Sub-optimal therapy of patients with primary biliary cholangitis (PBC) in the real-life stetting of the German PBC cohort.

Real-world data on the management of patients with primary biliary cholangitis (PBC) are so far scarce in Germany. Therefore, we aimed to establish a nationwide registry and describe the clinical characteristics and therapy of PBC patients.Three different cohorts defined as ursodeoxycholic acid (UDCA) responders, as inadequate responders according to Paris II criteria, and as newly diagnosed patients were prospectively recruited.This manuscript includes the baseline data of the project.In total, 33/77 (43%) contacted centres (58% of university hospitals, 38% of non-university hospitals, and 24% of private practices) recruited 515 patients including 204 UDCA responders, 221 inadequate responders to UDCA, and 90 newly diagnosed patients.All patients were treated with UDCA; however, a UDCA dosage below the recommended dosage of 13 mg/kg/d was observed in 38.5% of individuals after 12 months of treatment. UDCA dosages were lower in nonacademic compared to academic centres.Only 75/219 (38.5%) of inadequate responders to UDCA received a second-line therapy with obeticholic acid (OCA) and/or bezafibrate (BZF). OCA (13% vs. 4.5%) and BZF (14% vs. 6.5%) were significantly more often prescribed by academic vs. nonacademic centres.Pruritus (27% vs. 15.5%), fatigue (23% vs. 4.5%), and sicca syndrome (14% vs. 1%) were significantly more often reported by academic centres.The German PBC registry could be established, which indicates suboptimal therapy in a relevant proportion of patients and shows significant differences between academic and nonacademic centres. Results are fundamental to improving clinical management at different levels of care.

Successful hepatitis B and C screening in the health check-up in the German primary care setting.

Background & Aims: A goal of the World Health Organization's global hepatitis strategy is the elimination of chronic hepatitis C virus (HCV) infection by 2030. As part of its strategy, the Federal Joint Committee (Germany) decided to include hepatitis B and C screening in a preventive medical examination, which is performed at the primary care level in Germany. We investigated the results 1 year after implementation of screening between October 2021 and September 2022. Methods: HBsAg/HBV DNA and anti-HCV/HCV RNA screenings were identified by billing categories in 286,192 individuals of 11 ambulatory healthcare centers. Results: Compared to 30,106 HBsAg and 31,266 anti-HCV laboratory requisitions in the year 2018, the number of tests increased to 286,192 during the screening period. Compared to routine care, additional anti-HCV positive tests age dependently increased the tally by 98% (177 plus 170 positive cases in males) and 123% (96 plus 118 positive cases in females) in those aged 35-44 years up to 518% (17 plus 88 positive cases in males) and 514% (29 plus 149 positive cases in females) in those aged 75-84 years. Similar results were observed for HBsAg. Prevalences of HBsAg, anti-HCV and HCV RNA were 0.54%, 0.79% and 0.13%, respectively. Conclusions: A structured hepatitis screening program at the primary care level has been successfully established and leads to age- and-sex-dependent large additional effects compared to routine care. Impact and implications: Strategies to eliminate chronic hepatitis B and C virus infection are country specific and vary between clinical scenarios. Our analysis proves the efficacy of a screening program by primary care physicians compared to routine care in a low-prevalence country. This program should be accompanied by additional efforts in risk populations like people who inject drugs who are under-represented in the current screening approach.

Thy-1 restricts steatosis and liver fibrosis in steatotic liver disease.

BACKGROUND AND AIMS: Steatotic liver disease (SLD) is generally considered to represent a hepatic manifestation of metabolic syndrome and includes a disease spectrum comprising isolated steatosis, metabolic dysfunction-associated steatohepatitis, liver fibrosis and ultimately cirrhosis. A better understanding of the detailed underlying pathogenic mechanisms of this transition is crucial for the design of new and efficient therapeutic interventions. Thymocyte differentiation antigen (Thy-1, also known as CD90) expression on fibroblasts controls central functions relevant to fibrogenesis, including proliferation, apoptosis, cytokine responsiveness, and myofibroblast differentiation. METHODS: The impact of Thy-1 on the development of SLD and progression to fibrosis was investigated in high-fat diet (HFD)-induced SLD wild-type and Thy-1-deficient mice. In addition, the serum soluble Thy-1 (sThy-1) concentration was analysed in patients with metabolic dysfunction-associated SLD stratified according to steatosis, inflammation, or liver fibrosis using noninvasive markers. RESULTS: We demonstrated that Thy-1 attenuates the development of fatty liver and the expression of profibrogenic genes in the livers of HFD-induced SLD mice. Mechanistically, Thy-1 directly inhibits the profibrotic activation of nonparenchymal liver cells. In addition, Thy-1 prevents palmitic acid-mediated amplification of the inflammatory response of myeloid cells, which might indirectly contribute to the pronounced development of liver fibrosis in Thy-1-deficient mice. Serum analysis of patients with metabolically associated steatotic liver disease syndrome revealed that sThy-1 expression is correlated with liver fibrosis status, as assessed by liver stiffness, the Fib4 score, and the NAFLD fibrosis score. CONCLUSION: Our data strongly suggest that Thy-1 may function as a fibrosis-protective factor in mouse and human SLD.

Ultrasound-guided percutaneous biopsy for focal liver lesions: Adverse events and diagnostic yield in a single-centre analysis.

PURPOSE: Ultrasound-guided biopsy of focal liver lesions (FLL) is a well-established procedure with crucial impact on therapeutic decisions. The safety and accuracy depend on needle type, tumour location and comorbidities. Modern oncological concepts often require large tumour specimens which may increase the procedural risk. MATERIALS AND METHODS: We retrospectively collected data from consecutively scheduled ultrasound-guided FLL biopsies performed in an interdisciplinary ultrasound unit at a university hospital from 2015-2020. We analysed complication rates, diagnostic accuracy, and patient outcome in a one-year period. RESULTS: Of 426 scheduled interventions, 339 were included: 322 primary biopsies (40% female, median age 65 years, median BMI 25.4 kg/m2) and 17 rebiopsies in cases with undetermined diagnosis. Indications comprised 309 (96%) cases with suspected malignant lesions. Important comorbidities were type 2 diabetes (n = 107, 33%) and cirrhosis (n = 64, 20%). A conclusive histopathological diagnosis was achieved in 270 (84%) cases with a weak association with lesion size (OR 1.12 per cm, 95%CI 0.99-1.27). Greater BMI (OR 0.60 per 10 BMI points, 95%CI 0.34-1.05) showed a trend towards an insufficient diagnosis. Relevant complications occurred in 8 (2.5%) cases (2 major; 1 life-threatening). Multiple passes showed a trend towards adverse events (OR 2.32 for > 1 pass, 95%CI 0.99-5.42). 93 (29%) patients died during a median follow-up of 171 days. CONCLUSION: Ultrasound-guided FLL biopsy is an efficient and safe diagnostic measure. The limitations of the procedure and its associated risks should be considered in patients with advanced malignancies.

Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis-A real-world case series.

BACKGROUND AND AIMS: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis. APPROACH AND RESULTS: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9-17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12). CONCLUSIONS: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis.

Relevance of GLP-1 receptor agonists or SGLT-2 inhibitors on the recruitment for clinical studies in patients with NAFLD.

INTRODUCTION: Guidelines increasingly recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) to prevent cardiovascular and cardiorenal endpoints. Both drugs also show beneficial effects in nonalcoholic fatty liver disease (NAFLD). Preexisting GLP-1 RA and SGLT2i therapies are frequently defined as exclusion criterion in clinical studies to avoid confounding effects. We therefore investigated how this might limit recruitment and design of NAFLD studies. METHODS: GLP-1 RA and SGLT2i prescriptions were analyzed in NAFLD patients with diabetes mellitus recruited at a tertiary referral center and from the population-based LIFE-Adult-Study. Individuals were stratified according to noninvasive parameters of liver fibrosis based on vibration-controlled transient elastography (VCTE). RESULTS: 97 individuals were recruited at tertiary care and 473 from the LIFE-Adult-Study. VCTE was available in 97/97 and 147/473 cases.GLP-1 RA or SGLT2i were used in 11.9% of the population-based cohort (LSM < 8 kPa), but in 32.0% with LSM ≥ 8 kPa. In the tertiary clinic, it was 30.9% overall, independent of LSM, and 36.8% in patients with medium and high risk for fibrotic NASH (FAST score > 0.35). At baseline, 3.1% of the patients in tertiary care were taking GLP-1 RA and 4.1% SGLT2i. Four years later, the numbers had increased to 15.5% and 21.6%. CONCLUSION: GLP-1 RA and SGLT2i are frequently and increasingly prescribed. In candidates for liver biopsy for NASH studies (VCTE ≥ 8 kPa) the use of them exceeds 30%, which needs careful consideration when designing NASH trials.

Non-invasive assessment of steatohepatitis indicates increased risk of coronary artery disease.

INTRODUCTION: Fatty liver diseases (FLD), especially defined as metabolic dysfunction-associated FLD (MAFLD), is of growing importance for patients and health-care providers. Extrahepatic comorbidities, predominantly coronary artery disease (CAD), contribute to excess morbidity and mortality in FLD. Although the association of FLD and CAD is well known, underlying pathophysiological links are not fully understood. Non-invasive means of liver diagnostic enable a fast and thorough characterization of FLD. We therefore assessed the severity of FLD in a cohort of patients at risk of CAD. METHODS: Patients scheduled for coronary angiography were characterized by anthropometry, serum-based indices of liver fibrosis (NFS, FIB4), abdominal ultrasound and vibration controlled transient elastography (VCTE) including controlled attenuation parameter (CAP) and the Fibroscan-AST (FAST) score. Patients were stratified according to indication of therapeutic coronary intervention. RESULTS: 120 patients were recruited, MAFLD was found in 41%, while advanced fibrosis or cirrhosis were present in only 5%. Coronary vascular intervention was indicated in 42% (n = 50). Severity of steatosis assessed by CAP and risk of fibrosis defined by elevated liver stiffness (VCTE>8 kPa) and fibrosis indices were associated with the need for coronary intervention. FAST score, a marker of fibrotic steatohepatitis, was elevated in the intervention group (0.22 vs. 0.12, p<0.001). Multivariate regression analysis revealed FAST score as strongest predictor of CAD (OR 2.3 95%, CI 1.40-2.96). DISCUSSION: MAFLD is a frequent comorbidity in patients at CAD risk, but advanced liver disease has a low prevalence in patients undergoing elective coronary angiography. Therefore, a routine VCTE-based screening for FLD cannot be recommended in cardiac patients. The association of indicators of steatohepatitis with advanced CAD points to inflammatory processes as a conjoint mechanism of both diseases.

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis.

BACKGROUND: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. METHODS: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <-1·455 vs -1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. FINDINGS: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. INTERPRETATION: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. FUNDING: Innovative Medicines Initiative 2.

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

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.

Ocrelizumab-induced colitis and cytomegalovirus infection and their disadvantageous interaction with underlying multiple sclerosis.

Ocrelizumab is a humanized monoclonal antibody against the B-lymphocyte antigen CD20 and the only approved treatment option in primary progressive multiple sclerosis. Herpesvirus-related infections like cytomegalovirus (CMV) infections are common in patients receiving ocrelizumab, whereas gastrointestinal side effects with inflammatory bowel disease (IBD) like esophagitis or colitis are very rare. This case report describes the challenging clinical, endoscopic, and histologic features of an ocrelizumab-induced colitis overlapping with CMV infection and their disadvantageous interaction with the underlying multiple sclerosis.

Confirmation of guideline-defined hepatitis C screening strategies within the 'Check-Up35+' examination in the primary care setting.

BACKGROUND AND AIMS: Screening strategies for undiagnosed infections are fundamental for hepatitis C virus (HCV) elimination. We previously investigated HCV prevalence and screening strategies in an urban primary care setting. IV drug abuse, blood transfusion before 1992, immigration, or elevated ALT were identified as risk factors in a post hoc analysis and diagnosed 83% of unknown HCV-RNA-positive cases by screening only 26% of the population. We aimed to validate prospectively the proposed screening algorithm in two independent urban and rural cohorts and to analyse for potential differences. METHODS: Anti-HCV and ALT were included in a routine check-up together with a questionnaire covering risk factors. HCV-RNA was analysed in anti-HCV-positive individuals. RESULTS: In urban and rural areas, 4323 and 9321 individuals were recruited. The anti-HCV prevalence was 0.56% and 0.49%, and 0.1% of patients were HCV-RNA-positive in both regions. Fifty-two anti-HCV positive patients including eight HCV-RNA-positive cases were unaware of the infection (number needed to screen to detect one unknown anti-HCV-positive individual: 262). At least one of the three aforementioned risk factors or elevated serum ALT was present in 3000 patients (22%). Restricting HCV screening to only those with risk factors, 52% and 75% of all anti-HCV and HCV-RNA-positive undiagnosed patients were identified (number needed to screen: 111). CONCLUSIONS: We confirm prospectively the efficiency of a risk-based HCV screening. The risk-based algorithm should be evaluated in other countries with similarly low HCV prevalence as in Germany to achieve WHO HCV elimination goals.