1876-P: Impact of Diabetes on Liver Disease Progression in Patients with Advanced Fibrosis Due to Nonalcoholic Steatohepatitis (NASH)

AbstractThe inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case–control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.

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Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13040730 ◽

2021 ◽

Vol 13 (4) ◽

pp. 730

Author(s):

Moritz Peiseler ◽

Frank Tacke

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Disease Progression ◽

Immune Cells ◽

Nonalcoholic Steatohepatitis ◽

Adaptive Immune System ◽

Nonalcoholic Fatty Liver ◽

Inflammatory Processes ◽

New Treatment ◽

End Stage

Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC.

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Impact of genotype 3 on clinical outcome in patients with hepatitis C: both diabetes meliitus and liver disease progression

Journal of Hepatology ◽

10.1016/s0168-8278(17)31905-0 ◽

2017 ◽

Vol 66 (1) ◽

pp. S711-S712

Author(s):

W. Zanjir ◽

R. Maan ◽

B. Hansen ◽

O. Cerocchi ◽

H. Janssen ◽

...

Keyword(s):

Liver Disease ◽

Hepatitis C ◽

Clinical Outcome ◽

Disease Progression ◽

Genotype 3 ◽

Liver Disease Progression

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Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

Communications Biology ◽

10.1038/s42003-021-02413-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Lixiang Wang ◽

Xin Li ◽

Yuki Hanada ◽

Nao Hasuzawa ◽

Yoshinori Moriyama ◽

...

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Er Stress ◽

Disease Progression ◽

Acute Liver Injury ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Mitochondrial Fusion ◽

Related Protein ◽

Liver Disease Progression

AbstractMitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

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