 23.06 months. CHE was diagnosed using the validated Chinese standardized psychometric hepatic encephalopathy score. RESULTS: CHE was detected in 35.61% cirrhotic patients. During the follow-up, patients with CHE had a higher risk of developing OHE (log-rank 5.840, P = 0.016), exacerbation of ascites (log-rank 4.789, P = 0.029), and portal vein thrombosis (PVT) (log-rank 8.738, P = 0.003). Cox multivariate regression analyses revealed that CHE was independently associated with the occurrence of OHE, exacerbation of ascites, and PVT. Furthermore, patients with progression of cirrhosis were more likely to be diagnosed as CHE (log-rank 4.462, P = 0.035). At the end of the follow-up, patients with CHE had a lower survival rate compared to those without CHE (log-rank 8.151, P = 0.004). CHE diagnosis (hazard ratio 2.530, P = 0.008), together with elder age and higher Child-Pugh score, were risk factors for impaired survival in cirrhotic patients. CONCLUSION: CHE is associated with disease progression and poor survival in patients with cirrhosis, indicating that CHE may serve as an independent predictor of poor prognosis among these patients.

Prevalence and risk factors of covert hepatic encephalopathy in cirrhotic patients: A multicenter study in China.

OBJECTIVE: We aimed to investigate the prevalence of covert hepatic encephalopathy (CHE) in cirrhotic patients in China and its risk factors. METHODS: A multicenter prospective observational study was conducted from January 2021 to March 2022 at 16 medical centers across China to investigate the risk factors of CHE and establish a prediction model for CHE episodes. RESULTS: A total of 528 patients were enrolled in the study. Based on both the psychometric hepatic encephalopathy score and Stroop test results, the prevalence of CHE was 50.4% (266/528), and the consistency between these two tests was 68.9%. Multivariate analysis showed that age (odds ratio [OR] 1.043, 95% confidence interval [CI] 1.022-1.063, P < 0.001), duration of education (OR 0.891, 95% CI 0.832-0.954, P = 0.001), comorbidities of cardiovascular diseases, hypertension, cerebral apoplexy or diabetes mellitus (OR 2.072, 95% CI 1.370-3.133, P < 0.001), Child-Pugh score (OR 1.142, 95% CI 1.029-1.465, P = 0.025), and blood urea nitrogen concentration (OR 1.126, 95% CI 1.038-1.221, P = 0.004) were associated with CHE episodes. According to the Chronic Liver Disease Questionnaire, CHE patients had lower scores for abdominal symptoms and systemic symptoms (P < 0.001), indicating a poor health-related quality of life. Based on a stepwise Cox regression hazard model, we established a nomogram for determining the probabilities of CHE episodes, and the area under the receiver operating characteristic curve was 0.733 (95% CI 0.679-0.788) and 0.713 (95% CI 0.628-0.797) in the training and validation cohorts. CONCLUSIONS: CHE is a common complication of cirrhosis in China. Large-scale studies with long-term follow-up are needed to determine the natural history of Chinese CHE patients.