Splenectomy enhances liver regeneration through tumor necrosis factor (TNF)-alpha following dimethylnitrosamine-induced cirrhotic rat model.

BACKGROUND/AIMS: We demonstrated that partial splenic embolization for hematological disorders in cirrhotic patients also improved liver function. Therefore, we investigated the mechanism of the beneficial effects of splenectomy on a rat cirrhotic model. METHODOLOGY: 1) Rats were administered DMN (dimethylnitrosamine) after splenectomy (splenectomized DMN rats) or a sham operation (DMN rats). 2) After completion of DMN administration, a tumor necrosis factor-alpha inhibitor (E3330) was administered on the same day as the splenectomy. Histological examination and cytokine expressions were analyzed. RESULTS: The splenectomy apparently reduced liver damage. This may be partially due to the enhancement of liver regeneration since the proliferating cell nuclear antigen labeling index in the DMN-treated liver was significantly increased by splenectomy. Tumor necrosis factor-alpha was down-regulated in the DMN rats, whereas its expression was preserved in the splenectomized DMN rats. There were no apparent differences in the number of Kupffer cells between the splenectomized DMN and the DMN rats, suggesting that the down-regulation of tumor necrosis factor-alpha may contribute to the reduction of Kupffer cells' function. In addition, a tumor necrosis factor-alpha production inhibitor (E3330) significantly reduced the proliferating cell nuclear antigen labeling index after splenectomy. CONCLUSIONS: Splenectomy, in this model, may promote liver regeneration by preserving Kupffer cell function, especially the secretion of tumor necrosis factor-alpha.

Prospective study of laparoscopic findings with regard to the development of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis.

BACKGROUND: The laparoscopic findings of hepatocarcinogenesis are not well defined. The purpose of this prospective study was to evaluate the predictive value of laparoscopic findings with regard to the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-associated cirrhosis. METHODS: One hundred nineteen patients with HCV-associated cirrhosis who underwent laparoscopy were enrolled in this study. Ten laparoscopic variables, including degree of development and size of regenerating nodules, irregularity of regenerating nodules, and size of both hepatic lobes, were measured. The predictive value of each finding for the development of HCC was investigated by using univariate and multivariate analyses. RESULTS: HCC developed in a total of 42 of the 119 patients (35.3%) during a mean follow-up period of 62.9 months. The degree of regenerating nodules, the presence of irregular regenerative nodules, and atrophic right lobe were significant predictive factors for HCC with univariate analysis. In particular, 67.1% of patients with irregular regenerative nodules had HCC develop within 5 years. Multivariate analysis revealed that irregular regenerative nodules (relative risk 6.32, p = 0.012), the degree of regenerative nodules (relative risk 4.78, p = 0.029), and atrophic right lobe (relative risk 3.87, p = 0.048) were independent predictive factors. CONCLUSIONS: Morphologic observation of the liver surface by laparoscopy is important and provides information on factors that are statistically significant early predictors of the development of HCC.

Clinico-epidemiology of hepatitis C viral infection in northeastern Thailand.

Hepatitis C virus (HCV) is responsible for a large number of cases of chronic liver disease worldwide. A study of clinico-epidemiology of HCV infection was conducted in 214 patients who were seropositive for antibody to HCV (anti-HCV) in Srinagarind Hospital, Khon Kaen University, northeastern Thailand, during August 1997 to December 1998. There were 199 males, 15 females and their mean age was 34.96 +/- 9.75 years with a range from 16 to 72 years. The clinical features of acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC) and asymptomatic HCV infection were 2, 115, 15, 2 and 80 cases. Risk factors for HCV acquisition were intravenous drug use (IVDU), tattooing and blood transfusion in 46.7, 32.2 and 18.8% of cases, respectively. 23.36% had a history of multiple risk factors while 28.9% had no history of risk factor exposure.

Clinico-epidemiology of hepatitis B viral infection in Northeastern Thailand.

Hepatitis B viral (HBV) infection is a common disease world wide. A study of clinico-epidemiology of HBV infection was conducted in 381 patients who seropositive for hepatitis B surface antigen (HBsAg) in Srinagarind Hospital, Khon Kaen University, Northeastern Thailand, during August 1997 to December 1998. 293 males, 88 females and their mean age was 30.96 +/- 12.78 years with a range from 15 to 77 years. The clinical features of acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC) and asymptomatic carrier were 2.36, 34.12, 4.99, 1.05 and 57.48% of cases. Possible routes for HBV transmission were family history of hepatitis, tattooing, intravenous drug addict and blood transfusion in 20.3, 11.3, 8.2 and 6.9% of cases, respectively. Signs of chronic liver disease were common in liver cirrhosis and HCC. Acute fulminating hepatitis was not found in this study.

Detection of doxorubicin cardiotoxicity by using iodine-123 BMIPP early dynamic SPECT: quantitative evaluation of early abnormality of fatty acid metabolism with the Rutland method.

BACKGROUND: To evaluate the possibility of predicting the development of doxorubicin-induced cardiomyopathy, we performed quantitative assessment of the early kinetics of iodine-123 beta-methyl-iodophenyl-pentadecanoic acid (I-123 BMIPP) by means of dynamic myocardial SPECT. METHODS: Thirty-six patients with various malignancies were examined. I-123 BMIPP dynamic myocardial SPECT was performed before chemotherapy, after chemotherapy, or both. Immediately after the injection of I-123 BMIPP (111 MBq), 30-second dynamic SPECT data were acquired successively for 15 minutes. The left ventricular (LV) myocardium was divided into 8 segments in short-axial and vertical slices. By using the time-activity curve (TAC) of each myocardial segment [Mo(t)] as an output function and the TAC of the LV cavity [B(t)] as an input function, the Rutland equation, Mo(t)/B(t)= F + K Integral of(B(t)dt/B(t)), was used as a means of assessing all segments. RESULTS: Mo(t)/B(t) showed a good linear correlation with Integral of(B(t)dt/B(t)) from 30 seconds to 4 minutes in all 456 segments. The mean K value of 8 LV segments was significantly lower after chemotherapy than before chemotherapy (0.071+/-0.019 [n = 21] vs. 0.095+/-0.025 [n = 36], P<.001). In 21 patients in whom dynamic SPECT was performed both before and after chemotherapy, the mean K values of left ventricle showed a significant decrease, from 0.101+/-0.024 to 0.071 +/-0.019 (P<.0001). The fractional change in the value of K after chemotherapy showed a significant linear correlation with the administered dose of doxorubicin (r = 0.648, P<.002). CONCLUSION: I-123 BMIPP dynamic myocardial SPECT may be clinically useful, because it permits the early detection of doxorubicin-induced cardiomyopathy.

Expression of functional CD40 in human hepatocellular carcinoma.

CD40, a member of the tumor necrosis factor receptor (TNFR) family, plays a crucial role in the survival, proliferation, and differentiation in B cells. However, the expression of CD40 other than in B cells has not been well studied. Therefore, we investigated the expression and function of CD40 in hepatocellular carcinomas (HCCs). Expression of CD40 mRNA in 6 established HCC cell lines was analyzed by reverse-transcription polymerase chain reaction (RT-PCR) and CD40 expression on cell surface was examined by flow cytometrical analysis. We also examined the expression of CD40 in human HCC tissues (45 cases) and nontumor liver tissues (30 cases) by immunohistochemistry. To examine the function of CD40 in HCC cells, we investigated the effect of CD40 signaling on anti-Fas antibody and TNF-alpha-induced apoptosis in HepG2 cells. In addition, intracellular levels of cysteine protease P32 (CPP32) protein in HepG2 cells were also determined by Western blotting. We have shown that 6 HCC cell lines constitutively expressed CD40 mRNA and membrane-bound CD40 antigen, which was slightly up-regulated by interferon gamma (IFN-gamma). In addition, 60% of human HCC tissues demonstrated positive staining for CD40, whereas nontumor tissues showed little detectable staining. In HepG2 cells, CD40 stimulation does not affect cell viability, but significantly inhibited Fas and TNFR-mediated apoptosis in a dose-dependent manner by blocking the activation of CPP32. From these results, we conclude that CD40 expression in HCCs plays an important role in tumor biology, especially the resistance against Fas and TNFR-mediated apoptosis.

Long-term effect of prophylactic endoscopic injection sclerotherapy on liver function.

BACKGROUND/AIMS: The aim of this study was to investigate the long term effect of prophylactic endoscopic injection sclerotherapy (EIS) on liver function. METHODOLOGY: This study was a retrospective investigation of seventy-eight patients with liver cirrhosis, whose liver function was classified as Child's A before follow-up. Laboratory data were retrospectively examined before and after follow-up, and a comparison was made between the EIS group (n=21) and the non-treated group (n=57). RESULTS: In the 3 or more years of follow-up, cholinesterase and total cholesterol levels deteriorated in several severe-variceal cases. However, these levels did not deteriorate over the 3 or more years of follow-up in the EIS group. CONCLUSION: Prophylactic endoscopic injection sclerotherapy among patients with early stage LC may prevent the deterioration of liver function.

Flow cytometric analysis of IL-6 receptors on peripheral lymphocytes in patients with primary biliary cirrhosis.

Interleukin-6 receptors (IL-6R) and interleukin-1 receptors (IL-1R) on lymphocyte surfaces were analyzed, using flow cytometry and dye-labeled IL-6 and IL-1 beta, to examine the clinical and immunological significance of these receptors. Incubation of peripheral blood mononuclear cells in the presence of mitogen resulted in a remarkable increase of lymphocytes expressing the IL-6 and IL-1 beta receptors on the cell surface. The increase in lymphocytes bearing these cytokine receptors may reflect an increase in stimulated lymphocytes. When peripheral blood from patients with primary biliary cirrhosis (PBC) was examined for these receptors, the percentage of IL-6R positive cells was significantly higher in the patients than in healthy controls (P < 0.01). The increase in IL-6R positive cells was only significant for the T lymphocyte fraction (P < 0.01). No significant change in IL-1R was observed. There was a significant positive correlation between the percentage of IL-6R positive T lymphocytes and the titer of antimitochondrial antibody in patients with PBC. These findings concerning IL-6R may be noteworthy elucidating autoimmune etiological features of PBC.

Hepatocellular carcinoma in primary biliary cirrhosis: a case report and review of the Japanese literature.

We present a 66 year-old woman in the cirrhotic stage of primary biliary cirrhosis (PBC), who developed hepatocellular carcinoma (HCC). All serological tests for hepatitis B virus (HBV) and hepatitis C virus (HCV) were negative. We surveyed 16 reported cases (13 females and 3 males) of PBC associated with HCC in Japan. The presence of HCV RNA was determined by the polymerase chain reaction in all of the patients, 3 of whom (19%) were HCV RNA-positive. Although patients with PBC rarely develop HCC, it is suggested that HCV infection may play a minor role in the development of HCC in Japanese patients with PBC.

Liver cirrhosis with synchronous gas gangrene and spontaneous bacterial peritonitis due to E. coli.

We report a case of synchronous gas gangrene and spontaneous bacterial peritonitis associated with liver cirrhosis. The patient was a 52-year-old man who was being followed for decompensated liver cirrhosis. He experienced sudden onset lower abdominal pain with distension and pain in the left leg. A bullous lesion, with crepitation, later appeared in the thigh and showed air-bubbles on X-ray. Eschericia coli was cultured from ascites and the bullous lesions; there was associated gas gangrene. The patient died of bacteremia with disseminated intravascular coagulopathy 26 h after admission, despite receiving intensive care. We discuss the route of bacteria causing the spontaneous bacterial peritonitis and simultaneous gas gangrene.

Asymptomatic primary pulmonary hypertension associated with liver cirrhosis.

We report a case of asymptomatic primary pulmonary hypertension associated with liver cirrhosis (type B) and portal hypertension found by chance during a preoperative Swan-Gantz catheterization study. Our experience suggests that the actual prevalence of primary pulmonary hypertension associated with liver cirrhosis may be greater than that previously reported. During the follow-up of liver cirrhosis with portal hypertension, we should consider primary pulmonary hypertension, even if the patient is free of symptoms, and a chest X-ray check may be necessary.

Infection with GB virus C (GBV-C) in patients with fulminant hepatitis.

BACKGROUND/METHODS: There appear to be hepatitis viruses other than hepatitis A, B, C, D and E. One of these has been proposed with a designation of GB virus C. Sera from 44 patients with fulminant hepatitis were tested for RNA of GB virus C by reverse-transcription polymerase chain reaction with nested primers deduced from the putative non-structural 3 (helicase) region. RESULTS: RNA of GB virus C was detected in three (20%) of 15 patients with hepatitis B virus infection and three (12%) of 25 patients without markers of hepatitis A-E virus infection. Overall, GB virus C RNA was detected in six (14%) of the 44 patients with fulminant hepatitis, at a frequency significantly higher (p < 0.001) than that in three (0.9%) of 326 blood donors matched for age with the patients. CONCLUSIONS: These results indicate a role of GB virus C in inducing fulminant hepatitis either by itself or in concert with the other hepatitis viruses.

Osteodystrophy in patients with chronic hepatitis and liver cirrhosis.

Bone mineral density (BMD) of the lumber vertebrae and factors related to bone metabolism were determined in patients with chronic viral hepatitis and patients with liver cirrhosis to clarify correlations between hepatic dysfunction, considered to be one of the causes of hepatic osteodystrophy, and decrease in bone mass. BMD of the second to fourth lumbar vertebrae was determined with a Lunar (Madison, WI, USA) DPX, a dual-energy X-ray absorptiometry diagnostic system. BMD was significantly lowest in patients with liver cirrhosis, followed by patients with chronic hepatitis, and healthy subjects, in this order. There was a significantly positive but weak correlation between albumin and BMD. Levels of 25(OH)D and 1,25(OH)2D were significantly lower in patients with liver cirrhosis than in those with chronic hepatitis. BMD and vitamin D were decreased in all patients whose cholinesterase (ChE) was below 0.3 delta pH. Urinary pyridinoline (Upyr) was significantly higher in the patients with liver cirrhosis, in whom bone mass was decreased, than in the patients with chronic hepatitis, whereas serum osteocalcin levels were distributed in the upper normal range in patients with chronic hepatitis and those with liver cirrhosis. There was a positive correlation between 25(OH)D and serum osteocalcin levels in patients with liver cirrhosis. These results indicate that osteogenesis is decreased and suggest that the decrease in BMD which occurs in viral liver cirrhosis, probably related to decreased, bone formation and slight promotion of bone resorption, reflects deranged hepatic function. This is the first report of Upyr and urinary deoxypyridinoline (UDpyr) determination in patients with liver cirrhosis and patients with chronic hepatitis. The negative correlation of Upyr and UDpyr with ChE is a novel finding.