Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma. Interferons (IFNs) are crucial for HCV clearance and a sustained virological response (SVR). There is evidence that an appropriate endogenous IFN response is also required for an efficient final virus clearance by novel directly acting antiviral agents. Understanding the molecular mechanisms of IFN response for the treatment outcome remains therefore important.
In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF.Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-β superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure.These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.
Background & Aim: Submassive hepatic necrosis (SMHN) is the defining histological feature of acute-on-chronic liver failure (ACLF). In the areas of SMHN, liver progenitor cells (LPC) critically contribute to liver regeneration. This study investigated the key events that determine LPC-mediated liver regeneration in ACLF following SMHN.
Die fulminante Hepatitis (FH) und das akute Leberversagen (ALF) stellen ein klinisches Kontinuum einer raschen und schweren Leberfunktionsstörung dar, die einen akuten Symptombeginn, Gerinnungsstörung, hepatische Enzephalopathie, Nierenversagen und eine schlechte Gesamtprognose umfassen kann. Ihr schnelles Fortschreiten und die hohe Mortalität unterstreichen die Wichtigkeit einer möglichst frühen und präzisen Outcome-Vorhersage, vor allem weil die Lebertransplantation noch immer die einzig effektive Therapie darstellt.
Linked Content This article is linked to Bock et al and He et al papers. To view these articles visit https://doi.org/10.1111/apt.13578 and https://doi.org/10.1111/apt.13820 .
Fulminant hepatitis (FH) and acute liver failure (ALF) are the clinical conditions representative of severe liver injury and associated with a significant risk of death. As high urgency liver transplantation may be required, early outcome prediction is essential in these patients. Prognosis scores like the model for end-stage liver disease and the King's College criteria are helpful, but further possibilities to increase accuracy would be of great value.
Chronic viral hepatitis is linked to fibrotic liver injury that can progress to liver cirrhosis with its associated complications. Recent evidence suggests a role of senescence in liver fibrosis, although the senescence regulators contributing to fibrosis progression remain unclear. We therefore investigated the role of senescence for fibrosis progression in patients with chronic viral hepatitis. We found a remarkable up-regulation of the cell-cycle inhibitors p21, p27 and p16 and the senescence markers p-HP1γ and γ-H2AX in liver tissues from patients with chronic viral hepatitis compared to healthy liver tissues. Liver tissues with relevant fibrosis stages (F2 – 3) or cirrhosis (F4) revealed a significant increase of senescent cells compared to livers with no or minimal fibrosis (F0 – 1). In cirrhotic livers, a significantly higher number of p-HP1γ, p21 and p27 positive cells was detected compared to liver tissues with F2 – 3 fibrosis. Importantly, we identified T-cells as the dominant cell type contributing to increased senescence during fibrosis progression. Compared to healthy individuals, senescence-associated chitotriosidase activity was significantly elevated in sera from patients with chronic viral hepatitis and correlated with histological fibrosis stages and liver stiffness as assessed by transient elastography.
Summary Background Chronic viral hepatitis is linked to fibrotic liver injury that can progress to liver cirrhosis with its associated complications. Recent evidence suggests a role of senescence in liver fibrosis, although the senescence regulators contributing to fibrosis progression remain unclear. Aim To investigate the role of senescence and different senescence markers for fibrosis progression in patients with chronic hepatitis C virus ( HCV ) infection. Methods The expression of the cell cycle inhibitors p21, p27 and p16 as well as the senescence markers p‐ HP 1γ and γ‐H2 AX was analysed in liver tissue with different fibrosis stages. Senescence‐associated chitotriosidase activity was measured in sera of HCV patients (n = 61) and age‐matched healthy individuals (n = 22). Results We found a remarkable up‐regulation of the cell cycle inhibitors and senescence markers in chronic HCV infection compared to healthy liver tissue. Liver tissue with relevant fibrosis stages (F2‐3) or cirrhosis (F4) revealed a significant increase in senescent cells compared to livers with no or minimal fibrosis (F0‐1). In cirrhotic livers, a significantly higher number of p‐ HP 1γ, p21 and p27 positive cells was detected compared to liver tissue with F2‐3 fibrosis. Importantly, we identified T‐cells as the dominant cell type contributing to increased senescence during fibrosis progression. Compared to healthy individuals, serum chitotriosidase was significantly elevated and correlated with histological fibrosis stages and liver stiffness as assessed by transient elastography. Conclusions Senescence of hepatic T‐cells is enhanced in chronic viral hepatitis and increases with fibrosis progression. Serological detection of senescence‐associated chitotriosidase might allow for the non‐invasive detection of relevant fibrosis stages.
Aim Acute liver failure (ALF) is a syndrome of severe liver injury that may need urgent liver transplantation and is associated with significant risk of death. Early outcome prediction and further possibilities to increase accuracy of prognosis scores are important. Methods We examined 30 patients with ALF, according to the novel criteria of the Intractable Hepato‐Biliary Diseases Study Group, who underwent transjugular liver biopsy (TJLB) and investigated the relevance of histology for correct diagnosis and etiology. We assessed the suitability of necrosis (%), hepatic venous pressure gradients (HVPG), and hepatocentral venous gradients of serum biomarkers for outcome prediction. For this purpose, we calculated the difference of biomarker levels between hepatic vein (HV) and superior vena cava (SVC) blood samples. Results Histology of TJLB specimens contributed to finding the etiology in 83%. Necrosis (%) and HVPGs were not significantly different between outcome groups. In gradient measurements, caspase 3/7 activity and total cytokeratin 18 (CK‐18) (M65) had significant and relevant levels different from zero. Although they were not accurate for outcome prediction, differences between outcome groups were detected in caspase activation: levels of caspase 3/7 activity in the HV and caspase‐cleaved CK‐18 (M30) in the SVC were significantly higher in spontaneously recovered patients. Conclusions Our results underline the role of caspase activation in spontaneous recovery from ALF. Furthermore, the calculation of hepatocentral venous biomarker gradients could represent a new diagnostic tool whose clinical potential needs to be further investigated.
