TY  - JOUR
AB  - BACKGROUND AND AIMS: While low plasma butyrylcholinesterase (BChE) is a well-established marker of reduced liver synthesis capacity, the clinical significance of elevated BChE is unclear. In small studies, high BChE has long been suspected in hepatic steatosis and metabolic syndrome. We aimed to clarify the relation between BChE, liver fat and glucose metabolism in deeply phenotyped cohorts. METHODS: Plasma BChE activity was measured in 844 humans (554 women) of the cross-sectional Tübingen Diabetes Family Study, with a wide BMI range (17.7-55.1 kg/m2). It was furthermore measured before and after two independent lifestyle intervention studies in 215 and 116 participants. Liver fat was quantified with 1H-MR-spectroscopy, and metabolism was assessed by oral glucose tolerance tests. RESULTS: BChE was positively associated with liver fat, independent of sex, age and BMI. BChE was higher in participants with metabolic syndrome. BChE was positively associated with fasting and 2-h glycaemia, independent of sex, age and BMI. BChE was negatively associated with insulin sensitivity, independent of sex, age, BMI and liver fat. The reduction of liver fat and improvement in insulin sensitivity during lifestyle interventions are associated with the reduction in BChE, independent of body weight loss. CONCLUSIONS: Higher plasma BChE activity is linked to liver fat accumulation, as well as impaired glucose tolerance and insulin resistance, independent of liver fat. This suggests that BChE could be a marker for processes in hepatocytes that contribute to impaired glucose metabolism. Further investigations are needed to clarify the mechanistic contribution and potential diagnostic value of elevated BChE in hepatic steatosis and metabolic diseases.
AU  - Heni, M.
AU  - Hummel, J.*
AU  - Fritsche, L.
AU  - Wagner, R.
AU  - Relker, L.*
AU  - Machann, J.
AU  - Schick, F.
AU  - Birkenfeld, A.L.
AU  - Schleicher, E.
AU  - Königsrainer, A.*
AU  - Häring, H.-U.
AU  - Stefan, N.
AU  - Fritsche, A.
AU  - Peter, A.
C1  - 74138
C2  - 57337
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Elevated cholinesterase activity and the metabolic syndrome-dissecting fatty liver, insulin resistance and dysglycaemia.
JO  - Liver Int.
VL  - 45
IS  - 5
PB  - Wiley
PY  - 2025
SN  - 1478-3223
ER  - 

TY  - JOUR
AU  - Heni, M.*
AU  - Hummel, J.*
AU  - Fritsche, A.
AU  - Peter, A.
C1  - 74815
C2  - 57608
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Response to Xu and Gao: Robustness of butyrylcholinesterase associations with liver fat and insulin sensitivity.
JO  - Liver Int.
VL  - 45
IS  - 6
PB  - Wiley
PY  - 2025
SN  - 1478-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND AND AIMS: Hepatic immune cell analysis is critical for understanding chronic inflammatory liver diseases, such as primary sclerosing cholangitis (PSC) and steatotic liver disease. However, liver immunoprofiling is limited due to reliance on end-stage disease liver explants. Fine needle aspiration (FNA) is a minimally invasive technique that can overcome these limitations. We evaluate the safety and efficacy of liver FNA to profile hepatic immune subsets in non-infectious liver conditions. METHODS: Flow cytometry and single-cell RNA sequencing (scRNA-seq) were used to compare the hepatic immune cell composition and gene expression to that of matched peripheral blood mononuclear cells (PBMCs). RESULTS: We obtained liver FNAs from 38 patients. The median pain score was 0. No serious adverse effects were reported. Flow cytometry demonstrated enrichment of CD69+ T and natural killer (NK) cells in the liver (all Padj < 0.05). ScRNA-seq of 38 012 hepatic immune cells and 78 751 PBMCs in a patient subset showed specific enrichment of CXCR6+ NK, CD8+ central memory T, and mucosal-associated invariant T (MAIT) cells in the liver, and relatively lower CD4+ regulatory T cell (Treg) abundance (all Padj < 0.05). Gene expression and cell-cell interaction analyses revealed increases in cytokine production, signalling, and responsiveness in hepatic immune cells compared to PBMCs. CONCLUSIONS: FNA sampling is a safe approach for investigating the inflammatory landscape of PSC and other liver diseases. Single-cell profiling reveals that FNAs capture tissue-specific immune cell types and gene expression differences, suggesting this sampling method may provide a basis for future experimental medicine analyses.
AU  - Lynch, K.D.*
AU  - Curion, F.
AU  - Yeung, H.Y.*
AU  - Rich-Griffin, C.*
AU  - Agarwal, D.*
AU  - Ferry, H.*
AU  - Slater, A.J.*
AU  - Culver, E.L.*
AU  - Chapman, R.W.*
AU  - Keshav, S.*
AU  - Klenerman, P.*
AU  - Dendrou, C.A.*
C1  - 75821
C2  - 58101
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Navigating the hepatic immune landscape with fine needle aspiration of the liver-an emerging technique.
JO  - Liver Int.
VL  - 45
IS  - 11
PB  - Wiley
PY  - 2025
SN  - 1478-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND/AIMS: There is uncertainty regarding the hepatic efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH). We performed a meta-analysis of randomised controlled trials (RCTs) to examine the efficacy of GLP-1RAs in treating MASLD or MASH. METHODS: We systematically searched three electronic databases from inception until April 2025 to identify RCTs examining the efficacy of GLP-1RAs for the treatment of MASLD or MASH. The outcome measures included MASH resolution without worsening of fibrosis or improvement in at least one stage of fibrosis without worsening of MASH, along with reductions in liver fat content measured using magnetic resonance-based techniques. Meta-analysis was conducted using random-effects models. RESULTS: We identified 13 phase 2 or phase 3 RCTs (1811 participants). These trials diagnosed MASLD or MASH through liver biopsy (n = 4) or magnetic resonance-based techniques (n = 9). Regardless of diabetes status, among individuals with MASH and moderate-to-advanced fibrosis, GLP-1RAs (especially semaglutide 2.4 mg/week) for up to 72 weeks were superior to placebo in achieving MASH resolution (n = 3 RCTs; pooled random-effects odds ratio 3.48, 95% CI 2.69-4.51; I2 = 0%), and in improving liver fibrosis (pooled odds ratio 1.79, 95% CI 1.37-2.35; I2 = 0%). Among individuals with MASH-related compensated cirrhosis (n = 1 RCT available only), semaglutide did not lead to MASH resolution or improved fibrosis compared to placebo. Furthermore, GLP-1RAs reduced magnetic resonance-measured liver fat content (n = 9; pooled mean difference: -4.50%, 95% CI -6.60 to -2.40%; I2 = 95.9%). CONCLUSIONS: GLP-1RAs are a promising treatment option for MASLD or MASH. Further research is needed to evaluate the long-term effects of GLP-1RAs on liver-related clinical events.
AU  - Mantovani, A.*
AU  - Morandin, R.*
AU  - Fiorio, V.*
AU  - Lando, M.G.*
AU  - Stefan, N.
AU  - Tilg, H.*
AU  - Byrne, C.D.*
AU  - Targher, G.*
C1  - 75265
C2  - 57897
TI  - Glucagon-like peptide-1 receptor agonists improve MASH and liver fibrosis: A meta-analysis of randomised controlled trials.
JO  - Liver Int.
VL  - 45
IS  - 9
PY  - 2025
SN  - 1478-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND AND AIMS: Since described in 2015, NBAS-associated disease has emerged as an important cause of acute liver failure (ALF) in children. We analysed the variable expression, genotype-phenotype association, outcome and prognostic factors of the hepatic involvement. METHODS: Individuals with biallelic pathogenic NBAS variants were recruited within an international observational study, including new and previously published patients. RESULTS: We studied 230 individuals, including 13 previously unreported patients. The liver was the most frequently affected organ (63.4%), with 41.3% experiencing at least one ALF. The median age at onset was 0.9 years, the median age at last ALF 5 years, the latest ALF occurred at 24 years. Liver crises were triggered by febrile infections and presented with highly increased hepatic transaminases. Liver involvement varied significantly between the subgroups: 91.7% of patients with infantile liver failure syndrome type 2 and 88.9% of patients from the combined subgroup (variants affecting β-propeller domain) presented with ALF, whereas SOPH (stature, optic atrophy, Pelger-Huët anomaly) patients mostly had either no liver involvement (66.4%) or persistently elevated transaminases without ALF (28%). The rate of native liver survival was 83.9%; 16 individuals underwent liver transplantation and 24 died. CONCLUSION: Liver abnormalities are common and the leading cause of death in NBAS-associated disease. There is a clear genotype-phenotype association regarding the hepatic involvement. Liver crises occur primarily during infancy; however, early medical attention in case of febrile infections is necessary at all ages. Liver transplantation prevents ALF, but its risks must be weighed against the frequency and severity of liver crises decreasing with age.
AU  - Peters, B.*
AU  - Schlieben, L.D.
AU  - Brennenstuhl, H.*
AU  - Arikan, C.*
AU  - Bedoyan, S.M.*
AU  - Bulut, F.D.*
AU  - Crushell, E.*
AU  - Dionisi-Vici, C.*
AU  - Drab, A.*
AU  - Fichtner, A.*
AU  - Garcia, A.G.*
AU  - Fry, D.*
AU  - Garbade, S.F.*
AU  - Hammann, N.*
AU  - Hadzic, N.*
AU  - Hegarty, R.*
AU  - Jørgensen, M.H.*
AU  - Laaß, M.*
AU  - Lainka, E.*
AU  - Leghlam, L.*
AU  - Lurz, E.*
AU  - Mungan, H.N.*
AU  - Pietrobattista, A.*
AU  - Polo, B.*
AU  - Socha, P.*
AU  - Squires, J.E.*
AU  - Sun, T.*
AU  - Vogel, G.F.*
AU  - Prokisch, H.
AU  - Kölker, S.*
AU  - Hoffmann, G.F.*
AU  - Staufner, C.*
AU  - Lenz, D.*
C1  - 74814
C2  - 57611
TI  - Hepatic phenotype in NBAS-associated disease: Clinical course, prognostic factors and outcome in 230 patients.
JO  - Liver Int.
VL  - 45
IS  - 7
PY  - 2025
SN  - 1478-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND AND AIMS: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. METHODS: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. RESULTS: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. CONCLUSION: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.
AU  - Schaefer, B.*
AU  - Pammer, L.M.*
AU  - Pfeifer, B.*
AU  - Neururer, S.*
AU  - Troppmair, M.R.*
AU  - Panzer, M.*
AU  - Wagner, S.*
AU  - Pertler, E.*
AU  - Gieger, C.
AU  - Kronenberg, F.*
AU  - Lamina, C.*
AU  - Tilg, H.*
AU  - Zoller, H.*
C1  - 69872
C2  - 55220
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 838-847
TI  - Penetrance, cancer incidence and survival in HFE haemochromatosis-A population-based cohort study.
JO  - Liver Int.
VL  - 44
IS  - 3
PB  - Wiley
PY  - 2024
SN  - 1478-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a major disease burden in the population. While the bidirectional association between NAFLD and diabetes is established, little is known about the association of hepatic iron content and glycaemia. Moreover, analyses of sex-specific effects and of dynamic changes in glycaemia are scarce. METHODS: We investigated 7-year sex-specific trajectories of glycaemia and related traits (HbA1c, fasting glucose, fasting insulin, HOMA-IR, 2-h glucose and cross-sectional 2-h insulin) in a sample from a population-based cohort (N = 365; 41.1% female). Hepatic iron and fat content were assessed by 3T-Magnetic Resonance Imaging (MRI). Two-step multi-level models adjusted for glucose-lowering medication and confounders were applied. RESULTS: In women and men, markers of glucose metabolism correlated with hepatic iron and fat content. Deterioration of glycaemia was associated with increased hepatic iron content in men (normoglycaemia to prediabetes: beta = 2.21 s-1 , 95% CI [0.47, 3.95]). Additionally, deterioration of glycaemia (e.g. prediabetes to diabetes: 1.27 log(%), [0.84, 1.70]) and trajectories of glucose, insulin and HOMA-IR were significantly associated with hepatic fat content in men. Similarly, deterioration of glycaemia as well as trajectories of glucose, insulin and HOMA-IR was significantly associated with increased hepatic fat content in women (e.g. trajectory of fasting insulin: 0.63 log(%), [0.36, 0.90]). CONCLUSIONS: Unfavourable 7-year trajectories of markers of glucose metabolism are associated with increased hepatic fat content, particularly in women, whereas the association with hepatic iron content was less clear. Monitoring changes of glycaemia in the sub-diabetic range might enable early identification of hepatic iron overload and steatosis.
AU  - Niedermayer, F.
AU  - Su, Y.
AU  - von Krüchten, R.*
AU  - Thorand, B.
AU  - Peters, A.
AU  - Rathmann, W.*
AU  - Roden, M.*
AU  - Schlett, C.L.*
AU  - Bamberg, F.*
AU  - Nattenmüller, J.*
AU  - Rospleszcz, S.
C1  - 67855
C2  - 54333
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 2153-2166
TI  - Trajectories of glycaemic traits exhibit sex-specific associations with hepatic iron and fat content: Results from the KORA-MRI study.
JO  - Liver Int.
VL  - 43
IS  - 10
PB  - Wiley
PY  - 2023
SN  - 1478-3223
ER  - 

TY  - JOUR
AB  - BACKGROUND AND AIMS: In the CENTRAL trial context, we found diverse liver fat dynamics in response to different dietary interventions. Epigenetic mechanisms may contribute to the intraindividual variation. Moreover, genetic factors are involved in developing non-alcoholic fatty-liver disease (NAFLD), a disease reflected by an increase in intrahepatic fat (IHF). In this exploratory analysis, we primarily aimed to examine the effect of lifestyle interventions on NAFLD's DNA-methylation-related genes associated with IHF. METHODS: For 120 participants from the CENTRAL trial, an 18-month regimen of either low-fat (LF) or Mediterranean-low carbohydrate (MED/LC) diets, with or without physical activity (PA+/PA-), was instructed. Magnetic-Resonance-Imaging was used to measure IHF%, which was analyzed for association with CpG specific DNA-methylation levels of 41 selected candidate genes. Single-nucleotide polymorphisms known to be associated with NAFLD within the studied genes were genotyped by TaqMan assays. RESULTS: At baseline, participants (92% men;body-mass-index=30.2kg/m2 ) had mean IHF of 10.7% (59% NAFLD). Baseline-IHF% was inversely correlated with DNA-methylation at individual CpGs within AC074286.1, CRACR2A, A2MP1, FARP1 (p<0.05 for all multivariate models). FARP1 rs9584805 showed association with IHF, with the prevalence of NAFLD and baseline methylation level of the CpG site (cg00071727) associated with IHF%. Following 18-month lifestyle intervention, differential DNA-methylation patterns were observed between diets at cg14335324 annotated to A2MP1 (p=0.04, LF vs. MED/LC), and differential DNA-methylation between PA groups within AC074286.1, CRACR2A, and FARP1 CpGs (p<0.05 for all, PA- vs. PA+). CONCLUSIONS: This study suggests epigenetic markers for IHF and potential epigenetic remodeling after long-term lifestyle interventions.
AU  - Yaskolka Meir, A.*
AU  - Keller, M.
AU  - Müller, L.*
AU  - Bernhart, S.H.*
AU  - Tsaban, G.*
AU  - Zelicha, H.*
AU  - Rinott, E.*
AU  - Kaplan, A.*
AU  - Gepner, Y.*
AU  - Shelef, I.*
AU  - Schwarzfuchs, D.*
AU  - Ceglarek, U.*
AU  - Blüher, M.
AU  - Stumvoll, M.
AU  - Kovacs, P.*
AU  - Shai, I.*
C1  - 61953
C2  - 50532
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 2101-2111
TI  - Effects of lifestyle interventions on epigenetic signatures of liver fat: CENTRAL randomized controlled trial.
JO  - Liver Int.
VL  - 41
IS  - 9
PB  - Wiley
PY  - 2021
SN  - 1478-3223
ER  - 

TY  - JOUR
AB  - Background and aims Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent and nutrition intervention remains the most important therapeutic approach for NAFLD. Our aim was to investigate whether low- (LP) or high-protein (HP) diets are more effective in reducing liver fat and reversing NAFLD and which mechanisms are involved. Methods 19 participants with morbid obesity undergoing bariatric surgery were randomized into two hypocaloric (1500-1600 kcal/day) diet groups, a low protein (10E% protein) and a high protein (30E% protein), for three weeks prior to surgery. Intrahepatic lipid levels (IHL) and serum fibroblast growth factor 21 (FGF21) were measured before and after the dietary intervention. Autophagy flux, histology, mitochondrial activity and gene expression analyses were performed in liver samples collected during surgery. Results IHL levels decreased by 42.6% in the HP group, but were not significantly changed in the LP group despite similar weight loss. Hepatic autophagy flux and serum FGF21 increased by 66.7% and 42.2%, respectively, after 3 weeks in the LP group only. Expression levels of fat uptake and lipid biosynthesis genes were lower in the HP group compared with those in the LP group. RNA-seq analysis revealed lower activity of inflammatory pathways upon HP diet. Hepatic mitochondrial activity and expression of beta-oxidation genes did not increase in the HP group. Conclusions HP diet more effectively reduces hepatic fat than LP diet despite of lower autophagy and FGF21. Our data suggest that liver fat reduction upon HP diets result primarily from suppression of fat uptake and lipid biosynthesis.
AU  - Xu, C.*
AU  - Markova, M.*
AU  - Seebeck, N.*
AU  - Loft, A.
AU  - Hornemann, S.*
AU  - Gantert, T.*
AU  - Kabisch, S.*
AU  - Herz, K.*
AU  - Loske, J.*
AU  - Ost, M.*
AU  - Coleman, V.*
AU  - Klauschen, F.*
AU  - Rosenthal, A.*
AU  - Lange, V.*
AU  - Machann, J.
AU  - Klaus, S.*
AU  - Herzig, S.
AU  - Pivovarova-Ramich, O.*
AU  - Pfeiffer, A.F.H.*
C1  - 59642
C2  - 48972
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 2982-2997
TI  - High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels.
JO  - Liver Int.
VL  - 40
IS  - 12
PB  - Wiley
PY  - 2020
SN  - 1478-3223
ER  - 

TY  - JOUR
AB  - Background & Aims: MicroRNAs are important genetic regulators of physiological and pathophysiological processes including cancer initiation and progression of hepatoblastoma, the most common liver tumour in childhood. We aimed to identify malignant and metastasis promoting effects of miR-492, a miRNA, previously reported to be overexpressed in metastatic hepatoblastoma. Furthermore, we intended to evaluate its diagnostic and prognostic potential. Methods: Stable and transient overexpression of miR-492 in two liver tumour cell lines HepT1 and HUH7 was used to analyse features of metastatic tumour progression such as proliferation, anchorage-independent growth, migration and invasion. Via a mass spectrometry based proteomic screen, we investigated miRNA-492-dependent effects on proteome level and explored the underlying biology. One of the predicted target genes, CD44, was experimentally validated via luciferase assays. Diagnostic and prognostic properties of miR-492 were studied in hepatoblastoma tumour samples. Results: We show that miR-492 significantly enhances cell proliferation, anchorage-independent growth, migration and invasion of hepatoblastoma cells. We also identified and validated CD44, a transmembrane adhesion receptor for hyaluronan, as direct and functional target of miR-492. This miRNA has a strong direct impact on two CD44 isoforms (standard and v10). High miR-492 expression correlates with high-risk or aggressive tumours and further bears potential for predicting reduced event-free survival. Conclusions: We identified miR-492 and its target CD44 as regulators of a number of biological features important for malignancy and metastasis. Furthermore, we demonstrated the diagnostic and prognostic potential of miR-492, a promising novel therapeutic target and biomarker for hepatoblastoma.
AU  - von Frowein, J.*
AU  - Hauck, S.M.
AU  - Kappler, R.*
AU  - Pagel, P.*
AU  - Fleischmann, K.K.*
AU  - Magg, T.*
AU  - Cairo, S.*
AU  - Roscher, A.*
AU  - von Schweinitz, D.*
AU  - Schmid, I.*
C1  - 52700
C2  - 44233
SP  - 1280-1291
TI  - MiR-492 regulates metastatic properties of hepatoblastoma via CD44.
JO  - Liver Int.
VL  - 38
IS  - 7
PY  - 2018
SN  - 1478-3223
ER  -