Liver International最新文献

Background and aims: Ultrasound imaging and shear wave elastography (SWE) can be used to noninvasively stage hepatopathologies and are widespread in clinical practice. These techniques have recently been adapted for small animal use in a novel 3D in vivo imaging system capable of high-throughput automated scanning. Our goal was to evaluate the feasibility of using this imaging tool in the murine Western diet (WD) model, a highly translatable preclinical model of obesity, metabolic disease and liver fibrosis.

Methods: Female C57BL/6 mice (N = 48) were placed on WD or chow diet and imaged longitudinally for a period of 48 weeks. Imaging consisted of 3D B-mode and targeted SWE captures. Liver volume, liver echogenicity and liver stiffness were quantified from in vivo imaging data. A subset of mice was sacrificed at various timepoints (0, 12, 24 and 48 weeks) for histological workup. Correlation analysis was performed between in vivo imaging and histological measurements to determine level of agreement.

Results: Noninvasive imaging showed statistically significant increases in liver volume and echogenicity, but non-significant increase in liver stiffness in the WD-fed cohort, suggesting development of hepatomegaly and steatosis, but negligible fibrosis. Ex vivo analysis confirmed significant increases in liver weight, liver triglycerides and ALT, but limited increases in fibrosis corroborating noninvasive imaging results. Correlation analysis between imaging and histology demonstrated good agreement between liver volume/liver weight (R² = 0.85) and echogenicity/triglycerides (R² = 0.76).

Conclusions: This study demonstrated that noninvasive ultrasound liver assessments are feasible in the WD mouse model and closely reflect the underlying pathological state of the animal. Automated ultrasound can serve as a high-throughput noninvasive screening method for preclinical liver disease research and drug development.

Aims: Drug-induced liver injury (DILI) is a major global health concern resulting from adverse reactions to medications, supplements or herbal medicines. The relevance of DILI has grown with an aging population, the rising prevalence of chronic diseases and the increased use of biologics, including checkpoint inhibitors. This article aims to summarise current knowledge on DILI epidemiology and risk factors.

Methods: This review critically appraises available evidence on DILI frequency, outcomes and risk determinants, focusing on drug properties and non-genetic host factors that may influence susceptibility.

Results: DILI incidence varies across populations, with hospitalised patients experiencing notably higher rates than outpatients or the general population. Increased medication use, particularly among older adults and women, may partly explain age- and sex-based disparities in DILI incidence and reporting. Physiological changes associated with aging likely increase susceptibility to DILI in older adults, though further exposure-based studies are needed for definitive conclusions. Current evidence does not strongly support that women are inherently more susceptible to DILI than men; rather, susceptibility appears to depend on specific drugs. However, once DILI occurs, older age and female sex are associated with greater severity and poorer outcomes. Other less-studied host-related risk factors are also discussed based on available evidence.

Conclusions: This article summarises existing data on DILI frequency, outcomes, drug properties affecting hepatotoxicity and non-genetic host risk factors while identifying critical knowledge gaps. Addressing these gaps through future research could enhance understanding and support preventive measures.

Background and aims: Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS.

Methods and results: In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.

Background and aims: Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty.

Methods: We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP-1/GIP concentrations and MASLD and its related traits. Next, we conducted drug-target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD-related traits.

Results: Circulating 2-h GLP-1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (OR_GLP-1 = 0.168 [95% CI 0.033-0.839], p = 0.030; OR_GIP = 0.331 [95% CI 0.222-0.494], p = 6.31 × 10^-8). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531-0.849], p = 9.07 × 10^-4). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD-related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index.

Conclusions: GLP-1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement.

Background and aims: NOD2 mutations are associated with impaired gut mucosal barrier function. According to the systemic inflammation hypothesis, bacterial translocation is central in the development of decompensation. The aim was to evaluate whether the presence of NOD2 variants is associated with the development of first decompensation.

Method: Secondary analysis of prospectively collected consecutive patients with compensated cirrhosis, who were screened between 2014 and 2018. Patients with and without NOD2 variants were compared and stratified analysis according to the presence of varices was performed.

Results: 360 patients [239 (66%) men, median age 61 (53-69) years, 70 (19%) with NOD2 variants, 90 (25%) with varices] were followed for a median of 9 (4-16) months. Similar baseline characteristics were observed across NOD2 status groups, except for beta-blocker use (45% vs. 32% amongst variant carriers vs. non-carriers, p = 0.05). During follow-up, 34 patients (12%) developed their first decompensation, with no differences according to NOD2 status [HR 1.75 (95% CI 0.84-3.67)]. On multivariate analysis, only MELD remained an independent predictor of decompensation. Amongst patients with varices (n = 90), 18 (24.4%) carried a NOD2 variants, with a higher incidence of first decompensation [HR 3.00 (95% CI 1.08-8.32)], primarily due to ascites [HR 3.32 (95% CI 1.07-10.32)]. In this subgroup, MELD [HR 1.18 (95% CI 1.06-1.32)] and NOD2 variants [HR 2.91 (95% CI 0.95-8.89)] were determined to be independent predictors of decompensation.

Conclusions: The presence of NOD2 risk variants leads to a greater incidence of first decompensation only in compensated patients with varices.

Quek JWE, Loo JH, Jaroenlapnopparat A, et al. Prophylactic antibiotics in patients with alcohol-associated hepatitis receiving steroids: A systematic review and meta-analysis. Liver Int. 2024;44(9):2469-2476. doi:10.1111/liv.16014

In the article by Quek et al. [1], an error appeared in Table 1 where the included studies were wrongly referenced. The revised Table 1 with the correct references is shown here:

We apologize for the error.

REFERENCES

1. Quek JWE, Loo JH, Jaroenlapnopparat A, et al. Prophylactic antibiotics in patients with alcohol-associated hepatitis receiving steroids: a systematic review and meta-analysis. Liver Int. 2024;44(9):2469-2476. doi:10.1111/liv.16014

34. Louvet A, Labreuche J, Dao T, et al. Effect of prophylactic antibiotics on mortality in severe alcohol-related hepatitis: a randomized clinical trial. JAMA. 2023;329(18):1558-1566. doi:10.1001/jama.2023.4902

36. Kimer N, Meldgaard M, Hamberg O, et al. The impact of rifaximin on inflammation and metabolism in alcoholic hepatitis: a randomized clinical trial. PLoS ONE. 2022;17(3):e0264278. doi:10.1371/journal.pone.0264278

33. Kulkarni AV, Tirumalle S, Premkumar M, et al. Primary norfloxacin prophylaxis for APASL-defined acute-on-chronic liver failure: a placebo-controlled double-blind randomized trial. Am J Gastroenterol. 2022;117(4):607-616. doi:10.14309/ajg.0000000000001611

37. Jiménez C, Ventura-Cots M, Sala M, et al. Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis: a pilot study (RIFA-AH). Liver Int. 2022;42(5):1109-1120. doi:10.1111/liv.15207

22. Støy S, Laursen TL, Eriksen LL, Grønbæk H, Vilstrup H, Sandahl TD. No effect in alcoholic hepatitis of gut-selective, broad-spectrum antibiotics on bacterial translocation or hepatic and systemic inflammation. Clin Transl Gastroenterol. 2021;12(2):e00306. doi:10.14309/ctg.0000000000000306

38. Popescu A, Voiculescu M. Improved survival in patients with advanced alcoholic hepatitis (AAH) with a combined treatment associating a non-absorbable antibiotic rifaximin to corticoids plus ursodeoxycholic acid (UDCA). J Hepatol. 2009;50:S369. doi:10.1016/S0168-8278(09)61022-9

Background and aims: Severe alcohol-associated hepatitis (SAH) is associated with high short-term mortality, and failure of response to corticosteroids is associated with a mortality of ~70%-80% within 6 months. Granulocyte colony-stimulating factor (G-CSF) has been studied in steroid non-responders; however, the data are limited.

Methods: This is a multicentre retrospective cohort study. The study period was from January 2016 to November 2023. SAH was defined as alcohol-associated hepatitis (ICD-10-CM codes) with serum bilirubin ≥ 5.0 mg/dL and INR ≥ 1.5. Other aetiologies of acute hepatitis and biliary obstruction were excluded. The primary outcome was 90-day median overall survival in SAH patients treated with G-CSF compared with standard medical therapy (SMT) or corticosteroids. Propensity score (1:1) matching was performed to control confounding variables.

Results: Among 20 132 patients with SAH, 10800 (53.65%) were treated with corticosteroids and 224 (1.11%) G-CSF. The G-CSF group was younger (45.5 vs. 48.4) White (79.91% vs. 72.40%); however, there was no age or gender difference between G-CSF and corticosteroid groups. Whites and patients with more comorbidities received G-CSF more frequently than SMT or corticosteroids. After propensity score matching, 90-day overall survival was better in patients who received G-CSF (88.31% vs. 62.36%, p < 0.01) compared with SMT or corticosteroids (88.31% vs. 74.39%, p < 0.01). Patients on G-CSF had better 6-month transplant-free survival compared with SMT (83.53% vs. 55.36%, p < 0.001) or corticosteroids (82.89% vs. 60.21%, p < 0.001). Gastrointestinal bleeding was less common in G-CSF group compared with corticosteroids (5.02% vs. 10.50%, p < 0.001).

Conclusions: A small minority of patients with severe alcohol-associated hepatitis receive G-CSF. G-CSF improves 90-day overall survival in patients with severe alcohol-associated hepatitis and is non-inferior to corticosteroids.

Minder, A. E., L. G. Kluijver, J. Barman-Aksözen, E. I. Minder, and J. G. Langendonk. "Erythropoietic Protoporphyrias: Pathogenesis, Diagnosis and Management." Liver Int (Jul 16 2024).

Figures 1 to 4 were uploaded and published in poor quality. New images were uploaded to improve the figures.

We apologize for this error.