Ken Shirabe

Chapter 23 – Role of Autophagy in Liver Regeneration

Abstract Autophagy regulates protein and organelle turnover and produces adenosine 5′-triphosphate (ATP) by using the amino acids from degraded proteins. We generated liver-specific autophagy-related gene 5 (Atg5)-knockout (KO) mice to investigate the activity of autophagy-associated pathways in liver regeneration after partial hepatectomy (PHx). The proliferation of remnant liver in Atg5 KO mice was severely impaired by 70% PHx with a reduction in postoperative mitosis, but a compensating increase in hepatocyte size. PHx injured cellular mitochondria and induced the intracellular ATP and β-oxidation reduction. Besides, hepatic accumulation of p62 and ubiquitinated proteins were enhanced. These results indicated that the reorganization of intracellular proteins and organelles during autophagy was impaired in the regenerating liver in this setting. Upregulation of p21 was associated with hepatocyte senescence and irreversible growth arrest. In the results, autophagy plays a critical role in regenerating liver and in the preservation of cellular quality by preventing hepatocytes from becoming fully senescent and hypertrophic in liver regeneration.

Surgical management of recurrent intrahepatic cholangiocarcinoma: predictors, adjuvant chemotherapy, and surgical therapy for recurrence: A multi-institutional study by the Kyushu Study Group of Liver Surgery

Objectives of the present study were to identify predictors of the recurrence of intrahepatic cholangiocarcinoma (ICC), and to evaluate the survival benefit of adjuvant chemotherapy and surgical treatment for ICC recurrence. A multi‐institutional retrospective study was carried out in 356 patients with ICC who underwent curative surgery at one of 14 institutions belonging to the Kyushu Study Group of Liver Surgery. A total of 214 patients (60%) had recurrence. Predictors of ICC recurrence were as follows: positive for pathological intrahepatic metastasis (im), positive for lymph node metastasis (n), positive for pathological lymphatic infiltration (ly), pathological bile duct invasion (b), and tumor size ≥4.4 cm. Adjuvant chemotherapy was given to 120 patients (34%) and, in the patients with im or tumor size ≥4.4 cm, adjuvant chemotherapy showed a survival benefit. Only 37 patients (17%) underwent surgical treatment for ICC recurrence. The surgical treatment resulted in a good 5‐year survival rate (44%), which is similar to the rate obtained by the first operation for primary ICC. Prognosis of patients with primary im after the second operation was significantly worse (5‐year survival 18%) compared to patients without primary im. Primary im+ should be considered a contraindication for surgical treatment for ICC recurrence.