Liver Research最新文献

Alcohol-related liver disease (ALD) became an important health issue worldwide. Following chronic alcohol consumption, the development of ALD might be caused by metabolic and immunologic factors, such as reactive oxygen species (ROS) and pro-inflammatory cytokines. For example, hepatic cytochrome P450 2E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure. In addition, damage- and pathogen-associated molecular patterns stimulate their specific receptors in non-parenchymal cells, including Kupffer cells, hepatic stellate cells (HSCs), and lymphocytes, which result in hepatocyte death and infiltration of pro-inflammatory cells (e.g., neutrophils and macrophages) in the liver. Moreover, our studies have suggested the novel involvement of neurologic signaling pathways (e.g., endocannabinoid and glutamate) through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis. Additionally, agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis. Furthermore, organ-crosstalk has emerged as a critical issue in ALD. Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut, leading to endotoxin leakage into the portal circulation, or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver. In summary, this review addresses multiple pathogeneses of ALD, provides novel neurologic signaling pathways, and emphasizes the importance of organ-crosstalk in the development of ALD.

Acute liver failure (ALF) is a medical emergency due to massive hepatocyte loss. In such a harsh condition, maintaining transcriptional regulation in the remaining hepatocytes while activating similar transcription factor networks in liver progenitor cells (LPCs) to ensure essential liver functions are two critical processes to rescue patients from liver failure and death. In this review, we discuss the formation and functions of transcription networks in ALF and liver development. We focus on a hierarchical network of transcription factors that responds to different pathophysiological circumstances: (1) Under normal circumstances, pioneer factor forkhead box protein A2 (FOXA2) coordinates several constitutive hepatic transcription factors, such as hepatic nuclear factor 4 alpha (HNF4α) and CCAAT-enhancer binding protein α (C/EBPα), which ensure normal liver function; (2) When the expression of both HNF4α and C/EBPα in hepatocytes are disrupted by severe inflammation, retinoic acid receptor (RAR) is the alternative transcription factor that compensates for their absence; (3) When massive hepatic necrosis occurs, a similar transcription network including FOXA2 and HNF4α, is activated as a “rescue network” in LPCs to maintain vital liver functions when hepatocytes fail, and thus ensures survival. Expression of these master transcription factors in hepatocytes and LPCs is tightly regulated by hormone signals and inflammation. The performance of this hierarchical transcription network, in particularly the “rescue network” described above, significantly affects the clinical outcome of ALF.

Background and aims

There is currently no single model for predicting Wilson's disease (WD). We aimed to create a nomogram using daily clinical parameters to improve the accuracy of WD diagnosis in patients with abnormal liver function.

Methods

Between July 2016 and December 2020, we identified 90 WD patients with abnormal liver function who had homozygous or compound heterozygous mutations in the ATP7B gene. The control group included 128 patients with similar liver function but no WD during the same time period. To create a nomogram, we screened potential predictive variables using the least absolute shrinkage and selection operator model and multivariate logistic regression.

Results

We developed a nomogram for screening for WD based on six predictive factors: serum copper, direct bilirubin, uric acid, cholinesterase, prealbumin, and reticulocyte percentage. In the training cohort, the area under curve (AUC) of the nomogram reached 0.967 (95% confidence interval (CI) 0.946–0.988), while the area under the precision-recall curve was 0.961. Based on the optimal cutpoint of 213.55, our nomogram performed well, with a sensitivity of 96% and a specificity of 87%. In the validation cohort, the AUC of the nomogram was as high as 0.991 (95% CI 0.970–1.000).

Conclusions

We developed a nomogram that can predict the risk of WD prior to the detection of serum ceruloplasmin or urinary copper, greatly increasing screening efficiency for patients with abnormal liver function.

In many affluent nations, acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. The process of APAP-induced liver injury (AILI) is intimately tied to inflammation, including hepatocyte necrosis-caused initiation of inflammation, inflammation amplification that exacerbates liver injury, and the resolution of inflammation that triggers liver regeneration and repair. Excessive APAP metabolism in the liver eventually leads to hepatocyte necrosis and inflammation. Innate immune cells, such as neutrophils, eosinophils, monocytes, and gammadelta T cells, are recruited into the injured liver and release various cytokines. These immune cells and cytokines have been found to serve two purposes in AILI. In this review, we highlighted the dual role of inflammation, including inflammatory cytokines and inflammatory immune cells in AILI, and discussed possible explanations for contradictory findings.

Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.

Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome, which plays an important role in energy and nutrient balance, and protein or organelle quality control. The liver is the most important organ for metabolism. Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions, and the impairment of autophagy has been closely linked to various liver diseases. Therefore, a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy. In this review, we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, viral hepatitis, hepatocellular carcinoma, and acetaminophen-induced liver injury.

Background and aim

Advanced liver fibrosis is a major risk for developing hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) patients. Direct-acting antivirals (DAAs) which are used for treating HCV infection, produce more than 90% cure rate but do not seem to diminish the rate of occurrence or recurrence of HCC. This study aimed to investigate the effect of DAAs sofosbuvir (SOF) and daclatasvir (DAC) on carbon tetrachloride (CCl₄)-induced fibrotic changes in mice.

Methods

Eighty adult male Swiss albino mice were randomly allocated into 8 groups (10 mice/group): normal control group, SOF group (receiving SOF 80 mg/kg body weight (BW), oral gavage, daily), DAC group (receiving DAC 30 mg/kg BW, oral gavage, daily), SOF + DAC group (receiving a combination of both, daily), CCl4 model group (receiving CCl₄ 2 mL/kg BW, intraperitoneal twice weekly) and three CCl₄-intoxicated groups receiving either SOF or DAC or their combination. All CCl₄ groups received CCl₄ for 12 weeks followed by DAAs for another 12 weeks.

Results

CCl₄-induced a significant elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and produced histopathological evidence of fibrosis and liver degeneration along with a significant increase (P ≤ 0.001) of the proliferation markers (proliferating cell nuclear antigen (PCNA) and Ki-67), hepatic stellate cells (HSCs) activation markers (alpha-smooth muscle actin (α-SMA) and glial fibrillary acidic protein (GFAP)), fibrosis marker (matrix metalloproteinase-9 (MMP-9)) and pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-α)). CCl₄-intoxicated mice treated with SOF, DAC, or their combination revealed a significant amelioration (P ≤ 0.001) of CCl₄-induced elevation of liver enzymes, fibrotic changes, and liver degeneration along with a significant attenuation (P ≤ 0.001) of CCl₄-induced upregulation of all tested markers. The effects of SOF, DAC, and their combination on liver enzymes were comparable while the effect of SOF + DAC combination on mitigating CCl₄-induced upregulation of the proliferation and HSCs activation markers was significantly stronger than either SOF or DAC alone. As for MMP-9 and TNF-α, the effects of DAC and SOF + DAC combination were comparable and both were more significant than that of SOF alone.

Conclusions

SOF and DAC may possess an antifibrotic effect that is independent of their role as antiviral agents against CCl₄-induced liver injury. This might exclude the role of DAAs in early occurrence or accelerated recurrence of HCC through the progression of the HCV patients' pre-existing fibrosis. However, HCC patients treated with DAAs should be closely monitored with continuous HCC surveillance during and post-therapy.

Background

Biliary atresia is a rare congenital bile duct disease that is the leading cause of liver fibrosis in neonates. Granulocyte colony-stimulating factor (GCSF) is a potential therapy for hepatocellular diseases, but data on GCSF for cholestatic conditions remain limited.

Materials and methods

The current study examines the role of GCSF in improving bile duct obstruction in mice. Two doses were administered: 10.0 μg/kg/day and 61.5 μg/kg/day, which is the animal equivalent dose of 5.0 μg/kg in humans. Seven days (D7) after bile duct ligation (BDL), Swiss mice were treated with phosphate buffered saline or GCSF for 5 days. The intrahepatic adaptive response of BDL mice was evaluated on postsurgical days D12, D19, and D26.

Results

Treatment with 61.5 μg/kg of GCSF resulted in a significant increase in circulating leukocytes and neutrophils on D12. Amelioration of liver injury, as shown by reduced aspartate aminotransferase levels, increased albumin levels and survival rate, as well as reduced intrahepatic inflammation and hepatic myeloperoxidase expression, downregulated ductular proliferation, periportal fibroblast activation, and fibrosis, enhanced expressions of hepatocyte growth factor, peroxisome proliferator-activated receptor-alpha, and ki67, and suppressed expression of cleaved caspase-3 protein, was noted after treatment with 61.5 μg/kg of GCSF. Additionally, GCSF treatment was associated with an increased number of intrahepatic cd3^-Sca1⁺c-Kit⁺ bone marrow cells.

Conclusions

Treatment with 61.5 μg/kg of GCSF resulted in liver regeneration and survival in BDL mice was seen, suggesting its potential use for human liver diseases.

Alcohol-related liver disease (ALD) encompasses a spectrum of diseases caused by excessive alcohol consumption. ALD includes hepatic steatosis, steatohepatitis, variable degrees of fibrosis, cirrhosis, and alcohol-associated hepatitis (AH), the latter being the most severe acute form of the disease. Severe AH is associated with high mortality (reaching up to 30%–50%) at 90 days. The cornerstone of ALD, and particularly AH, treatment continues to be abstinence, accompanied by support measures such as nutritional supplementation and management of alcohol withdrawal syndrome (AWS). In severe AH with model for end-stage liver disease (MELD) score ≥21, corticosteroids can be used, especially MELD score between 25 and 39, where the highest benefit is achieved. Other key aspects of treatment include the early identification of infections and their associated management and the proper identification of potential candidates for liver transplantation. The development of new therapies based on the pathophysiology and mechanisms of liver injury are underway. This includes the modulation and management of the innate immune response, gut dysbiosis, bacterial translocation, and bacteria-derived products from the intestine. These hold promise for the future of AH treatment.