Mikkel Parsberg Werge

There are few reliable predictors for reduced pain after biliary sphincterotomy or medical therapy in patients with sphincter of Oddi dysfunction (SOD). We explored whether prolonged intestinal bile excretion time, dilated common bile duct (CBD) diameter, or elevated alanine aminotransferase (ALT) were associated with reduced pain after treatment for SOD. This is a retrospective, single‐centre study. Consecutive patients suspected of SOD were identified and screened. Medical treatment for SOD followed institutional standards in line with the Regional pain medication guidelines. The primary outcome was potential prognostic markers for reduced pain. In the biliary sphincterotomy group ( n = 34), 85% patients experienced reduced pain when evaluated in the outpatient clinic, while 60% of patients receiving medical therapy ( n = 159) experienced reduced pain ( p = 0.009). No association was found between the hepatobiliary scintigraphy excretion time nor ALT and reduced pain in either treatment group. However, a dilated CBD was associated with reduced pain (odds ratio 2.89; 95% CI [1.02;8.17]). In SOD patients, amelioration of pain in both medically and surgically treated patients is primarily associated with common bile duct dilation, rather than hepatobiliary scintigraphy excretion time or ALT.

Background & Aims: Early identification of decompensation in patients with cirrhosis is important to enable timely detection, management of complications and for effective treatment. This study investigates the biology of decompensation and aim to identify protein biomarkers for identification of high-risk patients. Methods: The primary analysis included plasma samples from 46 patients with metabolic dysfunction associated steatotic liver disease (MASLD) related cirrhosis. Plasma samples were depleted for the top 14 most abundant proteins and the proteome was measured by liquid chromatography tandem mass spectrometry. The dataset was divided into a training (14 compensated, 10 decompensated) and a test cohort of compensated patients (11 progressing to decompensation, 11 remaining compensated). Changes in protein levels were determined by ANCOVA and a prognostic model was developed using logistic regression. External validation was performed in an independent cohort of 120 patients with alcohol-related cirrhosis. Time-to-event analyses were conducted in this cohort using Cox regression. Results: 52 proteins involved in impaired hepatic function, fibrogenesis, immune activation, and metabolic changes were significantly different between compensated and decompensated patients. A prognostic model with four proteins (NBL1, LTBP4, APOC4, GHR), demonstrated predictive ability for future decompensation (AUC=0.93, 73% sensitivity, 100% specificity). In the external validation cohort, the model demonstrated generalizability (AUC=0.78, 72% sensitivity, 82% specificity). Validation cohort time-to-event analyses showed that higher baseline scores were associated with shorter time to liver-related events (HR 1.32; log-rank p = 0.027), underscoring the panel’s prognostic value. Conclusion: Our study indicates that patients with decompensated cirrhosis are characterized by proteomic signatures of fibrogenesis and metabolic dysfunction. Capturing these signatures could help identify patients at risk of complications and potentially those eligible for aetiology directed treatment. Impact and Implications: Addressing a critical unmet need for early detection of cirrhosis decompensation, our proteomic study identifies a four-protein panel with predictive ability for decompensation. These findings hold significant implications for hepatologists, clinical researchers, and healthcare systems, offering a novel tool to enhance prognostication and refine treatment strategies, potentially facilitating targeted patient monitoring. However, considering the small discovery sample size and the distinct aetiology of the external validation cohort, further validation is essential before broad clinical integration. Graphical

Aim: Increased growth differentiation factor 15 (GDF15) may reflect impaired metabolic health and an inflammatory state in metabolic dysfunction‐associated steatotic liver disease (MASLD). We investigated the role of GDF15 in histologically verified MASLD in a meal test (discovery) cohort (n = 20) and a prospective (validation) cohort with 2 years of follow‐up (n = 276).Methods: Participants were evaluated clinically and histologically in both cohorts. Fibrosis severity was classified as no/mild (F0/F1) or significant (F2–4). Plasma GDF15 was measured by enzyme‐linked immunosorbent assays and the SOMAScan platform. Hepatic GDF15 mRNA expression was analyzed by RNA in situ hybridization and bulk RNA‐sequencing. In addition, we used data from public single‐nucleus RNA‐sequencing datasets.Results: In both cohorts, plasma GDF15 was increased in MASLD compared with healthy controls (p < 0.0001) with the highest levels in patients with significant fibrosis (area under the curve 0.83; 95% confidence interval [CI], 0.76–0.91). The GDF15 levels were unaffected by a standardized meal and there was no difference in peripheral or hepatic venous concentrations. After 2 years, the increase in GDF15 levels was reduced in patients treated with glucagon‐like peptide receptor agonists (GLP‐1‐RA) compared to patients receiving lifestyle advice (−28%; 95% CI, −44 to −8; p = 0.01). Plasma GDF15 was associated with circulating insulin‐like growth factor 1 and related proteins. Hepatic GDF15 mRNA was mainly expressed in hepatocytes and in cholangiocytes in fibrotic areas and was increased in MASLD (p = 0.02) with the highest expression in the group with steatohepatitis (p = 0.009).Conclusions: Increased hepatic and circulating GDF15 are found in MASLD. Treatment with GLP‐1‐RA may reduce GDF15, possibly reflecting beneficial metabolic and inflammatory effects.

Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone-morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1+ myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.

Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

Background and aims: Pancreatic walled-off necrosis (WON) carries significant mortality and morbidity risks, often necessitating intensive care unit (ICU) admission. This retrospective study aimed to evaluate whether routine biochemical parameters at the time of the index endoscopic procedure could predict ICU admission and 1-year mortality following endoscopic treatment of WON. Materials and Methods: We retrospectively identified 201 consecutive patients who underwent endoscopic drainage for WON between January 1, 2010, and December 31, 2020. Associations between routine biochemical blood tests and outcomes were assessed using logistic regression models. Results: Within 1 year of the index endoscopy, 31 patients (15.4%) died, and 40 (19.9%) were admitted to the ICU due to sepsis. Preoperative electrolyte disturbances were more prevalent among ICU-admitted patients and nonsurvivors. Hyperkalemia, hypoalbuminemia, and elevated urea were significant predictors of 1-year mortality, while hypernatremia, elevated serum creatinine, and hypoalbuminemia predicted ICU admission. Predictive models exhibited good discriminative ability, with an AUC of 0.84 (95% CI,0,75–0.93) for 1-year mortality and 0.86 (95%CI, 0.79–0.92) for ICU admission. Conclusions: Preoperative imbalances in routine blood tests effectively predict adverse outcomes in endoscopically treated WON patients.

Chronic pancreatitis (CP) is the end-stage of continuous inflammation and fibrosis in the pancreas evolving from acute- to recurrent acute-, early, and, finally, end-stage CP. Currently, prevention is the only way to reduce disease burden. In this setting, early detection is of great importance. Due to the anatomy and risks associated with direct sampling from pancreatic tissue, most of our information on the human pancreas arises from circulating biomarkers thought to be involved in pancreatic pathophysiology or injury. The present review provides the status of circulating biomarkers involved in the development of and progression to CP.

Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone-morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1 ⁺ myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.

Introduction: Abdominal ultrasound (US) and CT are important tools for the initial evaluation of patients with liver disease. Our study aimed to determine the accuracy of these methods for diagnosing cirrhosis. Methods: In all, 377 participants from 4 prospective cohort studies evaluating patients with various liver diseases were included. All patients were included between 2017 and 2022 and had undergone a liver biopsy as well as US and/or CT. Using the histological assessment as the gold standard, we calculated diagnostic accuracy for US and CT. Liver biopsies were evaluated by expert histopathologists and diagnostic scans by experienced radiologists. Results: The mean age was 54 ± 14 years and 47% were female. Most patients had NAFLD (58.3%) or alcohol-associated liver disease (25.5%). The liver biopsy showed cirrhosis in 147 patients (39.0%). Eighty-three patients with cirrhosis had Child-Pugh A (56.4% of patients with cirrhosis) and 64 had Child-Pugh B/C (43.6%). Overall, the sensitivity for diagnosing cirrhosis by US was 0.71 (95% CI 0.62–0.79) and for CT 0.74 (95% CI 0.64–0.83). The specificity was high for US (0.94, 95% CI 0.90–0.97) and for CT (0.93, 95% CI 0.83–0.98). When evaluating patients with Child-Pugh A cirrhosis, sensitivity was only 0.62 (95% CI 0.49–0.74) for US and 0.60 (95% CI 0.43–0.75) for CT. For patients with Child-Pugh B/C, sensitivity was 0.83 (95% CI 0.70–0.92) for US and 0.87 (95% CI 0.74–0.95) for CT. When limiting our analysis to NAFLD (20% with cirrhosis), the sensitivity for US was 0.45 (95% CI 0.28–0.64) and specificity was 0.97 (95% CI 0.93–0.99). Conclusion: US and CT show moderate sensitivity and may potentially overlook compensated cirrhosis underlining the need for additional diagnostic testing. Export