Atsuyuki Ikeda

Leptin Receptor Somatic Mutations Are Frequent in HCV-Infected Cirrhotic Liver and Associated With Hepatocellular Carcinoma

BACKGROUND & AIMS Hepatocellular carcinoma develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of development of hepatocellular carcinoma in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in nontumor cirrhotic liver. METHODS We determined the whole exome sequences of 7 tumors and background cirrhotic liver tissues from 4 patients with HCV infection. We then performed additional sequencing of selected exomes of mutated genes, identified by whole exome sequencing, and of representative tumor-related genes on samples from 22 cirrhotic livers with HCV infection. We performed in vitro and in vivo functional studies for one of the mutated genes. RESULTS Whole exome sequencing showed that somatic mutations accumulated in various genes in HCV-infected cirrhotic liver tissues. Among the identified genes, the leptin receptor gene (LEPR) was one of the most frequently mutated in tumor and nontumor cirrhotic liver tissue. Selected exome sequencing analyses detected LEPR mutations in 12 of 22 (54.5%) nontumorous cirrhotic livers. In vitro, 4 of 7 (57.1%) LEPR mutations found in cirrhotic livers reduced phosphorylation of STAT3 to inactivate LEPR-mediated signaling. Moreover, 40% of Lepr-deficient (C57BL/KsJ-db/db) mice developed liver tumors after administration of thioacetamide compared with none of the control mice. CONCLUSIONS Based on analysis of liver tissue samples from patients, somatic mutations accumulate in LEPR in cirrhotic liver with chronic HCV infection. These mutations could disrupt LEPR signaling and increase susceptibility to hepatocarcinogenesis.

Visualization of blood drainage area from hypervascular hepatocellular carcinoma on ultrasonographic images during hepatic arteriogram: Comparison with depiction of drainage area on contrast‐enhanced ultrasound

Aim:  Corona enhancement is the visualized drainage area from a hypervascular tumor observed on single‐level dynamic computed tomography during hepatic arteriography (CTHA) and is thought to be a high‐risk area for micrometastases. However, because it cannot be visualized with ordinary ultrasonography (US), we aimed to visualize corona enhancement on US by means of arterial injection of the contrast material and to measure its thickness.

Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis.

Chronic inflammation triggers the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), and contributes to tumorigenesis through the accumulation of genetic aberrations. To gain further insight into the inflammation-mediated genotoxic events required for carcinogenesis, we examined the role of chronic inflammation in the emergence of genetic aberrations in the liver with constitutive AID expression. Treatment with thioacetamide (TAA) at low-dose concentrations caused minimal hepatic inflammation in both wild-type (WT) and AID transgenic (Tg) mice. None of the WT mice with low-dose TAA administration or AID Tg mice without hepatic inflammation developed cancers in their liver tissues over the 6 month study period. In contrast, all the AID Tg mice with TAA treatment developed multiple macroscopic hepatocellular carcinomas during the same observation period. Whole exome sequencing and additional deep-sequencing analyses revealed the enhanced accumulation of somatic mutations in various genes, including dual specificity phosphatase 6 (Dusp6), early growth response 1 (Egr1) and inhibitor of DNA binding 2 (Id2), which are putative tumor suppressors, in AID-expressing liver with TAA-mediated hepatic inflammation. Microarray and quantitative reverse transcription-polymerase chain reaction analyses showed the transcriptional upregulation of various genes including Dusp6, Egr1 and Id2 under hepatic inflammatory conditions. Together, these findings suggest that inflammation-mediated transcriptional upregulation of target genes, including putative tumor suppressor genes, enhances the opportunity for inflamed cells to acquire somatic mutations and contributes to the acceleration of tumorigenesis in the inflamed liver tissues.

Hepatitis C Treatment with Sofosbuvir and Ledipasvir Accompanied by Immediate Improvement in Hemoglobin A1c

Background/Aims: Direct-acting antiviral agents (DAAs) have increased the sustained viral response rate with minimal adverse effects and short treatment duration. In addition, recent data suggest the possibility that hepatitis C virus (HCV) clearance results in rapid improvement in metabolic pathways. The aim of the present study was to evaluate whether the DAA treatment without ribavirin lowers hemoglobin A1c (HbA1c) at 12 weeks after therapy completion. Methods: We performed an observational study to assess the effect of sofosbuvir and ledipasvir (SOF/LED) treatment on glycemic control. We compared HbA1c levels before and after treatment with SOF/LED, considering that anemia is not a side effect of these drugs. Results: In the 36 patients with HCV eradication, HbA1c levels decreased significantly after treatment (pre-treatment 5.85% vs. post-treatment 5.65%, p < 0.01). Conclusion: This pilot study shows the possibility that HCV eradication by SOF/LED was accompanied by an improvement of glucose metabolism in the population with or without diabetes, and suggests further investigation.

Hepatobiliary and pancreatic: Delayed ileal perforation following radiofrequency ablation of hepatocellular carcinoma

An 80-year-old man was diagnosed with a recurrence of hepatocellular carcinoma on a contrast-enhanced computed tomography (CT) scan (arrow, Figure 1a). The tumor was approximately 8 mm from the liver edge and did not appear to be adjacent to the gastrointestinal tract. After infusion chemotherapy via the hepatic artery, ultrasound-guided radiofrequency ablation was performed under local anesthesia using a single internally cooled electrode with a 2-cm tip exposure. A CT scan obtained 1 day after radiofrequency ablation showed appropriate necrosis of the tumor without any apparent complications (arrow, Figure 1b). However, 14 days after radiofrequency ablation, the patient returned to the Emergency Department with abdominal pain. A repeat CT scan showed free air in the mesentery and thickening of the small bowel wall in the mid-abdomen. An early laparotomy was performed and revealed thermal damage to the ileum with a pinhole-sized perforation (arrow, Figure 2) but the damaged ileum was not adherent to the liver. The damaged segment was resected with an end-to-end anastomosis and the patient had an uneventful recovery. Radiofrequency ablation is an effective treatment for hepatocellular carcinoma with complication rates that range from 2% to 10%. Early complications include bleeding into the peritoneal or pleural cavities, perforation of the gastrointestinal tract and the development of a liver abscess. Late complications can include seeding of tumor along the electrode track and the development of strictures within the biliary system. In relation to intestinal perforation, a large multicenter study recorded 7 cases in 2320 patients, a frequency of 0.3%. Two of these patients died. The site of the perforation was the transverse colon in 5 patients and this appeared to be associated with adhesions in the upper abdomen. Perforations were also reported in the stomach (1 case) and jejunum (1 case). All patients with perforation had tumor within 1 cm of the liver capsule. In the above patient, the neoplasm was close to the capsule but adjacent bowel was not shown on a CT scan. However, the apparent absence of adjacent bowel does not exclude the possibility of intestinal perforation. Furthermore, the clinical features of perforation can be delayed for at least 2 weeks after radiofrequency ablation.