Recurrence of primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation in Japan

Although there was some initial controversy, there is now a consensus that primary biliary cirrhosis (PBC) does indeed recur in both cadaveric and living donated allografts. Recurrence rate after deceased donor liver transplantation (LT) was reported to be 10.9–23% at 5 years. In the present study, we reviewed 221 PBC patients who underwent living-donor liver transplantation (LDLT) in Japan. The 5-year overall survival rate was 79%, and the rate of recurrence based on histological findings was 10% (7/70) after a median time of 36 months. Primary immunosuppression, withdrawal of corticosteroids and human leukocyte antigen matches were not associated with the recurrence. Recurrent PBC appears to have little impact on graft function and survival, but this may become a greater problem with longer follow up.
It is noteworthy that the 10-year survival of primary sclerosing cholangitis (PSC) patients who underwent LDLT wasfound to be only 39.1% in Japan, whereas that of PBC was 72.9%. Factors associated with the poor prognosis include biliary strictures, hepatobiliary and colorectal malignancies, and recurrence of PSC. In our study, we reviewed 66 patients with PSC who underwent LDLT in Japan. The 5-year survival rate was 72%, and the rate of recurrence diagnosed on histological and cholangiographic findings was 25% (11/44). Well-defined diagnostic criteria and longer studies are required to characterize the nature of recurrent PSC and its impact on graft survival in more detail.     

Modulation of collagen synthesis by fat-storing cells,isolated from CCl4-or vitamin A-treated rats

In an attempt to elucidate the role of fat-storing cells (FSCs) in liver fibrosis, we investigated the collagen synthesis by FSCs freshly isolated from rats treated with CCl₄, with vitamin A, and from untreated rats. FSCs from CCl₄-treated rats contained a small number of lipid droplets and an abundant rough endoplasmic reticulum (RER), while those from vitamin A-treated rats showed numerous large lipid droplets and scanty RER. The population doubling times of FSCs isolated from normal, CCl₄-treated, and vitamin A-treated rats were 38±4.3, 24±2.5, and 48±6.3 hr, respectively. The rate of collagen synthesis by FSCs from CCl₄-treated rats was four- to sixfold enhanced, while collagen synthesis by FSCs from vitamin A-treated rats was suppressed. The ratio of collagen type I to type III produced by FSCs from CCl₄ rats was enhanced as compared with control rats (94.7:5.3 vs 87.6:12.4). Therefore, FSCs can be considered to play an important role in the pathogenesis of liver fibrosis.     

Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan

The geographic distribution of hepatitis B virus (HBV) genotypes in Japan and its clinical relevance are poorly understood. We studied 731 Japanese patients with chronic HBV infection. HBV genotype was determined by the restriction fragment length polymorphism (RFLP) method after polymerase chain reaction (PCR). Of the 720 patients with positive PCR, 12 (1.7%) were HBV genotype A, 88 (12.2%) were genotype B, 610 (84.7%) were genotype C, 3 (0.4%) were genotype D, and 7 (1.0%) were of mixed genotype. Over 94% of patients on the Japanese mainland had genotype C, while 60% of the patients on Okinawa, the most southern islands, and 22.9% in the Tohoku area, the northern part of the mainland, harbored genotype B. Compared with genotype C patients, genotype B patients were older (53.6 to 42.2 years; P <.01), had a lower rate of positive hepatitis B e antigen (HBeAg) (18.4% to 50.6%; P <.01), and a lower level of serum HBV DNA (5.02 to 5.87 log genome equivalents (LGE)/mL; P <.01). The mean age of the genotype B patients with hepatocellular carcinoma was 70.1 +/- 9.2 years, compared with 55.2 +/- 9.7 of genotype C patients (P <.01). These results indicate that genotypes C and B are predominant in Japan, and there are significant differences in geographic distribution and clinical characteristics among the patients with the different genotypes.     

Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632

Intrahepatic metastasis is one of the most important prognostic factors for patients with hepatocellular carcinoma (HCC). Cell motility mediated by Rho- and p160 Rho-associated coiledcoil forming protein kinase (p160ROCK) signaling pathways has recently been shown to play a critical role in intrahepatic metastasis in human HCC. Furthermore, the stable introduction of dominant-negative p160ROCK into Li7 cells resulted in a reduced metastatic rate in mice with severe combined immunodeficiency (SCID). To investigate whether the specific p160ROCK inhibitor, Y-27632, could also inhibit intrahepatic metastasis, the effect of Y-27632 on the cell motility and intrahepatic metastasis of Li7 was investigated. Y-27632 markedly blocked actin reorganization and motility of Li7 cells mediated by lysophosphatidic acid (LPA). Y-27632 was administered continuously into the peritoneal cavity using a micro-osmotic pump, together with orthotopic implantation of Li7 cells into the liver of SCID mice. Phosphate-buffered saline (PBS) alone was administered as the control. The incidence of mice with metastatic nodules decreased in the Y-27632-treated group. The primary tumor volume at the site of injection was smaller in the Y-27632-treated group compared with the control group, but the difference was not statistically significant. Histologically, control tumors showed infiltrative growth into the sinusoidal area at the tumor boundary, whereas Y-27632-treated tumors showed expansive growth and low invasiveness. These findings confirm the importance of the Rho/p160ROCK signaling pathway in intrahepatic metastasis of human HCC, and indicate that Y-27632 may be useful for the prevention of intrahepatic metastasis of human HCC.     

Symposium (IV) : Alcohol and digestive organs

Journal of Gastroenterology -     

Living related heterotopic auxiliary partial liver transplantation for extremely small-for-size graft in fulminant liver failure

Adult living related liver transplantation seeks a balance between donor safety and the need to save the recipient's life. A small-for-size graft is a major obstacle for high-risk patients. We experienced a case of heterotopic auxiliary partial liver transplantation with extremely small-for-size graft for fulminant liver failure. The other reasons why we chose to perform heterotopic auxiliary partial liver transplantation were acute renal failure, subshock state, and a left lobe volume of 24% in the standard liver volume of the donor. Hepatic vein reconstruction was made using an inferior meserteric vein patch graft. Portal vein reconstruction was made using end-to-side anastomosis employing an interposed left external iliac vein. The left hepatic artery of the graft was connected to the distal gastroduodenal artery. The patient was discharged 3 months after transplantation. We would recommend heterotopic auxiliary partial liver transplantation as an optional procedure for patients with severe preoperative conditions or extremely small-for-size graft donors.     

Regional Differences on Production of Chemokines in Gastric Mucosa Between Helicobacter pylori-Positive Duodenal Ulcer and Gastric Ulcer

It is well known that antrum-predominantgastritis and pan-gastritis occurs in the patients withHelicobacter pylori-positive duodenal ulcer (DU) andgastric ulcer (GU), respectively. However, the role of chemokines in the pathogenesis of thesepathologies is unclear. We examined the regionaldifferences in mucosal chemokine production in patientswith DU and GU. The production of interleukin-8 (IL-8), growth-related gene (GRO) , andmacrophage inflammatory protein (MIP)-1 wasgreater in the antrum than in the corpus in DU patients.In the patients with GU, monocyte chemoattractantprotein (MCP)-1 levels in the mucosa adjacent to ulcer weregreater than those away for the ulcer in the corpus. Thereduction in chemokine production occurring inassociation with the eradication of H. pylori differed between DU and GU patients in the antrum (IL-8,P = 0.0394; GRO, P = 0.0149; MIP-1, P =0.0246; MCP-1, P = 0.0087). The data imply a differentpathogenesis may exist for the gastritis present in patients with DU and GU occurring in H.pylori-positive individuals.