Hepatology Communications最新文献

Background: Hepcidin, a peptide hormone primarily produced by the liver, regulates iron metabolism by interacting with its receptor, ferroportin. Studies have demonstrated that hepcidin participates in the progression of liver fibrosis by regulating HSC activation, but its regulatory effect on hepatocytes remains largely unknown.

Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 wild-type (WT) and hepcidin knockout (Hamp-/-) mice. Liver injury and inflammation were assessed in WT and Hamp-/- mice at 24 and 48 hours following acute CCl4 exposure. In addition, transcriptomic sequencing of primary hepatocytes was performed to compare gene expression profiles between WT and Hamp-/- mice 24 hours after liver injury. The function of the identified molecule Eif2ak3/PERK (protein kinase R(PKR)-like endoplasmic reticulum kinase), was evaluated both in vitro and in vivo.

Results: We found that serum hepcidin significantly increased during the progression of liver fibrosis induced by CCl4 and bile duct ligation. In addition, CCl4-treated Hamp-/- mice developed more severe liver injury, liver fibrosis, and hepatocyte apoptosis, with elevated Bax and decreased Bcl-2 expression, compared to the WT mice. Transcriptomic analysis of primary hepatocytes revealed that PERK was upregulated in Hamp-/- mice after CCl4 treatment, promoting apoptosis by regulating Bax and Bcl-2 expression. Subsequently, we demonstrated that hepcidin prevents hepatocyte apoptosis by inhibiting PERK both in vitro and in vivo.

Conclusions: Hepcidin inhibits hepatocyte apoptosis through suppression of the PERK pathway, highlighting its protective role in liver fibrosis and identifying a potential therapeutic target for the treatment of liver fibrosis.

It is known that thyroid hormone can regulate hepatic metabolic pathways including cholesterol, de novo lipogenesis, fatty acid oxidation, lipophagy, and carbohydrate metabolism. Thyroid hormone action is mediated by the thyroid hormone receptor (THR) isoforms and their coregulators, and THRβ is the main isoform expressed in the liver. Dysregulation of thyroid hormone levels, as seen in hypothyroidism, has been associated with dyslipidemia and metabolic dysfunction-associated fatty liver disease. Given the beneficial effects of thyroid hormone in liver metabolism and the advances illuminating the use of thyroid hormone analogs such as resmetirom as therapeutic agents in the treatment of metabolic dysfunction-associated fatty liver disease, this review aims to further explore the relationship between TH, the liver, and metabolic dysfunction-associated fatty liver disease. Herein, we summarize the current clinical therapies and highlight future areas of research.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are characterized by the destruction of the small bile ducts and the formation of multifocal biliary strictures, respectively, impairing bile flow. This leads to the hepatic accumulation of bile acids, causing liver injury and the risk of progression to cirrhosis and liver failure. First-line therapy for PBC is ursodeoxycholic acid, although up to 40% of treated individuals are incomplete responders, and there is no effective therapy for PSC, highlighting the need for better therapeutic options in these diseases. In addition, pruritus is a common symptom of cholestasis that has severe consequences for quality of life and is often undertreated or untreated. Nuclear receptors are pharmacological targets to treat cholestasis due to their multifactorial regulation of hepatic enzymatic pathways, particularly in bile acid metabolism. The peroxisome proliferator-activated receptor (PPAR) is of significant clinical interest due to its role in regulating bile acid synthesis and detoxification pathways. PPAR agonism by fibrates has traditionally been explored due to PPARα's expression in the liver; however, recent interest has expanded to focus on newer PPAR agonists that activate other PPAR isoforms, for example, δ, γ, alone or in combination. Several PPAR agonists have been investigated as second-line therapy for people living with PBC, including the recent accelerated United States Food and Drug Administration approval of elafibranor and seladelpar. This review evaluates available data on the efficacy and safety of the five PPAR agonists investigated for the treatment of cholestasis and associated pruritus in PBC and PSC, namely fenofibrate, bezafibrate, saroglitazar, elafibranor, and seladelpar.

Background: Children with autoimmune liver disease (AILD) may develop fibrosis-related complications necessitating a liver transplant. We hypothesize that tissue-based analysis of liver fibrosis by second harmonic generation (SHG) microscopy with artificial intelligence analysis can yield prognostic biomarkers in AILD.

Methods: Patients from single-center studies with unstained slides from clinically obtained liver biopsies at AILD diagnosis were identified. Baseline demographics and liver biochemistries at diagnosis and 1 year were collected. Clinical endpoints studied included the presence of varices, variceal bleeding, ascites, HE, and liver transplant. In collaboration with HistoIndex, unstained slides underwent SHG/artificial intelligence analysis to map fibrosis according to 10 quantitative fibrosis parameters based on tissue location, including total, periportal, perisinusoidal, and pericentral area and length of strings.

Results: Sixty-three patients with AIH (51%), primary sclerosing cholangitis (30%), or autoimmune sclerosing cholangitis (19%) at a median of 14 years old (range: 3-24) were included. An unsupervised analysis of quantitative fibrosis parameters representing total and portal fibrosis identified a patient cluster with more primary sclerosing cholangitis/autoimmune sclerosing cholangitis. This group had more fibrosis at diagnosis by METAVIR classification of histopathological review of biopsies (2.5 vs. 2; p = 0.006). This quantitative fibrosis pattern also predicted abnormal 12-month ALT with an OR of 3.6 (1.3-10, p = 0.014), liver complications with an HR of 3.2 (1.3-7.9, p = 0.01), and liver transplantation with an HR of 20.1 (3-135.7, p = 0.002).

Conclusions: The application of SHG/artificial intelligence algorithms in pediatric-onset AILD provides improved insight into liver histopathology through fibrosis mapping. SHG allows objective identification of patients with biliary tract involvement, which may be associated with a higher risk for refractory disease.

Background: Patients with cirrhosis have an increased risk of postoperative mortality, which is partially attributable to portal hypertension. Preoperative TIPS placement may reduce operative risk. Studies suggesting the benefits of preoperative TIPS are limited by residual confounding and lack of longitudinal laboratory data. To address these limitations, we used granular longitudinal data from the Veterans Health Administration.

Methods: This retrospective cohort study of Veterans Health Administration patients with cirrhosis who underwent major surgery from 2008 to 2022 identified patients who underwent TIPS placement within 6 months before surgery. Demographics, comorbidities, surgery type, and longitudinal laboratory data were incorporated into a propensity score using 5:1 caliper matching for receipt of TIPS. The propensity-matched cohort included 39 patients with preoperative TIPS and 171 without.

Results: Baseline characteristics were similar between groups. In Cox regression, recent TIPS was associated with an increased risk of postoperative mortality (HR: 2.69, 95% CI: 1.37-5.30, p = 0.004), redemonstrated in 500 random resampling events (median HR: 1.71). TIPS and non-TIPS patients had similar albumin, bilirubin, and international normalized ratio 6 months before surgery; however, immediately before surgery, TIPS patients had lower albumin (p = 0.009), higher bilirubin (p = 0.001), and higher international normalized ratio (p = 0.001).

Conclusions: In a propensity-matched analysis of patients with cirrhosis undergoing major surgery, recent TIPS was associated with increased postoperative mortality and worsened liver synthetic function in the immediate preoperative period. TIPS placement should be carefully considered in patients with cirrhosis who may undergo surgery.

Background: Reliable, noninvasive tools to diagnose at-risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high-risk patients with MASH (NAFLD activity score >4 and fibrosis score >2).

Methods: In this 3-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease, we first developed a multi-protein predictor for discriminating NAFLD activity score >4 based on SOMAscan proteomics quantifying 1305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N = 168) and enhanced by adding clinical variables to create the 9-feature MASH Dx score, which predicted MASH and also high-risk MASH (F2+). The MASH Dx score was validated in 2 independent, external cohorts from Germany (N = 139) and Brazil (N = 177).

Results: The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of 4 proteins (THBS2, GDF15, SELE, and IGFBP7) was verified by ELISA in the expanded discovery and independently in the 2 external cohorts. MASH Dx score incorporated these proteins with established MASH risk factors (age, body mass index, ALT, diabetes, and hypertension) to achieve good discrimination between MASH and metabolic dysfunction-associated steatotic fatty liver disease without MASH (AUC: 0.87-discovery; 0.83-pooled external validation cohorts), with similar performance when evaluating high-risk MASH F2-4 (vs. MASH F0-1 and metabolic dysfunction-associated steatotic fatty liver disease without MASH).

Conclusions: The MASH Dx score offers the first reliable noninvasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high-risk MASH in patient cohorts from the United States, Brazil, and Europe.

Background: An increasing number of HCC develops in the context of metabolic dysfunction-associated steatotic liver disease and its inflammatory form, metabolic dysfunction-associated steatohepatitis, even in the absence of cirrhosis. Chronic metabolic inflammation is the driving force of metabolic dysfunction-associated steatotic liver disease progression and a key factor in hepatocarcinogenesis. Given the prominent role of IL-1 signaling in inflammation and metabolic diseases, we investigated the relevance of the hepatocyte-specific IL-1 receptor type 1 knockout in metabolic dysfunction-associated steatohepatitis-related noncirrhotic HCC.

Methods: For HCC induction, Il1r1Hep-/- mice received a single i.p. injection of diethylnitrosamine at 2 weeks and were fed with high-fat plus high-carbohydrate diet, starting from 4 weeks. After 18 weeks of diet intervention, mice were sacrificed, and macroscopic and microscopic tumor loads were assessed.

Results: Knockout of the hepatic IL-1 receptor type 1 pathway significantly reduced liver tumor growth. Il1r1Hep-/- mice were also less susceptible to hepatic steatosis, insulin resistance, and associated hepatic c-Jun N-terminal kinase activation than their wild-type (WT) littermates. Reduced Ki-67 and cyclin D1 levels, as well as decreased phosphorylation of signal transducer and activator of transcription 3, occur in Il1r1Hep-/- livers, lowering cancer cell proliferation and growth. Additionally, in Il1r1Hep-/- livers, the chemokine (C-X-C motif) ligand 1/2-driven accumulation of myeloid-derived suppressor cells and CD8+ T-cell infiltration were reduced compared to the wild type.

Conclusions: Metabolic inflammation mediated by the hepatocytic IL-1 receptor type 1 is a cofactor in mutagenic hepatocarcinogenesis. Targeting IL-1 signaling could be an adjunct strategy to the current immunomodulatory HCC treatments.

Background: Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints.

Methods: We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7).

Results: We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF.

Conclusions: Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure.

Background: Metabolic-associated steatohepatitis (MASH) is one of the most prevalent liver diseases worldwide, with a global prevalence estimated between 3% and 5%, posing a significant health burden. Human liver organoids (HLOs) have previously been generated to model steatohepatitis, offering a potential cellular disease model for studying MASH. However, the current HLO model lacks detailed molecular characterizations and requires further improvement.

Methods: HLOs derived from human pluripotent stem cells were treated with oleic acid and TGFβ to mimic the MASH progression. Treated HLOs were then analyzed using both bulk and single-cell RNA sequencing. Functional characterization was performed through staining with BODIPY, TMRM, CellROX, and Collagen I, as well as terminal deoxynucleotidyl transferase dUTP nick end labeling and ELISA assays. In addition, a test using the MASH HLO model to validate the hepatoprotective effects of several herb extracts was also conducted.

Results: Both RNA-seq and single-cell RNA sequencing demonstrated a close resemblance of multiple molecular signatures and key intercellular communications in and between hepatocyte-like cells and stellate-like cells in the MASH HLO model, compared to human MASH. Furthermore, functional characterizations revealed progressive features of human MASH in the MASH HLO model, including severe steatosis, oxidative stress, mitochondrial dysfunction, inflammation, and fibrosis. In addition, the Schisandra extracts have been demonstrated to have significant antioxidative, anti-inflammatory, and antifibrotic properties in the context of MASH.

Conclusions: This study offers an improved HLO disease model of human MASH, which can be potentially applied to facilitate the understanding of the MASH pathogenesis and the discovery of effective treatments.