Portal branch ligation with a continuous hepatocyte growth factor supply makes extensive hepatectomy possible in cirrhotic rats

Abstract

In a cirrhotic liver, the regenerative ability and specific functions are so impaired that excessive resection easily complicates postoperative liver dysfunction, which frequently leads to life-threatening multiple-organ failure. Hepatocyte growth factor (HGF), first identified as the most potent stimulator of DNA synthesis in primary hepatocytes, not only stimulates liver regeneration, but also accelerates hepatic function, improves fibrosis, and protects liver cells against injury. Therefore, we investigated the efficacy of preoperative portal branch ligation (PBL) (which can induce compensatory hypertrophy of the unaffected lobes) combined with a continuous HGF supply in the performance of extensive hepatectomy in cirrhotic rats. Cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine (DMN) three times per week for 3 weeks. Five days after the last injection, when 70% hepatectomy is lethal, the rats underwent portal ligation of the left lateral and median branches (corresponding to approximately 70% of the total volume of the liver). Simultaneously, they were continuously treated with either recombinant human HGF (rhHGF) or vehicle from an intraperitoneally implanted osmotic pump. Four days after the portal ligation, the occluded lobes were resected. The HGF treatment rapidly increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. The blood chemical analysis indicated that HGF significantly suppressed the posthepatectomy liver dysfunction. Most importantly, the HGF treatment markedly improved the survival rate of the rats at 48 hours after the major hepatectomy. In conclusion, PBL combined with a continuous HGF supply makes extensive hepatectomy possible in cirrhotic rats, mainly by promoting the hypertrophy of the unaffected lobes. (HEPATOLOGY 1998;28:756-760.)Most of the primary hepatocellular carcinomas (HCC) reported in Japan are associated with chronic hepatitis or cirrhosis. 1 Although nonsurgical therapeutic options such as percutaneous ethanol injection therapy and transcatheter arterial embolization have been developed, surgical resection still plays a central role in the treatment of HCC. However, the regenerative ability and specific functions of a cirrhotic liver are so impaired that patients with HCC are at a high risk of postoperative liver failure, when resected over the extent of the safely resectable limit. 2 This serious complication, if uncontrolled, frequently leads to life-threatening multipleorgan failure. Although reducing the hepatic volume to be resected would lower the incidence of this complication, it might raise the risk of intrahepatic recurrence, and increase the number of patients who could not undergo curative surgeries. Therefore, the enlargement of the safely resectable limit in a cirrhotic liver has been an important goal to improve the survival rate of patients with HCC.Preoperative percutaneous transhepatic portal embolization (PTPE), a modification of portal branch ligation (PBL), [3][4][5] has been used clinically t...

Two-Stage Portal Vein Ligation Facilitates Liver Regeneration in Rats

“…Drugs that facilitate liver regeneration include granulocyte colony-stimulating factor [17] , CD133+ bone marrow cells [18] , plasminogen activator [19] , hepatocyte growth factor [20] , nitric oxide [21] , prostaglandins [21] , estrogen [22] and erythropoietin [23] . Techniques that facilitate liver regeneration include combined use of hepatic artery ligation [24] , combined use of intrahepatic biliary ablation [25] and combined use of hyperbaric oxygen- ation [26] .…”

Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin?

“…Pertinent to this point, it is worth mentioning that cirrhosis is associated with impaired liver regeneration both in humans 72,73 and in experimental animals. 74,75 Thus, it is reasonable to hypothesize that such a growth-impaired background could foster the selective emergence of rare hepatocytes, 76 with either normal or altered phenotype. This is in agreement with the hypothesis of Park et al, 60 who proposed that dysplastic nodules arise as clonal expansions of altered hepatocytes in a process that runs in parallel with the development of liver cirrhosis.…”

Gene Transfer of c-met Confers Protection Against d-Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

“…Among various hepatotrophic factors, HGF is a pleiotropic paracrine factor with mitogenic, motogenic, and morphogenic activities on hepatocytes [11]. In various animal models of liver injury, including a partial hepatectomy, liver cirrhosis, hepatotoxicity, and hepatic fibrosis, HGF has been demonstrated to activate protein synthesis, stimulate hepatocyte growth, and prevent cellular death [21][22][23][24][25][26], suggestive of its potential as a therapeutic agent. Fig.…”