Lower uromodulin serum levels are associated with poorer prognosis in patients with cirrhosis and hepatorenal syndrome type 2.

Hepatorenal syndrome (HRS) is associated with a dismal prognosis in patients with cirrhosis, and therapeutic options are limited. Biomarkers to identify patients with poor response to therapy are urgently needed. This study aimed to evaluate the predictive value of serum levels of uromodulin (sUMOD) in patients with cirrhosis and HRS treated with terlipressin and albumin (T/A). In total, 156 patients [81 patients with HRS treated with T/A, 42 patients with cirrhosis without kidney injury, and 33 patients with cirrhosis with prerenal acute kidney injury (AKI)] were included. sUMOD levels were analyzed by ELISA. Patients with HRS were prospectively followed for the composite endpoint of hemodialysis-/liver transplantation-free survival (HD/LTx-free survival). Of the 81 patients with HRS, 40 had HRS type 1 and 41 type 2. In the cohort of patients with HRS treated with T/A, median sUMOD level was 100 ng/mL (IQR 64; 144). sUMOD differed significantly between patients with HRS compared with patients without AKI (P = 0.001) but not between patients with HRS and prerenal AKI (P = 0.9). In multivariable analyses, sUMOD levels in the lowest quartile were independently associated with a lower rate of complete response to T/A (OR 0.042, P = 0.008) and a higher risk for reaching the composite endpoint of HD/LTX-free survival (HR 2.706, P = 0.013) in patients with HRS type 2 treated with T/A. In contrast, sUMOD was not significantly associated with these outcomes in patients with HRS type 1. sUMOD may be a valuable biomarker for identifying patients with HRS type 2 treated with T/A to predict response and prognosis.NEW & NOTEWORTHY Biomarkers identifying patients with hepatorenal syndrome (HRS) and poor response to therapy are urgently needed. In this study, lower serum uromodulin (sUMOD) levels were associated with poorer response to therapy with terlipressin and albumin and consequently with poorer prognosis in patients with HRS type 2. In patients with HRS type 1, there was no association between sUMOD and poorer prognosis.

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.

Noninvasive assessment of liver disease severity in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes.

BACKGROUND AND AIMS: We evaluated the diagnostic accuracy of simple, noninvasive tests (NITs) in NAFLD patients with type 2 diabetes (T2D). METHODS AND RESULTS: This was an individual patient data meta-analysis of 1780 patients with biopsy-proven NAFLD and T2D. The index tests of interest were FIB-4, NAFLD Fibrosis Score (NFS), aspartate aminotransferase-to-platelet ratio index, liver stiffness measurement (LSM) by vibration-controlled transient elastography, and AGILE 3+. The target conditions were advanced fibrosis, NASH, and fibrotic NASH(NASH plus F2-F4 fibrosis). The diagnostic performance of noninvasive tests. individually or in sequential combination, was assessed by area under the receiver operating characteristic curve and by decision curve analysis. Comparison with 2278 NAFLD patients without T2D was also made. In NAFLD with T2D LSM and AGILE 3+ outperformed, both NFS and FIB-4 for advanced fibrosis (area under the receiver operating characteristic curve:LSM 0.82, AGILE 3+ 0.82, NFS 0.72, FIB-4 0.75, aspartate aminotransferase-to-platelet ratio index 0.68; p < 0.001 of LSM-based versus simple serum tests), with an uncertainty area of 12%-20%. The combination of serum-based with LSM-based tests for advanced fibrosis led to a reduction of 40%-60% in necessary LSM tests. Decision curve analysis showed that all scores had a modest net benefit for ruling out advanced fibrosis at the risk threshold of 5%-10% of missing advanced fibrosis. LSM and AGILE 3+ outperformed both NFS and FIB-4 for fibrotic NASH (area under the receiver operating characteristic curve:LSM 0.79, AGILE 3+ 0.77, NFS 0.71, FIB-4 0.71; p < 0.001 of LSM-based versus simple serum tests). All noninvasive scores were suboptimal for diagnosing NASH. CONCLUSIONS: LSM and AGILE 3+ individually or in low availability settings in sequential combination after FIB-4 or NFS have a similar good diagnostic accuracy for advanced fibrosis and an acceptable diagnostic accuracy for fibrotic NASH in NAFLD patients with T2D.

Prevalence of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Multicenter Study.

INTRODUCTION: The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high risk and to pave the way for personalized screening approaches. METHODS: In this study, data of patients recruited at 10 centers across Europe and the United States were analyzed. Only patients without clinical signs of hepatic encephalopathy were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤-4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed. RESULTS: In total, 1,868 patients with cirrhosis with a median model for end-stage liver disease (MELD) of 11 were analyzed (Child-Pugh [CP] stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 patients (35%). After excluding patients with a history of overt hepatic encephalopathy, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), whereas it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (Spearman ρ = -0.16, P < 0.001). DISCUSSION: The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches.

Significant liver fibrosis is a predictor of poor health-related quality of life in people living with HIV.

PURPOSE: Liver-related comorbidities can impair the health-related quality of life (HRQL) in people living with human immunodeficiency virus (HIV) (PLWH). However, the role of hepatic steatosis and significant fibrosis in PLWH remains incompletely characterized. Therefore, the aim of this study was to explore the association of hepatic steatosis and significant fibrosis on the HRQL using the medical outcomes study HIV health survey (MOS-HIV) in PLWH. METHODS: A total of 222 PLWH were included in the final analysis of this cohort study. Metabolic comorbidities, socioeconomic factors, and HIV-related parameters were assessed. Hepatic steatosis and fibrosis were measured using vibration-controlled transient elastography (VCTE). The MOS-HIV survey, containing two summary scores (physical health summary (PHS) and mental health summary (MHS)) and ten domains, was used to assess the HRQL. Clinical predictors were identified using multivariable linear regression models. RESULTS: The majority of this cohort was male, and the median age was 52 years, with a high prevalence of hepatic steatosis (n = 81, 36.5%). Significant fibrosis was present in 7.7% (n = 17). The mean PHS and MHS scores were 52.7 ± 9.5 and 51.4 ± 10.5, respectively. The lowest scores were in the general health perception (GHP) and energy/fatigue (EF) domains. A high BMI and waist circumference were associated with a poor PHS score. Lower education, unemployment, arterial hypertension, and significant fibrosis remained independent predictors of an impaired HRQL. CONCLUSION: Metabolic comorbidities, significant fibrosis, and a lower socioeconomic status may negatively affect the HRQL in PLWH. Considering the negative impact of significant fibrosis on the outcome, counseling and preventive measures according to current guidelines are recommended in this subgroup of PLWH.

How do (false) positively screened patients experience a screening programme for liver cirrhosis or fibrosis in Germany? A qualitative study.

OBJECTIVE: This study aimed to explore psychosocial consequences of (false) positive liver screening results and to identify influencing factors for perceived strain within a multistage screening programme for liver cirrhosis and fibrosis in Germany. METHODS: Between June 2018 and May 2019, all positively screened patients were asked to participate in the study (n = 158). N = 11 telephone interviews and n = 4 follow-up interviews were conducted. Semi-structured telephone interviews were carried out. The analysis followed a structuring content analysis approach. Thereby, categories were first defined deductively. Second, the categories were revised inductively based on the data. RESULTS: The main themes found regarding the consequences of the screening were categorised in emotional reactions and behavioural reactions. Few respondents described negative emotional consequences related to screening. Those seem to be mostly driven by suboptimal patient-provider communication and might be worsened when transparent information transfer fails to happen. As a result, patients sought information and support in their social environment. All patients reported positive attitudes towards liver screening. CONCLUSION: To reduce the potential occurrence of psychosocial consequences during the screening process, medical screening should be performed in the context of transparent information. Regular health communication on the side of health professionals and increasing patients' health literacy might contribute to avoiding negative emotions in line with screening. PATIENT OR PUBLIC CONTRIBUTION: This study recognises the wide-ranging patients' perspectives regarding the consequences of liver screening which should be taken into consideration when implementing a new screening programme to ensure a patient-centred approach.

Diabetes mellitus - risk factor and potential future target for hepatic encephalopathy in patients with liver cirrhosis?

Hepatic encephalopathy (HE) is one of the major complications of cirrhosis, and its presence is associated with poor survival. Several risk factors for HE are well established, including age, history of HE, portosystemic shunts, or poorer liver function. In recent years, diabetes mellitus (DM) has emerged as another potential risk factor for the development of HE. This may be important for many patients, as the incidence of type 2 DM (T2DM) is increasing worldwide and, consequently, the incidence of NAFLD-related cirrhosis is rising simultaneously. In addition, DM is a critical factor in the progression of other liver diseases, such as alcohol-related liver disease. Thus, the number of patients with cirrhosis and comorbid T2DM will also increase. To date, the prevalence of DM already ranges between 22 - 40% in patients with cirrhosis. DM-associated factors that may influence the risk of HE include systemic inflammation, insulin resistance with increased muscle protein breakdown as well as autonomic dysfunction with prolonged intestinal transit time and small intestinal bacterial overgrowth. Currently, the evidence for an association between DM and both minimal and overt HE is weak and it seems likely that only poor glycemic control has an impact on HE risk. In addition, there are some early signs indicating that DM may impair the response of patients with HE to pharmacological therapies such as rifaximin. Thus, improvements in the management of glycemic control may be a candidate future target to reduce the risk of HE. In this concise review, we summarize the current evidence on the association between DM and HE and its potential future implications.

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.

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.

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.

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis.

OBJECTIVE: Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. DESIGN: Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. RESULTS: Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy. CONCLUSION: Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.

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.

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.

Burden of depression and anxiety disorders per disease codes in patients with lymphoma in Germany.

PURPOSE: The aim of this study was to explore the incidence of depression and anxiety disorder diagnoses in a large German cohort of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) diagnoses in comparison to patients without cancer over a 10-year time frame. METHODS: Patients with HL (n=687) and NHL (n=4130) were matched to cohorts without a cancer diagnosis (n=687 and 4130) by age, sex, and yearly consultation frequency. The primary outcome of the study was the incidence of depression and anxiety disorders. The relationship between lymphoma, separated into HL and NHL, and both depression and anxiety disorders was investigated using Cox regression models. RESULTS: We compared 687 patients with HL with 687 matched non-cancer individuals and 4130 patients with NHL with 4130 matched non-cancer individuals. Within 10 years of the index date, 24.0% of patients with HL and 22.3% of patients with NHL were diagnosed with depression. Anxiety disorders were diagnosed in 6.7% and 5.3% of patients with HL and NHL, respectively. On regression analyses, HL (HR 2.30, 95% CI 1.65-3.21, p<0.001) and NHL (HR 2.09, 95% CI 1.81-2.41, p<0.001) were positively associated with incident depression. The HR for anxiety disorders was 1.64 (95% CI 1.24-2.16, p<0.001) in patients with NHL, while HL was not associated with incident anxiety disorders (HR 1.21, 95% CI 0.71-2.07, p<0.478). CONCLUSION: Lymphoma constitutes a risk factor for emerging depression and anxiety disorders. Following the diagnosis of lymphoma, screening and strategies to prevent the occurrence of these diseases seem warranted.

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.

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.

Incident Dementia in Elderly Patients with Nonalcoholic Fatty Liver Disease in Germany.

Dementia and NAFLD are two frequent conditions that share underlying risk factors mainly in the realm of metabolic disease. Additionally, an association between NAFLD and brain aging has been proposed. Therefore, we investigated the hypothesis if NAFLD is an independent risk factor for emerging dementia. In this population-based cohort study, elderly patients (≥ 65 years) with NAFLD diagnosed between 2000 and 2015 were matched 1:1 to a cohort without NAFLD based on ICD-10 coding in the Disease Analyzer database. Matching criteria were age, sex, physician, index year, and co-diagnoses associated with dementia. The primary outcomes of this study were all-cause dementia diagnoses, the incidence of vascular dementia, and antidementive drug prescription. A total of 22,317 patients with NAFLD were matched to 22,317 patients without NAFLD. Within 10 years of the index date, 16.0% of patients with NAFLD and 15.6% of the patients without NAFLD were diagnosed with dementia. On Cox regression analysis, there is no association between NAFLD and the incidence of all-cause dementia (HR 0.97, 95% CI 0.92-1.04), vascular dementia (HR 0.89, 95% CI 0.78-1.02), or the new prescription of antidementive therapy (HR 0.87, 95% CI 0.76-1.01). In sensitivity analyses, there was no association between NAFLD and dementia in different age-groups as well as men or women. In conclusion, in this database study of elderly patients coded with NAFLD no independent association with incident dementia was detected. Risk assessment regarding dementia in patients with NAFLD should be carried out in the same way as for metabolic burdened patients.

Health-related quality of life in patients with autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare chronic liver disease. Impaired health-related quality of life (HRQL) contributes to the overall disease burden. At current, only limited data related to the impact of treatment response on HRQL are available. OBJECTIVE: The aim of the study was to determine the impact of biochemical remission on HRQL. METHODS: Patients with AIH were prospectively enrolled between July 2018 and June 2019. A liver disease-specific tool, the chronic liver disease questionnaire (CLDQ) and the generic EQ-5D-5L were used to quantify HRQL. Treatment response was assessed biochemically by measurement of immunoglobulin G, ALT and AST. The cohort was divided into two groups according to their biochemical remission status in either complete vs. incomplete remission. Clinical as well as laboratory parameters and comorbidities were analysed using univariable and multivariable analysis to identify predictors of poor HRQL. RESULTS: A total of 116 AIH patients were included (median age: 55; 77.6% female), of which 9.5% had liver cirrhosis. In this cohort, 38 (38.4%) showed a complete and 61 (61.6%) an incomplete biochemical remission at study entry. The HRQL was significantly higher in patients with a complete as compared to an incomplete biochemical remission (CLDQ overall score: 5.66 ± 1.15 vs. 5.10 ± 1.35; p = 0.03). In contrast, the generic EQ-5D-5L UI-value was not different between the groups. Multivariable analysis identified AST (p = 0.02) and an incomplete biochemical remission (p = 0.04) as independent predictors of reduced HRQL (CLDQ total value). CONCLUSION: Patients with a complete biochemical remission had a significantly higher HRQL. Liver-related quality of life in patients living with AIH is dependent on the response to immunosuppressive treatment.

Inflammatory Bowel Disease as a Precondition for Stroke or TIA: A Matter of Crohn's Disease Rather than Ulcerative Colitis.

BACKGROUND: As a chronic systemic inflammation may be associated with an increased risk of vascular events, the aim of the present study was to assess the incidence of stroke and transient ischemic attack (TIA) in patients with inflammatory bowel disease over a period of 15 years. METHODS: This cohort study included patients for whom the initial diagnosis of an inflammatory bowel disease (IBD) (Crohn's disease: CD and ulcerative colitis: UC) was documented anonymously between 2000 and 2015 in 1,262 general practices in Germany. IBD patients were matched to patients without IBD using propensity scores based on age, sex, physician, co-diagnoses and co-therapies. Cox regression models were used to study the incidence of stroke and TIA as a function of CD and UC. RESULTS: Each of the matched groups included 11,947 participants. In the IBD group, 43.5% had CD and 56.5% UC respectively. Higher incidences of both stroke and TIA were detected for IBD (stroke: 279.0 versus 222.6 cases per 100,000 patient years, HR 1.30, p=0.011; TIA: 203.1 versus 141.1 cases per 100,000 patient years, HR 1.42, p=0.006). Stroke and TIA incidences (cases per 100,000 patient years) were higher than in controls (stroke: 314.7 versus 204.5, HR: 1.50, p=0.013; TIA: 183.8 versus 95.3, HR: 1.93, p=0.004) in CD patients only. No relevant differences in incidences were found for patients with UC. CONCLUSION: While CD turned out to be a relevant precondition for stroke or TIA, this was not the case for UC.