DNA methylation of angiotensin Ⅱ receptor gene in nonalcoholic steatohepatitis-related liver fibrosis

AIM To clarify whether Agtr1 a methylation is involved in the development of nonalcoholic steatohepatitis(NASH)-related liver fibrosis in adult rats.METHODS A choline-deficient amino acid(CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis.Agtr1 a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid(CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR.Hepatic stellate cells(HSCs) were isolated by collagenase digestion of the liver,followed by centrifugation of the crude cell suspension through a density gradient.Agtr1 a methylation and its gene expression were also analyzed during the activation of HSCs.RESULTS The mean levels of Agtr1 a methylation in the livers of CDAA-fed rats(11.5% and 18.6% at 8 and 12 wk,respectively) tended to be higher(P = 0.06 and 0.09,respectively) than those in the livers of CSAA-fed rats(2.1% and 5.3% at 8 and 12 wk,respectively).Agtr1 a was not methylated at all in quiescent HSCs,but was clearly methylated in activated HSCs(13.8%,P < 0.01).Interestingly,although Agtr1 a was hypermethylated,the Agtr1 a m RNA level increased up to 2.2-fold(P < 0.05) in activated HSCs compared with that in quiescent HSCs,suggesting that Agtr1 a methylation did not silence its expression but instead had the potential to upregulate its expression.These findings indicate that Agtr1 a methylation and its upregulation of gene expression are associated with the development of NASH-related liver fibrosis.CONCLUSION This is the first study to show that DNA methylation is potential y involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis.

Cholangiocarcinoma developed in a patient with IgG4-related disease

A 77-year-old man with jaundice and a pancreatic head tumor was referred to our hospital in August2006.The initial laboratory tests,computed tomography(CT)scan,magnetic resonance imaging(MRI),and endoscopic retrograde cholangiopancreatography suggested IgG4-related cholangitis and autoimmune pancreatitis.Oral prednisolone(PSL)was then administered.This treatment reduced the size of the pancreatic parenchyma,and the lower common bile duct(CBD)returned to its normal size.Thus,the oral PSL was gradually tapered to a maintenance dose.In February 2010,a CT scan and MRI showed segmental wall thickening and stenosis of the middle CBD,the progression of which led to extrahepatic obstructive jaundice.We suspected the emergence of a cholangiocarcinoma rather than the exacerbation of the IgG4-related sclerosing cholangitis because the stricture of the CBD was short and localized.Then,a percutaneous transhepatic biliary drainage was performed.The biopsy specimens obtained via the percutaneous transhepatic tract indicated an abnormal glandular formation,suggesting the presence of a moderate,well-differencated adenocarcinoma.The gross examination,microscopic examination and immunohistochemical analysis of the pancreaticoduodenectomy specimen suggested that a cholangiocarcinoma developed from the IgG4-related sclerosing cholangitis.

Efficacy and HCC development after DAA therapy for patients with chronic hepatitis C:a single center retrospective cohort study

Aim: The development of hepatocellular carcinoma (HCC) is reduced after interferon based treatment in patients with chronic hepatitis C (CHC). A new therapy using direct-acting antiviral agents (DAA) has been widely applied since 2014 for CHC. The purpose of this study is to investigate the efficacy, safety and development of HCC after DAA treatment. Methods: The authors enrolled 33 consecutive patients who were treated with DAA for CHC at the hospital between January 2015 and March 2016. The laboratory data were collected at the start and 24 weeks after DAA therapy. Results: The authors analyzed 33 patients (18 male, 15 female, mean age of 68-year-old). The hepatic C virus genotypes were type 1 (27 patients) and type 2 (6 patients). The number of patients treated with sofosbuvir (SOF) +ledipasvir, daclatasvir + asunaprevir and SOF + ribavirin was 14, 13 and 6, respectively. The sustained virological response (SVR24) rate was 100%. Aspartate aminotransferase, alanine aminotransferase and FIB4-index were significantly decreased after SVR24. Adverse effects were observed in 9 patients (anemia, 5;liver function test disorder, 2;sarcoidosis, 1;pruritus, 1). With regard to HCC development, one elderly patient (3.0%) had multiple HCC recurrence after SVR24. Conclusion: DAA therapy achieved a high SVR24 rate with a good serological response. However, one patient had multiple HCC recurrence. These findings indicate that careful follow-up may be essential after DAA therapy.