Due to improved medical care, life expectancy in patients with cystic fibrosis (CF) has veritably improved over the last decades. Importantly, cystic fibrosis related liver disease (CFLD) has become one of the leading causes of morbidity and mortality in CF patients. However, CFLD might be largely underdiagnosed and diagnostic criteria need to be refined. The underlying pathomechanisms are largely unknown, and treatment strategies with proven efficacy are lacking. This review focuses on current invasive and non-invasive diagnostic standards, the current knowledge on the pathophysiology of CFLD, treatment strategies, and possible future developments.

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.

Summary: Background: Aetiological therapy improves liver function and may enable hepatic recompensation in decompensated cirrhosis.Aims: We explored the potential for recompensation in patients with decompensated primary biliary cholangitis (PBC) – considering a biochemical response to ursodeoxycholic acid (UDCA) according to Paris‐II criteria as a surrogate for successful aetiological treatment.Methods: Patients with PBC were retrospectively included at the time of first decompensation. Recompensation was defined as (i) resolution of ascites and hepatic encephalopathy (HE) despite discontinuation of diuretic/HE therapy, (ii) absence of variceal bleeding and (iii) sustained liver function improvement.Results: In total, 42 patients with PBC with decompensated cirrhosis (age: 63.5 [IQR: 51.9–69.2] years; 88.1% female; MELD‐Na: 13.5 [IQR: 11.0–15.0]) were included and followed for 41.9 (IQR: 11.0–70.9) months after decompensation. Seven patients (16.7%) achieved recompensation. Lower MELD‐Na (subdistribution hazard ratio [SHR]: 0.90; p = 0.047), bilirubin (SHR per mg/dL: 0.44; p = 0.005) and alkaline phosphatase (SHR per 10 U/L: 0.67; p = 0.001) at decompensation, as well as variceal bleeding as decompensating event (SHR: 4.37; p = 0.069), were linked to a higher probability of recompensation. Overall, 33 patients were treated with UDCA for ≥1 year and 12 (36%) achieved Paris‐II response criteria. Recompensation occurred in 5/12 (41.7%) and in 2/21 (9.5%) patients with vs. without UDCA response at 1 year, respectively. Recompensation was linked to a numerically improved transplant‐free survival (HR: 0.46; p = 0.335). Nonetheless, 4/7 recompensated patients presented with liver‐related complications after developing hepatic malignancy and/or portal vein thrombosis and 2 eventually died.Conclusions: Patients with PBC and decompensated cirrhosis may achieve hepatic recompensation under UDCA therapy. However, since liver‐related complications still occur after recompensation, patients should remain under close follow‐up.

Background: Primary biliary cholangitis (PBC) may progress to cirrhosis and clinically significant portal hypertension (CSPH). This study assesses different features of CSPH and their distinct prognostic impact regarding decompensation and survival in patients with PBC.Methods: Patients with PBC were identified during a database query of our digital patient reporting system.Results: A total of 333 PBC patients (mean age 54.3 years, 86.8% females, median follow-up 5.8 years) were retrospectively assessed and 127 (38.1%) showed features of CSPH: 63 (18.9%) developed varices, 98 (29.4%) splenomegaly, 62 (18.6%) ascites and 20 (15.7%) experienced acute variceal bleeding. Splenomegaly, portosystemic collaterals and esophageal varices were associated with an increased 5-year (5Y) risk of decompensation (15.0%, 17.8% and 20.9%, respectively). Patients without advanced chronic liver disease (ACLD) had a similar 5Y-transplant free survival (TFS) (96.6%) compared to patients with compensated ACLD (cACLD) but without CSPH (96.9%). On the contrary, PBC patients with cACLD and CSPH (57.4%) or decompensated ACLD (dACLD) (36.4%) had significantly decreased 5Y survival rates. The combination of LSM < 15 kPa and platelets ≥ 150G/L indicated a negligible risk for decompensation (5Y 0.0%) and for mortality (5Y 0.0%). Overall, 44 (13.2%) patients died, with 18 (40.9%) deaths attributed to CSPH-related complications.Conclusion: In PBC, features of CSPH may occur early and indicate an increased risk for subsequent decompensation and mortality. Hence, regular screening and on-time treatment for CSPH is crucial. Combining LSM and platelets serves as a valuable preliminary assessment, as LSM < 15 kPa and platelets ≥ 150G/L indicate an excellent long-term outcome.

Infections with Gram-negative bacteria are still among the leading causes of infection-related deaths. Several studies suggest that the chalcone xanthohumol (XN) found in hop (Humulus lupulus) possesses anti-inflammatory effects. In a single-blinded, placebo controlled randomized cross-over design study we assessed if the oral intake of a single low dose of 0.125 mg of a XN derived through a XN-rich hop extract (75% XN) affects lipopolysaccharide (LPS)-induced immune responses in peripheral blood mononuclear cells (PBMCs) ex vivo in normal weight healthy women (n = 9) (clinicaltrials.gov: NCT04847193) and determined associated molecular mechanisms. LPS-stimulation of PBMCs isolated from participants 1 h after the intake of the placebo for 2 h resulted in a significant induction of pro-inflammatory cytokine release which was significantly attenuated when participants had consumed XN. The XN-dependent attenuation of proinflammatory cytokine release was less pronounced 6 h after the LPS stimulation while the release of sCD14 was significantly reduced at this timepoint. The LPS-dependent activation of hTLR4 transfected HEK293 cells was significantly and dose-dependently suppressed by the XN-rich hop extract which was attenuated when cells were co-challenged with sCD14. Taken together, our results suggest even a one-time intake of low doses of XN consumed in a XN-rich hop extract can suppress LPS-dependent stimulation of PBMCs and that this is related to the interaction of the hop compound with the CD14/TLR4 signaling cascade.

Recent research has linked sphingolipid (SL) metabolism with cystic fibrosis transmembrane conductance regulator (CFTR) activity, affecting bioactive lipid mediator sphingosine-1-phosphate (S1P). We hypothesize that loss of CFTR function in cystic fibrosis (CF) patients influenced plasma S1P levels. Total and unbound plasma S1P levels were measured in 20 lung-transplanted adult CF patients and 20 healthy controls by mass spectrometry and enzyme-linked immunosorbent assay (ELISA). S1P levels were correlated with CFTR genotype, routine laboratory parameters, lung function and pathogen colonization, and clinical symptoms. Compared to controls, CF patients showed lower unbound plasma S1P, whereas total S1P levels did not differ. A positive correlation of total and unbound S1P levels was found in healthy controls, but not in CF patients. Higher unbound S1P levels were measured in ΔF508-homozygous compared to ΔF508-heterozygous CF patients (p = 0.038), accompanied by higher levels of HDL in ΔF508-heterozygous patients. Gastrointestinal symptoms were more common in ΔF508 heterozygotes compared to ΔF508 homozygotes. This is the first clinical study linking plasma S1P levels with CFTR function and clinical presentation in adult CF patients. Given the emerging role of immunonutrition in CF, our study might pave the way for using S1P as a novel biomarker and nutritional target in CF.