Higher scores in the Clinical Frailty Scale are associated with covert and overt hepatic encephalopathy in patients with cirrhosis.

BACKGROUND: Frailty increases the vulnerability to internal and external stressors and may therefore be an indicator of a higher frequency of cirrhosis complications. We aimed to investigate the association of the Clinical Frailty Scale (CFS) with covert (CHE) and overt HE (OHE) development in patients with cirrhosis. METHODS: This study analyzed data of 228 patients with cirrhosis. Frailty was assessed using CFS. Patients were examined for the presence of CHE (using PHES) at study inclusion and followed for OHE. RESULTS: Median CFS was 3 and 26 (11 %) patients were at least pre-frail (CFS>3). In multivariable logistic regression analysis in patients without a history of OHE (n = 195), a higher CFS was associated with the presence of CHE at baseline (OR 1.6, p = 0.039). During follow-up, 42 (18 %) patients developed an episode of OHE. In multivariable competing risk regression analyses, a higher CFS was independently associated with the development of an OHE episode in the total cohort (sHR 1.97, p < 0.001) and in the subcohort of patients without a history of OHE (sHR 1.88, p = 0.008). CONCLUSION: CFS appears to be a reliable tool to identify patients at higher risk of HE in whom intensified monitoring and treatment may be justified.

Comparison of Inflammatory Cytokine Levels in Hepatic and Jugular Veins of Patients with Cirrhosis.

Background: Systemic inflammation with elevated inflammatory cytokines is a hallmark in patients with cirrhosis and the main driver of decompensation. There is insufficient data on whether inflammatory cytokine levels differ between hepatic and jugular veins, which may have implications for further immunological studies. Methods: Blood from the hepatic and jugular veins of 40 patients with cirrhosis was collected during hepatic venous pressure gradient (HVPG) measurements. Serum levels of 13 inflammatory cytokines (IL-1ß, Int-α2, Int-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33) were quantified by cytometric bead array. Results: Cytokine levels of IFN-α2, IFN-γ, TNF-α, IL-6, IL-8, IL-10, IL-17A, IL-18, IL-23, and IL-33 were significantly elevated in patients with decompensated cirrhosis compared to patients with compensated cirrhosis. When comparing patients with clinically significant portal hypertension (CSPH, HVPG ≥ 10 mmHg) to patients without CSPH, there were significantly enhanced serum levels of IL-6 and IL-18 in the former group. There was no significant difference between cytokine serum levels between blood obtained from the jugular versus hepatic veins. Even in subgroup analyses stratified for an early cirrhosis stage (Child-Pugh (CP) A) or more decompensated stages (CP B/C), cytokine levels were similar. Conclusion: Cytokine levels increase with decompensation and increasing portal hypertension in patients with cirrhosis. There is no relevant difference in cytokine levels between hepatic and jugular blood in patients with cirrhosis.

Development and evaluation of a virtual reality driving test for patients with cirrhosis.

BACKGROUND: Patients with cirrhosis and especially those with HE may have impaired driving skills and may be prone to car accidents. This proof-of-concept study aimed to develop and evaluate the applicability of a virtual reality (VR)-based driving test in patients with cirrhosis. Additionally, the association between the results in the VR test and car accidents was investigated. METHODS: A short driving test using a VR head-mounted display (HTC Vive Pro Eye) was developed to simulate five hazardous situations. The patient has to pull the brake when the hazardous situations occur. The time from triggering the event to pressing the brake is recorded as reaction time. Total reaction time (TRT) is defined as the combined reaction time to all 5 events. Car accidents were assessed retrospectively (previous 12 months) and patients were followed prospectively for 6 months. Minimal HE (MHE) was diagnosed using Psychometric Hepatic Encephalopathy Score. RESULTS: In total, 112 outpatients with cirrhosis and 52 controls without cirrhosis were recruited. MHE was detected in 14% (n = 15). Patients with cirrhosis and MHE (5.67 s) had higher TRTs compared to patients without MHE (5.02 s) and controls without cirrhosis above the age of 50 (4.98 s) (MHE vs. no MHE or controls p<0.01, no MHE vs. controls: not significant). Seven patients reported car accidents during the twelve months prior to study inclusion. TRTs were numerically higher in patients with reported car accidents (p = 0.099). When patients who stopped driving for HE-related/cirrhosis-related reasons (n = 14) were added to the group of patients with accidents, then a longer TRT was significantly associated with the modeled outcome in univariable (p<0.01) and multivariable analyses (OR 2.83, p<0.01). Two car accidents occurred during follow-up. Both patients had TRTs above the 90th percentile. CONCLUSIONS: The VR driving test is easy and rapid to perform in patients with cirrhosis and could be helpful as a point-of-care tool for predicting car accidents.

Validation of the CLIF-C OF Score and CLIF-C ACLF Score to Predict Transplant-Free Survival in Patients with Liver Cirrhosis and Concomitant Need for Intensive Care Unit Treatment.

Both the Chronic Liver Failure Consortium (CLIF-C) organ failure score (OFs) and the CLIF-C acute-on-chronic-liver failure (ACLF) score (ACLFs) were developed for risk stratification and to predict mortality in patients with liver cirrhosis and ACLF. However, studies validating the predictive ability of both scores in patients with liver cirrhosis and concomitant need for intensive care unit (ICU) treatment are scarce. The aim of the present study is to validate the predictive ability of the CLIF-C OFs and CLIF-C ACLFs regarding the rationale of ongoing ICU treatment and to investigate their predictive ability regarding 28-days (short-), 90-days (medium-), and 365-days (long-term) mortality in patients with liver cirrhosis treated in an ICU. Patients with liver cirrhosis and acute decompensation (AD) or ACLF and concomitant need for ICU treatment were retrospectively analyzed. Predictive factors for mortality, defined as transplant-free survival, were identified using multivariable regression analyses and the predictive ability of CLIF-C OFs, CLIF-C ACLFs, MELD score, and AD score (ADs) was assessed by determining the AUROC. Of 136 included patients, 19 patients presented with AD and 117 patients with ACLF at ICU admission. In multivariable regression analyses, CLIF-C OFs as well as CLIF-C ACLFs were independently associated with higher short-, medium-, and long-term mortality after adjusting for confounding variables. The predictive ability of the CLIF-C OFs in the total cohort in short-term was 0.687 (95% CI 0.599-0.774). In the subgroup of patients with ACLF, the respective AUROCs were 0.652 (95% CI 0.554-0.750) and 0.717 (95% CI 0.626-0.809) for the CLIF-C OFs and for the CLIF-C ACLFs, respectively. ADs performed well in the subgroup of patients without ACLF at ICU admission with an AUROC of 0.792 (95% CI 0.560-1.000). In the long-term, the AUROCs were 0.689 (95% Cl 0.581-0.796) and 0.675 (95% Cl 0.550-0.800) for CLIF-C OFs and CLIF-C ACLFs, respectively. The predictive ability of CLIF-C OFs and CLIF-C ACLFs was relatively low to predict short- and long-term mortality in patients with ACLF with concomitant need for ICU treatment. However, the CLIF-C ACLFs may have special merit in judging futility of further ICU treatment.

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

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

Costs of a structured early detection program for advanced liver fibrosis and cirrhosis: insights on the "plus" of Check-up 35.

BACKGROUND: The implementation of an early detection program for liver cirrhosis in a general population has been discussed for some time. Recently, the effectiveness of a structured screening procedure, called SEAL (Structured Early detection of Asymptomatic Liver cirrhosis), using liver function tests (AST and ALT) and APRI to early detect advanced fibrosis and cirrhosis in participants of the German "Check-up 35" was investigated. METHODS: This study identifies the expected diagnostic costs of SEAL in routine care and their drivers and reports on prevailing CLD etiologies in this check-up population. The analysis is based on theoretical unit costs, as well as on the empirical billing and diagnostic data of SEAL participants. RESULTS: Screening costs are mainly driven by liver biopsies, which are performed in a final step in some patients. Depending on the assumed biopsy rates and the diagnostic procedure, the average diagnostic costs are between EUR 5.99 and 13.74 per Check-up 35 participant and between EUR 1,577.06 and 3,620.52 per patient diagnosed with fibrosis/cirrhosis (F3/F4). The prevailing underlying etiology in 60% of cases is non-alcoholic fatty liver disease. DISCUSSION: A liver screening following the SEAL algorithm could be performed at moderate costs. Screening costs in routine care depend on actual biopsy rates and procedures, attendance rates at liver specialists, and the prevalence of fibrosis in the Check-up 35 population. The test for viral hepatitis newly introduced to Check-up 35 as once-in-a-lifetime part of Check-up 35 is no alternative to SEAL.

Bevacizumab in combination with octreotide rescues a patient with liver cirrhosis, GAVE syndrome and refractory hemorrhage - a case report.

Gastric antral vascular ectasia (GAVE) syndrome is a rare but often challenging etiology of upper gastrointestinal bleeding (UGIB).We report on a 60-year-old patient with liver cirrhosis, GAVE syndrome and recurrent and refractory GAVE-related UGIB. During a 5-month hospital stay, the patient required a total of 82 packed red blood cells (pRBCs) and 23 gastroscopies. All endoscopic approaches, including multiple argon plasma coagulation and band ligation sessions, remained unsuccessful. Antrectomy was waived because of the high perioperative mortality risk in Child-Pugh B liver cirrhosis. TIPS insertion also failed to control the bleeding. Only continuous intravenous octreotide infusion slowed the bleeding, but this forced the patient to be hospitalized. After 144 inpatient days, administration of subcutaneous octreotide allowed the patient to be discharged. However, the patient continued to require two pRBCs every 2-3 weeks. Based on recently published data, we treated the patient with bevacizumab (anti-VEGF antibody) off-label at a dose of 7.5 mg/kg body weight every three weeks in nine single doses over six months. Since the first administration, the patient has remained transfusion-free, has not required hospitalization, and leads an active life, working full-time. He remains on octreotide, which has been reduced but not yet discontinued. Additionally, no adverse events were observed.Thus, in patients with liver cirrhosis and refractory GAVE-related hemorrhage, bevacizumab combined with subcutaneous octreotide should be considered as an effective and durable pharmacological treatment option.

Health literacy in gastrointestinal diseases: a comparative analysis between patients with liver cirrhosis, inflammatory bowel disease and gastrointestinal cancer.

Currently, there are only few data on health literacy in patients with chronic gastrointestinal diseases such as gastrointestinal cancer, inflammatory bowel disease (IBD) and, in particular, liver cirrhosis available. Moreover, head-to-head comparisons between patients with these different diseases are lacking. In this study, 379 patients were enrolled. Of these, 102 patients had gastrointestinal cancer, 86 had IBD, and 191 had cirrhosis. Health literacy was quantified using the Health Literacy Questionnaire (HLQ) developed by Osborne et al. (Swinburne University, Australia) and was compared between these three groups. Patients with cancer had the best health literacy across all nine subscales of the HLQ, while patients with cirrhosis had the poorest. In detail, patients with cirrhosis had significantly poorer health literacy than patients with cancer or IBD in subscales such as "feeling understood and supported by healthcare providers", "having sufficient information to manage my health", "appraisal of health information", "ability to actively engage with healthcare providers" or "understanding health information well enough to know what to do" (p < 0.05 for cirrhosis versus IBD or cancer, respectively). In conclusion, health literacy differs remarkably between patients with chronic gastrointestinal diseases such as cirrhosis, IBD or gastrointestinal cancers.

13 C-Methacetin Breath Test Predicts Survival in Patients With Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

INTRODUCTION: The 13 C-methacetin breath test ( 13 C-MBT) is a dynamic method for assessing liver function. This proof-of-concept study aimed to investigate the association between 13 C-MBT values and outcomes in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). METHODS: A total of 30 patients with HCC were prospectively recruited. Of these, 25 were included in baseline and 20 in longitudinal analysis. 13 C-MBTs were performed before the first and second TACE session. Patients were followed for at least 1 year. RESULTS: At baseline, the median 13 C-MBT value was 261 µg/kg/hr (interquartile range 159-387). 13 C-MBT, albumin-bilirubin, Child-Pugh, and Model for End-Stage Liver Disease scores were associated with overall survival in extended univariable Cox regression ( 13 C-MBT: standardized hazard ratio [sHR] 0.297, 95% confidence interval [CI] 0.111-0.796; albumin-bilirubin score: sHR 4.051, 95% CI 1.813-9.052; Child-Pugh score: sHR 2.616, 95% CI 1.450-4.719; Model for End-Stage Liver Disease score: sHR 2.781, 95% CI 1.356-5.703). Using a cutoff of 140 µg/kg/hr at baseline, 13 C-MBT was associated with prognosis (median overall survival 28.5 months [95% CI 0.0-57.1] vs 3.5 months [95% CI 0.0-8.1], log-rank P < 0.001). Regarding prediction of 90-day mortality after second 13 C-MBT, the relative change in 13 C-MBT values yielded an area under the receiver-operating characteristic curve of 1.000 ( P = 0.007). DISCUSSION: Baseline and longitudinal 13 C-MBT values predict survival of patients with HCC undergoing TACE. The relative change in 13 C-MBT values predicts short-term mortality and may assist in identifying patients who will not benefit from further TACE treatment.

Frailty as Tested by the Clinical Frailty Scale Is a Risk Factor for Hepatorenal Syndrome in Patients With Liver Cirrhosis.

INTRODUCTION: Frailty is common in patients with cirrhosis and increases the vulnerability to internal and external stressors. This study aimed to investigate the impact of frailty, as defined by the Clinical Frailty Scale (CFS), on the risk of acute kidney injury (AKI) and hepatorenal syndrome (HRS-AKI) in hospitalized patients with liver cirrhosis. METHODS: We analyzed data of 201 nonelectively hospitalized patients with cirrhosis and without higher-grade chronic kidney disease. Patient characteristics were captured within the first 24 hours of hospital admission, and frailty was assessed using the CFS. Patients were followed for the development of AKI and/or HRS-AKI during the hospital stay. RESULTS: In the total cohort, median CFS was 3 (interquartile range 3-4), and 34 (16.9%) patients were frail (CFS >4). During the hospital stay, 110 (54.7%) and 49 (24.3%) patients developed AKI or HRS-AKI, respectively. Patients with AKI or HRS-AKI had a significantly higher CFS than patients without kidney injury (P < 0.001 each). In multivariable analyses, a higher CFS was independently associated with the development of AKI (odds ratio [OR] 1.467, 95% confidence interval (CI) 1.065-2.021) in the total cohort and HRS-AKI (OR 1.809, 95% CI 1.263-2.591) in the subcohort of patients with a history of ascites. In addition, there was a strong association between frailty (OR 3.717, 95% CI 1.456-9.491) and HRS-AKI. DISCUSSION: Frailty in patients with cirrhosis is associated with AKI and HRS-AKI. In this context, CFS appears to be a reliable tool to identify patients at high risk for developing AKI or HRS-AKI on hospital admission.

Liver Frailty Index for Prediction of Short-Term Rehospitalization in Patients with Liver Cirrhosis.

Background: Stratifying patients with liver cirrhosis for risk of rehospitalization is challenging with established scoring systems for chronic liver disease. Frailty captures the physical characteristics of patients with cirrhosis. Its value for predicting short-term rehospitalizations in hospitalized patients remains to be defined. Methods: Eighty-three non-electively hospitalized patients with liver cirrhosis were analyzed in this study. Frailty was assessed during the last 48 h of hospital stay with the liver frailty index (LFI). Patients were followed for 30-day rehospitalization. Results: In total, 26 (31%) patients were rehospitalized within 30 days. The median LFI was 4.5, and 43 (52%) patients were identified as frail. Rehospitalized patients had a significant higher LFI compared to patients without a rehospitalization within 30 days. In multivariable analysis, LFI as a metric variable (OR 2.36, p = 0.02) and lower platelet count (OR 0.98, p < 0.01) were independently associated with rehospitalization. LFI and its subtest chair stands had the best discriminative ability to predict rehospitalization, with AUROCs of 0.66 and 0.67, respectively. An LFI cut-off of >4.62 discriminated best between patients with and without elevated risk for rehospitalization within 30 days. Conclusions: Measures of frailty could be useful to identify patients at higher risk for short-term rehospitalization.

Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL.

BACKGROUND & AIMS: Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible. METHODS: SEAL was a prospective cohort study with a control cohort from routine care data. Individuals participating in the general German health check-up after the age of 35 ("Check-up 35") at their primary care physicians were offered a questionnaire, liver function tests (aspartate and alanine aminotransferase [AST and ALT]), and follow-up. If AST/ALT levels were elevated, the AST-to-platelet ratio index (APRI) score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care. RESULTS: A total of 11,859 participants were enrolled and available for final analysis. The control group comprised 349,570 participants of the regular Check-up 35. SEAL detected 488 individuals with elevated APRI scores (4.12%) and 45 incident cases of advanced fibrosis/cirrhosis. The standardized incidence of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83‰ vs. 3.36‰). The comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in standard care was inconclusive (marginal odds ratio 1.141, one-sided 95% CI 0.801, +Inf). Of note, when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection on average than routine care (marginal odds ratio 1.590, one-sided 95% CI 1.080, +Inf; SEAL 3.51‰, controls: 2.21‰). CONCLUSIONS: The implementation of a structured screening program may increase the early detection rate of cirrhosis in the general population. In this context, the SEAL pathway represents a feasible and potentially cost-effective screening program. REGISTRATION: DRKS00013460 LAY SUMMARY: Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. This study demonstrates that the implementation of a structured screening program using easily obtainable measures of liver function may increase the early detection rate of cirrhosis in the general population. In this context, the 'SEAL' pathway represents a feasible and potentially cost-effective screening program.

Characteristics of bacterial infections and prevalence of multidrug-resistant bacteria in hospitalized patients with liver cirrhosis in Germany.

INTRODUCTION AND OBJECTIVES: Bacterial infections are associated with a dismal prognosis in patients with liver cirrhosis. Data on their prevalence and the associated pathogen spectra in Germany are scarce. This study aimed to evaluate the impact of bacterial infections on mortality in hospitalized patients with liver cirrhosis and to analyze the prevalence of multidrug-resistant (MDR) bacteria in a German tertiary care center. PATIENTS AND METHODS: Consecutive, non-electively hospitalized patients with liver cirrhosis were enrolled in this study between 03/2019-06/2021. All patients underwent clinical, laboratory and microbiological testing to detect potential bacterial infections. Patients were followed for 30 days regarding the composite endpoint of death or liver transplantation (mortality). RESULTS: In total, 239 patients were recruited (median MELD 18). Bacterial infection was detected in 81 patients (33.9%) at study inclusion. A total of 70 patients (29.3%) developed a hospital-acquired infection. When comparing community-acquired and hospital-acquired infections, the pathogen pattern shifted from a gram-negative to a more gram-positive spectrum and showed an increase of Staphylococcus spp.. MDR bacteria were detected in seven infected patients (5.8%). 34 patients reached the composite endpoint during 30-days follow-up. In multivariable logistic regression analysis, the presence of infection during hospitalization remained independently associated with higher mortality (OR 2.522, 95% CI 1.044 - 6.091, p = 0.040). CONCLUSIONS: This study demonstrates that bacterial infections are common in hospitalized patients with liver cirrhosis in Germany and are a major determinant of short-term mortality. Our data highlight the importance of regional differences in MDR bacteria and may guide physicians' decision-making regarding calculated antibiotic treatment.

Outcomes in patients receiving palliative chemotherapy for advanced biliary tract cancer.

BACKGROUND & AIMS: Advanced biliary tract cancer (ABTC) is associated with a poor prognosis. Real-world data on the outcome of patients with ABTC undergoing sequential chemotherapies remain scarce, and little is known about treatment options beyond the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX. This study aimed to evaluate the outcome of patients with regard to different oncological therapies and to identify prognostic factors. METHODS: From January 2010 until December 2019, 142 patients started palliative chemotherapy at our tertiary care liver center. Overall survival (OS) was calculated using Kaplan-Meier plots. Prognostic factors were evaluated using cox proportional-hazards. RESULTS: Patients received a median number of 2 lines of chemotherapy. Median OS was 6.7, 15.2 and 18.2 months for patients who received 1, 2 and 3 lines of chemotherapy, respectively. Patients treated with FOLFIRINOX had a significantly extended OS of 23.8 months (log-rank test: p = 0.018). The univariate cox regression analysis identified several clinical parameters associated with survival (e.g. albumin, bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9 levels). CONCLUSIONS: Our study provides real-world data on the prognosis of ABTC including survival times for patients receiving third and later lines of chemotherapy. LAY SUMMARY: Real-world data depicting the outcome of patients with advanced biliary tract cancer outside the framework of controlled trials remain rare despite being extremely important for clinical decision-making. This study therefore provides important real-world data on the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX, as well as on other chemotherapy regimens or later lines of chemotherapy. It further demonstrates that the use of FOLFIRINOX is associated with promising survival and that there is an association between various clinical parameters such as pre-therapeutic albumin, bilirubin or carbohydrate antigen 19-9 levels and survival.

Continued alcohol consumption and hepatic encephalopathy determine quality of life and psychosocial burden of caregivers in patients with liver cirrhosis.

BACKGROUND: Patients with liver cirrhosis suffer from significantly reduced health-related quality of life and are often dependent on support from caregivers. In this context, caregivers often suffer from impaired quality of life (QoL) as well as psychosocial burden (PB). The aim of the present study was to identify factors influencing QoL and PB of caregivers in order to improve the social care of patients and caregivers. METHODS: In this cross-sectional study, 106 patients with liver cirrhosis and their caregivers were included. (Health-related) QoL was surveyed in patients (CLDQ) and caregivers (SF-36) and PB was determined by Zarit Burden Interview. RESULTS: Alcohol related liver cirrhosis (55%) was the predominant etiology of liver cirrhosis and the median MELD of the cohort was 14. QoL did not differ between patients with and without alcohol-related liver cirrhosis (p = 0.6). In multivariable analysis, continued alcohol consumption (p = 0.020), a history of hepatic encephalopathy (HE) (p = 0.010), poorer QoL of patients (p = 0.030) and poorer QoL of caregivers (p = 0.005) were associated with a higher PB of caregivers. Factors independently associated with poorer QoL of caregivers were continued alcohol consumption (p = 0.003) and a higher PB of caregivers (p = 0.030). CONCLUSION: Caregivers of patients with liver cirrhosis suffer from impaired QoL and PB, especially in case of continued alcohol consumption or the occurrence of HE.

Validation of EncephalApp_Stroop as screening tool for the detection of minimal hepatic encephalopathy in German patients with liver cirrhosis.

BACKGROUND: In contrast to overt hepatic encephalopathy (OHE), the diagnosis of minimal HE (MHE) is challenging in patients with cirrhosis requiring elaborate, specialized testing. The EncephalApp_Stroop is a smartphone-based application established as screening tool for the diagnosis of MHE but has not yet been validated in a German cohort and country specific cut-offs are currently missing. METHODS: 93 patients with cirrhosis were enroled into this study. Psychometric hepatic encephalopathy score (PHES) was used to detect MHE, and a subset of the patients was tested with critical flicker frequency (CFF). All patients underwent testing with EncephalApp_Stroop. Cut-off thresholds for EncephalApp_Stroop were calculated according to Youden's Index and a separate cut-off was determined with focus on sensitivity. RESULTS: 24 (26%) patients had MHE according to PHES. EncephalApp_Stroop had a strong correlation with PHES (r=-0.76, p<0.001), while there was only a modest correlation with CFF (r=-0.51, <0.001). On time as well as on+off time discriminated best between patients with and without MHE with AUROCS of 0.87 for both measures. According to Youden's index, a cut-off of >224.7 s (sec) (on+off time) discriminated best between patients with and without MHE with a sensitivity of 71% and a specificity of 88%. The adjusted cut-off value for on+off time with focus on sensitivity (sensitivity:specificity weighed 2:1) was 185.1 s, yielding an optimized sensitivity of 92% and a negative predictive value of 96%. By using this cut-off as a pre-screening test in a stepwise diagnosis algorithm, elaborate testing with PHES could have been avoided in 49% of all patients. CONCLUSION: EncephalApp_Stroop may be useful in a stepwise diagnosis algorithm or even as a stand-alone screening tool to detect MHE in German patients with cirrhosis.

Evaluation of IL-6 for Stepwise Diagnosis of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis.

Diagnosis of minimal hepatic encephalopathy (MHE) requires psychometric testing, which is time-consuming and often neglected in clinical practice. Elevated Interleukin-6 (IL-6) serum levels have been linked to MHE. The aim of this study was to investigate the usefulness of IL-6 as a biomarker in a stepwise diagnostic algorithm to detect MHE in patients with liver cirrhosis. A total of 197 prospectively recruited patients without clinical signs of hepatic encephalopathy (HE) served as the development cohort. Another independent cohort consisting of 52 patients served for validation purposes. Psychometric Hepatic Encephalopathy Score (PHES) was applied for the diagnosis of MHE. Fifty (25.4%) patients of the development cohort presented with MHE. Median IL-6 levels were more than twice as high in patients with MHE than in patients without HE (16 vs. 7 pg/mL; P < 0.001). On multivariable logistic regression analysis, higher IL-6 levels (odds ratio 1.036; 95% confidence interval [CI] 1.009-1.064; P = 0.008) remained independently associated with the presence of MHE. IL-6 levels ≥ 8pg/mL discriminated best between patients with and without MHE in receiver operating characteristic (ROC) analysis (area under the ROC 0.751). With a cutoff value of ≥7 pg/mL, further elaborate testing with PHES could be avoided in 38% of all patients with a sensitivity of 90% (95% CI 77%-96%) and a negative predictive value (NPV) of 93% (95% CI 84%-98%). This diagnostic accuracy was confirmed in the validation cohort (sensitivity 94%; NPV 93%). Conclusion: Using IL-6 serum levels as a biomarker in a stepwise diagnostic algorithm to detect MHE could substantially reduce the number of patients requiring testing with PHES and in turn the workload. IL-6 may have especially helped in patients who are unable to perform other screening tests.

Prescription rates of common medications in patients with decompensated cirrhosis in Germany.

BACKGROUND: Adequate pharmacological treatment is of pivotal importance to improve prognosis in patients with decompensated liver cirrhosis. We studied the adherence to recommended pharmacological treatments as secondary prevention in cirrhotic patients following a first decompensation in German primary care. METHODS: Using the Disease Analyzer Database, the current study sample included patients with liver cirrhosis who had an initial diagnosis of a first decompensation event between 2015 and 2018 (index date) and a follow-up time of at least 6 months after the index date. Pharmacological treatments following the 6 months after the index date were studied. RESULTS: The study included 1538 patients with a first decompensation event. The frequency of first-time complications of cirrhosis was 60% new onset of ascites, 25% overt hepatic encephalopathy (HE), 3% spontaneous bacterial peritonitis (SBP), and 12% acute variceal bleeding. The adherence to guideline-recommended treatment following the initial decompensation was highest for ascites, with 91.3% of patients receiving diuretics. Non-selective beta-blockers following an event of variceal bleeding were prescribed in 69.1% and lactulose and/or rifaximin in 59.1% after a bout of HE. The frequency of prescriptions of antibiotics after SBP was 60.4%. Potenzially harmful prescribed medications included non-steroidal anti-inflammatory drugs in 15.5%, benzodiazepines in 12.8%, opioids in 9.5%, and proton pump inhibitors in 73.7%. CONCLUSION: Our findings underline the need for intensified efforts to distribute practice guidelines for liver cirrhosis and increase awareness of over-prescribing of potentially harmful medication.

Elevated serum levels of methylglyoxal are associated with impaired liver function in patients with liver cirrhosis.

Methylglyoxal (MGO) is a highly reactive dicarbonyl species that forms advanced glycation end products (AGEs). The binding of these AGEs to their receptor (RAGE) causes and sustains severe inflammation. Systemic inflammation is postulated to be a major driver in the progression of liver cirrhosis. However, the role of circulating MGO levels in liver cirrhosis remains unknown. In this study, we investigated the serum levels of two dicarbonyl species, MGO and glyoxal (GO) using tandem mass spectrometry (HPLC-MS/MS) and evaluated their association with disease severity. A total of 51 inpatients and outpatients with liver cirrhosis of mixed etiology and different disease stages were included. Elevated MGO levels were seen in an advanced stage of liver cirrhosis (p < 0.001). High MGO levels remained independently associated with impaired liver function, as assessed by the model for end-stage liver disease (MELD) (ß = 0.448, p = 0.002) and acute decompensation (AD) (ß = 0.345, p = 0.005) scores. Furthermore, MGO was positively correlated with markers of systemic inflammation (IL-6, p = 0.004) and the development of ascites (p = 0.013). In contrast, no changes were seen in GO serum levels. Circulating levels of MGO are elevated in advanced stages of liver cirrhosis and are associated with impaired liver function and liver-related parameters.

Association Between Serum Levels of Neurofilament Light Chains and Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis.

INTRODUCTION: Serum biomarkers for the diagnosis of minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis would be desirable. In this proof-of-concept study, we investigated the association between MHE and serum levels of neurofilament light chains (sNfL) in patients with liver cirrhosis. METHODS: sNfL were studied in patients with liver cirrhosis (with or without MHE) and controls (patients with ischemic stroke, transitory ischemic attack, and healthy individuals). MHE was diagnosed using the Psychometric Hepatic Encephalopathy Score. RESULTS: Patients with MHE showed higher sNfL than patients without MHE and controls. In multivariable analyses, higher sNfL were independently associated with the presence of MHE. sNfL had a reliable discriminative power for the detection of MHE with an area under the curve of 0.872. DISCUSSION: MHE is associated with higher sNfL.