Mitochondrial swelling and microtubule depolymerization are associated with energy depletion in axon degeneration.

Although mitochondrial dysfunction is intimately related to axonal degeneration following nerve injury, the molecular mechanisms of mitochondrial swelling and its mechanistic relation to axonal degeneration are largely unknown. Previous studies have demonstrated that axonal degeneration in the injured peripheral nerves shows two morphologically distinct phases: (1) A latency period (∼24h), in which the morphology of axonal cytoskeletons seems unchanged, followed by (2) an execution period (36-48h), which shows a catastrophic granular degeneration of most axonal structures in rodent axons. In the present study, we found that, in the sciatic nerve axotomy model, energy failure and microtubule depolymerization occurred during the latency period whereas mitochondrial swelling and neurofilament degradation started in the execution period. The energy repletion with NAD or an NAD/pyruvate mixture inhibited microtubule depolymerization, mitochondrial swelling and axonal degeneration in transected sciatic nerve axons. In addition, microtubule perturbing agents enhanced axonal degeneration and mitochondrial swelling. Extracellular calcium chelation did not affect energy failure, microtubule depolymerization or mitochondrial swelling, but it did prevent neurofilament degradation. These findings suggest that an early disturbance in energy dynamics regardless of mitochondrial swelling might be a key trigger for the initiation of axonal degeneration and that extracellular calcium influx is a late effector for neurofilament degradation.

Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naïve patients with HBV-related decompensated cirrhosis.

Patients with decompensated cirrhosis owing to chronic hepatitis B viral (HBV) infection have a high morbidity/mortality rate, and the treatment remains a challenge. We studied the safety and efficacy of telbivudine and lamivudine in such patients. This noninferiority, double-blind trial randomized 232 treatment-naive patients with decompensated HBV (1:1) in 80 academic hospitals to receive once-daily telbivudine 600 mg or lamivudine 100 mg for 104 weeks. Primary composite endpoint was proportion of patients with HBV DNA <10 000 copies/mL, normal alanine aminotransferase (ALT) and Child-Turcotte-Pugh score improvement/stabilization at week 52. Response rates using a post hoc modified endpoint (HBV DNA <300 copies/mL [57 IU/mL] and ALT normalization) in intent-to-treat analysis (missing = failure) were 56.3%vs 38.0% after 76 weeks (P = 0.018) and 45.6%vs 32.9% after 104 weeks (P = 0.093) for telbivudine vs lamivudine. Telbivudine treatment was an independent predictive factor for HBV DNA <300 copies/mL and ALT normalization (P = 0.037). Response rates with protocol-defined composite endpoint in intent-to-treat analysis (M = F) were 56.2 vs 54.0% (noninferiority not achieved) and 39.1%vs 36.4% (noninferiority achieved) in telbivudine and lamivudine groups at 52 and 104 weeks. Telbivudine treatment was associated with a significant improvement in glomerular filtration rate compared to lamivudine treatment and was also associated with a trend for improvement in survival (87%vs 79%). No cases of lactic acidosis were reported. Telbivudine compared to lamivudine was associated with a higher rate of patients with both viral suppression and ALT normalization, a trend towards a higher rate of survival and significant improvement in glomerular filtration.

Pre-operative transarterial chemoembolization for resectable hepatocellular carcinoma adversely affects post-operative patient outcome.

BACKGROUND: Long-term outcomes after hepatic resection for hepatocellular carcinoma are not satisfactory because of high recurrence rates. Aim To assess whether a single session of pre-operative transarterial chemoembolization affects post-operative outcome. METHODS: We analysed outcomes retrospectively in 334 consecutive patients who underwent hepatic resection for hepatocellular carcinoma, initially judged resectable. Ninety-seven of these patients had each undergone a single session of pre-operative transarterial chemoembolization (transarterial chemoembolization + hepatic resection group), whereas 237 had not (hepatic resection group). RESULTS: Most clinicopathological characteristics were similar in the two groups. The overall survival rate was significantly higher in the hepatic resection than in the transarterial chemoembolization + hepatic resection group (P = 0.011), whereas their disease-free survival rates were comparable (P = 0.67). The overall and disease-free survival rates of the transarterial chemoembolization + hepatic resection group with incomplete tumour necrosis were significantly lower than those of the hepatic resection group (P < 0.001 and P = 0.006, respectively). Multivariate analysis showed that pre-operative transarterial chemoembolization, serum alpha-fetoprotein elevation (>1000 ng/mL), tumour size (>5 cm) and vascular invasion were independent risk factors for poor overall survival after hepatic resection. CONCLUSIONS: A single session of pre-operative transarterial chemoembolization for initially resectable hepatocellular carcinoma worsens overall survival rate. It may also increase the risk of tumour recurrence in patients who achieve incomplete tumour necrosis.

Mechanism of histone deacetylase inhibitor Trichostatin A induced apoptosis in human osteosarcoma cells.

Although histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in malignancy, how they exert their effect on osteosarcoama cells is as yet unclear. This study was undertaken to investigate the underlying mechanism of a HDAC inhibitor Trichostatin A (TSA)-induced apoptosis in a osteosarcoma cell line HOS. We observed that TSA treatment decreased the viability of the cells and prominently increased acetylation of histone H3. Evidence was obtained indicating that TSA induced apoptosis of HOS cells as follows: (1) Generation of DNA fragmentation; (2) activation of procaspase-3; (3) cleavage of PARP; and (4) increase of DNA hypoploidy. The reduction of MMP and the release of cytochrome c to cytosol were also shown, indicating that TSA induces apoptosis in HOS cells in a histone acetylation- and mitochondria-dependent fashions. We also examined whether TSA can sensitize HOS cells to the action of an antitumor agent genistein. The combination therapy of TSA and genistein showed synergistic anticancer effect indicating that TSA can be considered as a novel therapeutic strategy for osteosarcoma not only from its direct apoptosis-inducing activity but also from the possibility of sensitization to other antitumor agents.

Quantitative polymerase chain reaction assay for serum hepatitis B virus DNA as a predictive factor for post-treatment relapse after lamivudine induced hepatitis B e antigen loss or seroconversion.

BACKGROUND AND AIMS: Lamivudine induces favourable virological and biochemical responses but post-treatment relapses are frequent, even in patients with hepatitis B e antigen (HBeAg) loss or seroconversion. The aim of this study was to determine whether extended lamivudine therapy for up to 12 months after HBeAg loss/seroconversion could decrease the risk of post-treatment virological relapse. In addition, we monitored serum hepatitis B virus (HBV) DNA levels using a quantitative polymerase chain reaction (PCR) assay during extended lamivudine therapy and analysed predictive factors for post-treatment relapse. PATIENTS AND METHODS: A total of 49 patients who exhibited HBeAg loss/seroconversion during lamivudine therapy received extended lamivudine therapy for six months (group 1, n=23) or 12 months (group 2, n=26) after HBeAg loss/seroconversion. Serum HBV DNA levels were quantified by a PCR based assay at the time of HBeAg loss/seroconversion, and at cessation of therapy. RESULTS: Post-treatment virological relapse rates at two years were 59% in group 1 and 50% in group 2. Age, time interval to HBeAg loss/seroconversion, and serum HBV DNA levels at the time of cessation of therapy were independent predictive factors for post-treatment relapse. The post-treatment relapse rate was 37% at two years in patients with serum HBV DNA levels of <200 copies/ml but 73% in those with > or =10(3) copies/ml. CONCLUSIONS: Extended lamivudine therapy for up to 12 months did not decrease the rate of post-treatment virological relapse, and monitoring of serum HBV DNA by a quantitative PCR method was helpful in predicting post-treatment relapse.

Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase.

BACKGROUND AND AIMS: Interferon (IFN) induced hepatitis B e antigen (HBeAg) seroconversion is durable in 80-90% of chronic hepatitis B patients. Preliminary reports on the durability of HBeAg seroconversion following lamivudine are contradictory. We investigated the durability of response following IFN, lamivudine, or IFN-lamivudine combination therapy in a meta-analysis of individual patient data. PATIENTS AND METHODS: Twenty four centres included 130 patients in total with an HBeAg seroconversion (HBeAg negative, antibodies to hepatitis B e antigen positive) at the end of antiviral therapy: 59 with lamivudine, 49 with interferon, and 22 with combination therapy. Relapse was defined as confirmed reappearance of HBeAg. RESULTS: The three year cumulative HBeAg relapse rate by the Kaplan-Meier method was 54% for lamivudine, 32% for IFN, and 23% for combination therapy (p=0.01). Cox regression analysis identified pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and therapy as independent predictive factors of post-treatment relapse; Asian race, previous therapy, centre, and type of study were not predictive of relapse. The relative HBeAg relapse risk of lamivudine compared with IFN therapy was 4.6 and that of combination therapy to IFN therapy 0.7 (p(overall)=0.01). CONCLUSIONS: The durability of HBeAg seroconversion following lamivudine treatment was significantly lower than that following IFN or IFN-lamivudine combination therapy. The risk of relapse after HBeAg seroconversion was also related to pretreatment levels of serum ALT and HBV DNA, but independent of Asian race.

Adult-to-adult living donor liver transplantation at the Asan Medical Center, Korea.

Between February 1997 and December 2001, 311 adult-to-adult living donor liver transplants (A-A LDLTs) were performed at the Asan Medical Center for patients above 20 years of age. Indications for A-A LDLT were: chronic hepatitis B (203), chronic hepatitis C (5), hepatocellular carcinoma (64), alcoholic cirrhosis (9), cryptogenic cirrhosis (4), secondary biliary cirrhosis (5), primary biliary cirrhosis (1), Wilson' s disease (2), autoimmune hepatitis (1), hepatic tuberculosis (1), cholangiocarcinoma (1), fulminant hepatic failure (14) and primary non-function of cadaveric liver graft (1). Of 311 A-A LDLTs, 36 were of medical high urgency, 20 were for acute and subacute hepatic failure, 15 were for hepato-renal syndrome and 1 was for primary non-function. Recipient age ranged from 27 to 64 years. Donor age ranged from 16 to 62 years. There was no donor mortality. Implanted liver grafts were categorized into seven types: 175 modified right lobe (MRL), 70 left lobe, 32 right lobe, 20 dual grafts, 10 left lobe plus caudate lobe, three extended right lobe and one posterior segment. In MRL, the tributaries of the middle hepatic vein were reconstructed by interpositioning a vein graft. Indication for dual graft implantation was the same as single graft A-A LDLT, and four of 20 were emergency cases. Of 20 dual grafts, 14 received two left lobes, four received a left lobe and a lateral segment, one received a right lobe and a left lobe and one received a lateral segment and a posterior segment. Graft volume ranged from 28% to 83% of the standard liver volume of the recipients. There were 33 (10.6%) in-hospital mortalities (< 4 months) among the 310 patients after 311 A-A LDLTs. Of the 36 patients receiving emergency transplants, 31 survived. These encouraging results justify the expansion of A-A LDLT in coping with increasing demands, even in urgent situations. We have aimed to introduce the establishment of the efficacy of A-A LDLT in various end-stage chronic and acute liver diseases, as well as new technical advances to overcome small graft-size syndrome by using dual-graft implantation and MRL, both of which were first developed in our department.

Close correlation of p53 mutation to microvascular invasion in hepatocellular carcinoma.

Mutation of p53 is a poor prognostic indicator of hepatocellular carcinoma (HCC). Although poor histologic differentiation of HCC has been associated with p53 mutations, the exact reasons for unfavorable clinical outcomes in patients with HCC remain to be clarified. In this study, we evaluate the association between p53 mutation and histopathologic features of HCCs, as well as tumor recurrences and survival. We examined 20 HCCs and surrounding liver tissues from patients who underwent surgical resection, and we performed direct sequencing of p53 gene. p53 mutations were found in 9 of 20 HCCs; none were found in the surrounding liver tissue. p53 mutations were frequent in large, multinodular, and poorly differentiated HCCs. Five of 9 with p53 mutation (in contrast, none of 11 with wild-type mutation) showed microvascular invasions. Hepatocellular carcinoma recurred in 6 of 9 with p53 mutation, in contrast to only 2 of 11 with wild-type mutation. The 1-year survival rate with p53 mutation was significantly lower than that with wild-type. In conclusion, it is suggested that p53 mutations tend to be commonly associated with microvascular invasions, which may result in micrometastasis, followed by frequent recurrences.

Plasma isocitrate dehydrogenase as a marker of centrilobular hepatic necrosis in patients with hyperthyroidism.

Isocitrate dehydrogenase (ICDH) may be useful for differentiating centrilobular from periportal necrosis in rats with liver injury. In this study, we assessed the usefulness of ICDH as a marker of centrilobular necrosis in patients with hyperthyroidism. Isocitrate dehydrogenase and alanine aminotransferase (ALT) activities were measured in the plasma of 56 patients with hyperthyroidism, 16 patients with chronic viral hepatitis (CVH), and 17 controls. Isocitrate dehydrogenase levels were higher in patients with hyperthyroidism than in those with CVH or in the controls (p < 0.01 and p < 0.001, respectively), even though ALT levels were higher in patients with CVH than in patients with hyperthyroidism (p < 0.01). Isocitrate dehydrogenase/ALT ratios were also higher in patients with hyperthyroidism than in those with CVH (p < 0.0001). Isocitrate dehydrogenase correlated to ALT levels in patients with hyperthyroidism or CVH (p < 0.05). In a patient with hyperthyroidism, ICDH levels decreased progressively to normal, and the ALT level and thyroid function were normalized. Thus, the plasma ICDH or ICDH/ALT ratio might be useful for differentiating centrilobular from periportal necrosis and for monitoring the degree of hepatic necrosis in patients with hyperthyroidism.

Association between insulin-like growth factor-2 and metastases after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma: a prospective study.

BACKGROUND: Hypoxia up-regulates insulin-like growth factor-2 (IGF-2) and thus stimulates the growth of hepatocellular carcinoma (HCC) cells. In the current study, the authors prospectively evaluated changes in plasma IGF-2 levels in HCC patients after transcatheter arterial chemoembolization (TACE), which usually results in hypoxic insult to liver tissue. The authors also examined the association between changes in plasma IGF-2 levels after TACE and HCC progression, especially in relation to metastasis. METHODS: Plasma IGF-2 levels were measured before and 4 weeks after TACE in 46 patients with HCC. Three months after TACE, the patients were evaluated for the occurrence of metastatic HCC. RESULTS: In 13 of the 46 patients, post-TACE plasma IGF-2 levels decreased by > 20% (Group 1) compared with their basal levels; in 18 patients, the IGF-2 levels changed within 20% (Group 2) and in 15 patients the IGF-2 levels increased by > 20% (Group 3). Plasma IGF-2 levels had a tendency to increase in patients with large-sized tumors, high serum alpha-fetoprotein (AFP) levels, and the heterogeneous uptake of iodized oil. Metastatic foci were found in 9 patients in Group 3 (60%), in contrast to only 3 patients in Group 2 (17%) and in none of the patients in Group 1 (P = 0.001). On multivariate analysis, higher Child-Pugh scores and increased plasma IGF-2 levels (Group 3) were found to be independent risk factors for metastasis. CONCLUSIONS: Increased plasma IGF-2 levels after TACE, which are common in patients with large-sized tumors and high serum AFP levels, appear to be associated with the occurrence of metastatic HCC after TACE.

Isocitrate dehydrogenase as a marker of centrilobular hepatic necrosis in the experimental model of rats.

BACKGROUND AND AIMS: Serum alanine aminotransferase (ALT) and aspartate aminotransferase may not detect centrilobular hepatic necrosis (CLN) of a mild degree because these enzymes are known to be located predominantly in the periportal area. The aim of this study was to evaluate the usefulness of plasma isocitrate dehydrogenase (ICDH), which is located predominantly in the centrilobular zone, as a marker of CLN. METHODS: In 56 adult male rats, centrilobular (n = 21) and periportal hepatic necrosis (PPN; n = 21) were induced experimentally by the intraperitoneal injection of bromobenzene and allylalcohol, respectively. Seven rats were used as solvent controls in both groups. Isocitrate dehydrogenase and ALT activities were measured in the plasma of rats with mild to moderate hepatic necrosis (17 CLN and 19 PPN). Isocitrate dehydrogenase and ALT were compared according to the sampling time (12, 24 and 48 h) and the location of hepatic necrosis. Ratios of ICDH/ALT were also calculated and compared between CLN and PPN groups at any time points. RESULTS: Plasma ICDH activities were higher in rats with CLN than in those with PPN. In contrast, plasma ALT levels were higher in rats with PPN than in those with CLN at 12 h and were similar in both groups after 12 h. The ICDH/ALT ratios were much higher in rats with CLN compared to those with PPN (P< 0.001). The ratios were above 1.0 in 13 of 17 rats (77%) with CLN in contrast to none of the 19 rats with PPN. CONCLUSIONS: Our data suggested that the plasma ICDH/ALT ratio might be useful to differentiate between mild to moderate degrees of CLN from PPN, at least in the experimental model of rats.

Ischemic bile duct injury as a serious complication after transarterial chemoembolization in patients with hepatocellular carcinoma.

BACKGROUND: Bile duct injuries after transarterial chemoembolization (TACE) have been reported; however, the exact pathogenic mechanisms and clinical implications of the injuries remain to be clarified. STUDY: A total of 950 consecutive patients with hepatocellular carcinoma (HCC) were studied. Among them, 807 were treated with TACE and the remaining 143 were treated with transarterial chemoinfusion (TACI) of cisplatin. RESULTS: None of 143 patients with HCC treated with TACI were found to have any radiographic evidence of biliary injury. In contrast, of the 807 patients treated with TACE, 17 (2%) developed biliary complications. Of all complications, 12 (71%) were subcapsular bilomas; 3 (17%), focal strictures of the common hepatic duct or common bile duct; and 2 (12%), diffuse mild dilatation of the intrahepatic bile ducts. Interestingly, 2 of the 12 bilomas were found in the lobe that was not embolized with gelatin sponge particles. The median numbers of TACE tended to be greater in the patients with focal stricture than in those with bilomas (6.0 vs. 2.5; p = 0.08). All 3 patients with focal strictures and 4 of the 12 patients with bilomas had associated serious bacterial infections at presentation. CONCLUSIONS: Bilomas seem to be caused by iodized oil rather than gelatin sponge particles; focal strictures of large bile ducts seem to be caused by gelatin sponge particles. We suggest that adjustments in the amounts of iodized oil or gelatin sponge particles and in the sites of embolization may reduce ischemic biliary injuries after TACE.

Cholangioscopic findings in bile duct tumors.

BACKGROUND: Cholangioscopy has been used in the treatment of bile duct stones and the diagnosis of various bile duct tumors. However, the cholangioscopic characteristics of the various types of bile duct tumors have not been clearly described. We analyzed the results of cholangioscopic examinations and classified the findings according to tumor histology. METHODS: Cholangioscopic findings from 111 patients with benign or malignant bile duct tumors were reviewed. The mucosal changes, the presence of neovascularization, and the patterns of luminal narrowing were analyzed and compared with the histologic diagnosis. RESULTS: Bile duct adenocarcinoma can be classified into 3 different types according to the cholangioscopic findings: nodular, papillary, and infiltrative. Bile duct adenoma, hepatocellular carcinoma and other types of bile duct cancer such as mucin-hypersecreting cholangiocarcinoma, biliary cystadenocarcinoma, and squamous cell carcinoma also presented unique cholangioscopic characteristics. CONCLUSIONS: Bile duct tumors exhibit characteristic cholangioscopic findings and cholangioscopy seems to be useful for differential diagnosis.

Experimental model of hepatic fibrosis following repeated periportal necrosis induced by allylalcohol.

BACKGROUND/AIMS: In most patients with chronic viral hepatitis the predominant lobular location of hepatic necrosis and fibrosis is the periportal zone. We established a new simple model of hepatic fibrosis in rats by repetitive periportal necrosis with allylalcohol. METHODS: Of 40 male adult rats, 30 were injected with 0.62 mmol/kg of allylalcohol intraperitoneally twice a week, the remaining 10 with normal saline as controls. Ten rats were killed at each of 4, 8, and 16 weeks later. The extent of fibrosis was evaluated according to the portal-portal extent. Transforming growth factor (TGF) beta1 mRNA in liver tissues was detected by reverse transcriptase polymerase chain reaction, and its levels were determined by the endpoint titers of serial two-fold dilutions of cDNA. RESULTS: After 4 weeks, periportal fibrosis was produced in only 6 out of 10 rats, and was mild in extent. However, after 8 weeks, 8 out of 9 survivors showed moderate to severe fibrosis, which corresponded to a score of 7 or more. The extent of fibrosis correlated significantly with the amount of collagen and TGFbeta1 mRNA expression in liver tissues. The collagen content and expression of TGFbeta1 mRNA were also upregulated significantly in liver tissues with a fibrosis score of 7 or more. CONCLUSIONS: Hepatic fibrosis can be sufficiently induced by repetitive intraperitoneal injection of 0.62 mmol/kg of allylalcohol twice a week for 8 weeks. This simple model of hepatic fibrosis, in which TGFbeta1 is overexpressed at the transcriptional level, may be useful in the study of patients who have predominantly periportal necrosis and fibrosis.

Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea.

It has been suggested that hepatitis B e antigen (HBeAg) seroconversion after lamivudine therapy is durable in Caucasians with chronic hepatitis B (CHB). However, little is known whether it is also durable in endemic areas of hepatitis B virus (HBV) infection. We evaluated the posttreatment durability of lamivudine-induced HBeAg seroconversion and the predictive factors for relapse in Korean patients with CHB. We retrospectively analyzed 98 HBeAg-positive patients with CHB who were treated with lamivudine between August 1996 and December 1997. Lamivudine was given at a dose of 150 mg per day. After HBeAg seroconversion, lamivudine was continued for an additional 2 to 4 months, and posttreatment monitoring continued for up to 24 months. HBeAg seroconversion was achieved in 34 of the 98 patients (34.7%). The mean duration of treatment in these seroconverters was 9.3 +/- 3.0 months. During the follow-up period, the cumulative relapse rates at 1 year and 2 years posttreatment were 37.5% and 49.2%, respectively. Most relapses were accompanied by elevation of serum alanine transaminase (94%) and reappearance of HBeAg (81%). Pretreatment serum HBV DNA levels and the duration of additional lamivudine therapy after HBeAg seroconversion were 2 independent predictive factors for posttreatment relapse. In conclusion, lamivudine-induced HBeAg seroconversion was not durable in this endemic area. And the duration of additional lamivudine therapy after HBeAg seroconversion significantly affected the posttreatment relapse. Further studies are needed to determine the duration of lamivudine and to elucidate the cause of high relapse after HBeAg seroconversion in endemic areas of HBV.

Expression of transforming growth factor-alpha mRNA in livers of patients with chronic viral hepatitis and hepatocellular carcinoma.

BACKGROUND: Transforming growth factor-alpha (TGFalpha) is an important autocrine growth factor of hepatocytes. The authors evaluated the roles of TGFalpha in chronic viral hepatitis (CVH) and hepatocellular carcinoma (HCC). METHODS: The authors measured the amounts of TGFalpha mRNA in liver tissues from 18 patients with HCC, 31 patients with CVH, and 7 normal controls. " Hot-start" reverse transcription-polymerase chain reaction (RT-PCR) using oligo-dT and specific primers detected TGFalpha mRNA in total cellular RNA extracted from liver tissues. The levels of TGFalpha mRNA were determined by the end point titers of serial, two-fold dilutions of cDNA. The amounts of hepatitis B virus RNA (HBV-RNA) in livers of patients with chronic hepatitis B also were measured by Northern blot hybridization. RESULTS: TGFalpha mRNA levels were extremely higher in patients with HCC compared with patients with CVH and normal controls, and the levels in patients with CVH also were elevated compared with normal controls. The levels of TGFalpha mRNA were overexpressed in the underlying livers of patients with HCC compared with patients with CVH, although they were lower than those found in HCC tissues. The levels of TGFalpha mRNA were higher in samples from patients with chronic hepatitis B than in samples from patients with chronic hepatitis C. The levels of TGFalpha mRNA were not correlated with serum alanine aminotransferase or HBV-RNA levels in liver tissues in patients with chronic hepatitis B. However, the expression of TGFalpha mRNA tended to be higher in the livers of patients with raised serum alpha-fetoprotein levels. CONCLUSIONS: The overexpression of TGFalpha mRNA in the liver seems to be associated with the regeneration of hepatocytes rather than hepatic necrosis or viral replication. Also, it may be related closely to the development or progression of HCC, especially in the livers of patients with chronic hepatitis B.

Combined therapy consisting of intraarterial cisplatin infusion and systemic interferon-alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis.

BACKGROUND: Hepatocellular carcinoma (HCC) patients with major vascular involvement or extrahepatic metastasis are not good candidates for surgery or transarterial chemoembolization (TACE). In this study, the authors evaluated the efficacy of combined therapy with intraarterial cisplatin infusion and systemic administration of interferon-alpha (IFN-alpha) as a palliative treatment for these patients. METHODS: Sixty-eight HCC patients with major portal vein thrombosis (n = 47) or distant metastasis (n = 27) were randomly allocated to 1 of 3 groups. Group I (n = 19) received combined therapy consisting of intraarterial cisplatin infusion and systemic IFN-alpha, Group II (n = 23) received intraarterial cisplatin infusion, and Group III (n = 26) was managed with only supportive care. Cisplatin 2 mg/kg was infused through the proper hepatic artery every 8 weeks, and IFN-alpha 3 million IU/m2 was administered subcutaneously 3 times a week. RESULTS: The partial response (defined as a 50% or greater reduction in the product of the 2 longest perpendicular tumor measurements) rate of Group I was significantly higher than that of Group II (33% vs. 14%; P < 0.05). Also, the 1-year survival rate of Group I (27%) was higher than that of Group II (9%) or Group III (0%) (P < 0.05 and P < 0.01, respectively). The median survival period of Group I was 19 weeks, which was significantly longer than that of Group II (11 weeks) or Group III (5 weeks) (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: These results suggest that combined therapy consisting of intraarterial cisplatin infusion and systemic IFN-alpha may be useful as a palliative treatment for HCC patients with major vascular involvement or extrahepatic metastasis.

Fibrosing cholestatic hepatitis: a report of three cases.

Fibrosing cholestatic hepatitis is an aggressive and usually fatal form of viral hepatitis in immunosuppressed patients. We report three cases of fibrosing cholestatic hepatitis in various clinical situations. Case 1 was a 50-year-old man who underwent a liver transplant for hepatitis B virus (HBV)-associated liver cirrhosis. Two and a half years after the transplant, he complained of fever and jaundice, and liver enzymes were slightly elevated. Serum HBsAg was positive. Case 2 was a 30-year-old man in an immunosuppressed state after chemotherapy for acute lymphoblastic leukemia. He was a HBV carrier. Liver enzymes and total bilirubin were markedly elevated. Case 3 was a 50-year-old man who underwent renal transplantation as a known HBV carrier. One year after the transplant, jaundice developed abruptly, but liver enzymes were not significantly elevated. Microscopically lobules were markedly disarrayed, showing ballooning degeneration of hepatocytes, prominent pericellular fibrosis, and marked canalicular or intracytoplasmic cholestasis. Portal inflammation was mild, but interphase activity was definite and cholangiolar proliferation was prominent. Hepatocytes were diffusely positive for HBsAg and HBcAg in various patterns. Patients died of liver failure within 1 to 3 months after liver biopsy in spite of anti-viral treatment.

Expression of transforming growth factor beta-1 in chronic hepatitis and hepatocellular carcinoma associated with hepatitis C virus infection.

BACKGROUND: Transforming growth factor beta-1 (TGF beta 1) has been suggested to play a role in the development, growth or progression of hepatocellular carcinoma (HCC). Genotype and serum titer of HCV also affect the occurrence of HCC in chronic hepatitis C. In this study, we were to evaluate the effects of genotype or serum titer of HCV on the expression of TGF beta 1. We also intended to examine the correlation between the up-regulation of TGF beta 1 and the association with HCC in patients with chronic hepatitis C. METHODS: We studied 19 patients with chronic hepatitis C and 18 with HCC associated with HCV infection. HCV genotype was determined by line probe reverse hybridization assay and the amount of HCV-RNA was quantitated by branched DNA signal amplification assay. Serum TGF beta 1 level was measured by enzyme linked immunosorbent assay. RESULTS: HCV genotypes of patients with HCC were similar to those without it. Serum HCV-RNA titer was higher in genotype 1b than in non-1b (p < 0.05). Serum TGF beta 1 levels were higher in HCC than in chronic hepatitis (p < 0.05). However, there was no significant difference in the serum TGF beta 1 level between genotype 1b and non-1b. Also, it was not correlated with the serum HCV-RNA titer or alanine aminotransferase levels. CONCLUSION: TGF beta 1 seems to be overexpressed in HCC compared to that of chronic hepatitis C: it was not affected by serum ALT levels, genotype or serum HCV titer. It is suggested that TGF beta 1 may be associated with the malignant transformation of hepatocyte or the progression of HCV-associated HCC.

Proton magnetic resonance spectroscopy (1H-MRS) findings for the brain in patients with liver cirrhosis reflect the hepatic functional reserve.

OBJECTIVE: Proton magnetic resonance spectroscopy (1H-MRS) has been used to assess the metabolic changes in the brain in patients with liver cirrhosis. Decreased myo-inositol and increased glutamine levels were noted to be the most sensitive spectroscopic markers for cirrhotic patients with hepatic encephalopathy (HE). The purpose of this study was to assess how the abnormalities seen on the 1H-MRS of the brain in patients with liver cirrhosis are related to clinical and laboratory parameters. METHODS: In a prospective study, localized 1H-MRS was performed in the basal ganglia and parietal white matter regions in liver cirrhosis patients with (n = 48) and without (n = 52) HE and chronic hepatitis (CH) (n = 15), and in normal controls (n = 20). RESULTS: Among cirrhotic patients, the myo-inositol levels were significantly lower (p < 0.01) and the glutamine levels were higher (p < 0.05) for patients with HE than for those without HE. The myo-inositol and glutamine levels, respectively, were inversely (r = -0.50; p < 0.001) and linearly (r = 0.50; p < 0.001) related to the Child-Pugh score. However, by subgroup analysis of Child-Pugh class C patients, there were no significant differences in the myo-inositol and glutamine levels between cirrhotic patients with (n = 40) and without HE (n = 24). A follow-up study of eight cirrhotic patients with HE showed no significant differences in the myo-inositol and glutamine levels after clinical improvement of HE. CONCLUSIONS: The abnormalities seen on the 1H-MRS of the brain of patients with liver cirrhosis are not likely to reflect the severity of HE or acute alteration in the level of consciousness. Rather, we believe they represent the chronic metabolic derangement of the brain associated with hepatic functional reserve.