Long-term pegylated interferon monotherapy following 72 weeks of pegylated interferon and ribavirin in hepatitis C virus genotype-1-infected slow responders.

OBJECTIVE: Slow responders to pegylated interferon (Peg-IFN) and ribavirin (RBV) among patients infected with hepatitis C virus (HCV) genotype 1 may benefit from an extended treatment course. The aim of this study was to determine the efficacy of persistent negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy. METHODS: A total of 46 HCV genotype 1-infected slow responders were treated for 72 weeks with Peg-IFN and RBV combination therapy alone (n=25) or additional long-term biweekly treatment with 90 µg of Peg-IFN-α2a (n=21). The criterion for the completion of long-term Peg-IFN monotherapy was defined as the attainment of constantly negative HCV RNA in the serum over 96 weeks during IFN treatment. RESULTS: The patients with sustained negative serum HCV RNA during 96 weeks of IFN treatment had a higher rate of sustained virological response (SVR) than those without (81 vs. 40%, p=0.012). A multivariate analysis identified sustained negativity of serum HCV RNA over 96 weeks of IFN treatment to be a predictive factor for SVR. CONCLUSION: In the present study, sustained negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy of Peg-IFN and RBV resulted in beneficial virological outcomes among HCV genotype 1-infected slow responders.

Does hepatic oxidative stress enhance activation of nuclear factor-E2-related factor in patients with nonalcoholic steatohepatitis?

The imbalance of hepatic oxidant and antioxidant status is an important pathophysiological mechanism in nonalcoholic steatohepatitis (NASH). The nuclear factor-E2-related factor (Nrf2) is a key transcription factor regulating a plethora of antioxidant genes involved in antioxidant defense. To clarify the mechanisms of hepatic antioxidant defenses in human NASH, the aim of the current study was to examine oxidative stress-induced Nrf2 activation in the livers of patients with NASH. Liver biopsies were obtained from 19 NASH patients. Normal liver tissue was obtained from surgical resection specimens of 15 patients. The proportion of hepatocytes with 8-hydroxydeoxyguanosine (8-OHdG)-positive nuclei was increased in NASH livers compared with that in normal livers. Hepatic Nrf2 protein levels were increased with enhanced accumulation of hepatocellular nuclear Nrf2, which was positively correlated with that of 8-OHdG. Hepatic expression of γ-glutamylcysteine synthetase (γGCS), glutathione peroxidase 2 (GPx2), thioredoxin (TRX), and heme oxygenese 1 (HO-1), but not thioredoxin reductase 1 (TrxR1), was upregulated, and the protein levels of γGCS were positively correlated with those of Nrf2. Collectively, our findings lead to the hypothesis that oxidative stress may enhance Nrf2 activation in the livers of patients with NASH.

Differential expression of hepatic apurinic/apyrimidinic endonuclease 1, a DNA repair enzyme, in chronic hepatitis.

AIM: To determine hepatic expression of apurinic/apyrimidinic endonuclease 1 (APE-1) and 8-hydroxydeoxyguanosine (8-OHdG) in patients with chronic hepatitis B and C. METHODS: Liver biopsies were obtained from 27 patients with chronic hepatitis B virus (HBV), 30 with chronic hepatitis C virus (HCV), 6 with autoimmune hepatitis (AIH), and 6 with primary biliary cirrhosis (PBC). Normal liver tissue was obtained from surgical resection specimens of four patients. Hepatic APE-1 protein and mRNA expression were assayed by Western blot and by real-time polymerase chain reaction, respectively. Hepatocellular APE-1 and 8-OHdG expression were determined by immunohistochemistry. RESULTS: The staining intensity of hepatocellular nuclear APE-1 was lower in the HBV group than in the other groups (P < 0.05). Hepatic APE-1 protein levels were reduced in the HBV group relative to the other groups. Hepatic APE-1 mRNA levels were also lower in the HBV group. The proportion of hepatocytes with 8-OHdG-positive nuclei was increased in the HCV, AIH and PBC groups (P < 0.05), but not in the HBV group. Hepatocellular nuclear APE-1 levels were positively correlated with hepatocellular 8-OHdG levels in both the HBV and HCV groups (HBV, r = 0.34, P < 0.05; HCV, r = 0.54, P < 0.01). CONCLUSION: An imbalance between oxidative DNA damage and APE-1 expression may contribute to hepatocarcinogenesis in chronic viral hepatitis.

Relationship between urinary fractional excretion of sodium and life prognosis in liver cirrhosis patients.

AIM: Renal vasoconstriction in generalized vasodilatation with blood pooling and the consequent reduction in effective arterial volume is the pathophysiological basis of liver cirrhosis (LC). Low levels of fractional excretion of sodium (FENa) are an effective marker of hypoperfusion of the renal artery. However, the relationship between levels of FENa, LC severity and life prognosis has not yet been elucidated. METHODS: We examined 57 LC patients (39 men and 18 women; mean age, 70.5 ± 8.8 years; underlying liver disease, type B hepatitis in eight patients, type C hepatitis in 37, alcoholic hepatitis in four and others in eight) with renal dysfunction (estimated glomerular filtration rate (eGFR) <60 mL/min) who were admitted to our hospital. RESULTS: Nine patients died because of uremia, liver failure, gastrointestinal bleeding and infection. No differences were found in patient background and blood pressure. However, in addition to differences in the levels of aspartate aminotransferase (AST), cholinesterase, albumin, prothrombin time (PT), eGFR and Model for End-Stage Liver Disease (MELD) score, the patients who died had significant differences in levels of FENa. The levels of FENa were significantly and inversely correlated with blood urea nitrogen, total bilirubin, AST, Child-Pugh score and MELD score, and were significantly and positively correlated with cholinesterase, albumin and PT. Moreover, the sensitivity (88%) and specificity (93%) of the levels of FENa of less than 0.4% to predict death were remarkably high. CONCLUSION: Levels of FENa may reflect LC severity and may be associated with the life prognosis of LC patients.

Postoperative bile leakage managed by interventional intrabiliary ethanol ablation.

We report a case of postoperative bile leakage that was successfully managed by intrabiliary ethanol ablation. A 68-year-old man with peritoneal and liver metastases from a jejunal gastrointestinal stromal tumor (GIST), which were refractory to molecular-targeted agents, underwent extended left lobectomy and peritoneal tumor resection. Bile leakage from the drainage tube persisted at a constant volume of 100 ml per day. On the 20th postoperative day, fistulography through a drainage tube and endoscopic cholangiography revealed biliary leakage from the bile ducts of segments 5 and 1. Since these bile ducts did not communicate with the proximal hilar bile ducts, two 5F balloon catheters were separately advanced into the leaking bile ducts via the drainage tube on day 30, and 1 ml absolute ethanol was injected into both of these catheters for 10 minutes. After three sessions of ethanol ablation, the bile leakage stopped. Although the bile leakage from segment 1 relapsed five days later, it gradually decreased and then stopped again until day 70. Intrabiliary ethanol ablation using the interventional technique is useful for managing bile leakage after hepatectomy when the leaking distal bile duct is isolated from the proximal biliary tree.

Hemorrhagic radiation gastritis successfully treated with repeated intra-arterial steroid infusions.

Intra-arterial steroid infusion therapy has previously been shown to be effective for inflammatory bowel disease; however, few cases in which it has been used for the treatment of hemorrhagic radiation gastritis have been reported. We report the case of a 70-year-old Japanese man with hemorrhagic radiation gastritis induced by radiation therapy for para-aortic lymph node metastases of hepatocellular carcinoma. Two months after completing radiation therapy, acute persistent bleeding occurred in the gastric irradiation area. Although argon plasma coagulation was performed five times over a month, the bleeding continued and the patient showed persistent anemia that required 50 units of blood transfusion. Finally, the patient was given intra-arterial steroid infusions through the right gastric artery and the right gastroepiploic artery. After three intra-arterial steroid infusions, the melena stopped, and the anemia no longer progressed. Hemorrhagic radiation gastritis was successfully treated with repeated intra-arterial steroid infusions through the regional vessels to the gastric mucosa. Repeated intra-arterial steroid infusions could be a clinically useful option for the treatment of intractable bleeding from radiation gastritis.

A case of systemic lupus erythematosus with liver damage.

A 38-year-old woman with systemic lupus erythematosus (SLE) presented with liver damage during prednisolone therapy. Because her liver damage did not improve, she was admitted to our hospital. Laboratory findings revealed liver enzyme elevation, impaired glucose tolerance, and insulin resistance. Pathological examination revealed marked diffuse macro and microvesicular fatty infiltration. Because the patient did not consume alcohol, she was given a diagnosis of nonalcoholic steatohepatitis. To improve her insulin resistance, we administered pioglitazone therapy for 1 week; however, subsequent laboratory findings did not indicate any improvement in her liver damage. Assuming that SLE might have caused liver damage, we administered high-dose prednisolone therapy; subsequent laboratory findings indicated that her serum complement titer and the level of liver enzymes improved. Abdominal computed tomography revealed that the Hounsfield number of the liver increased to normal after treatment. Fat infiltration of the liver improved after treatment, which confirmed the fact that her liver damage had been due to SLE.

Enhanced hepatic Nrf2 activation after ursodeoxycholic acid treatment in patients with primary biliary cirrhosis.

The cytoprotective mechanisms of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) have not been fully clarified. UDCA has some antioxidant properties. Nuclear factor-E2-related factor-2 (Nrf2) plays a critical role in protecting a variety of tissues against oxidative stress. Therefore, to investigate the potential antioxidant effects of UDCA in PBC, we determined the intracellular status of both oxidant stress and antioxidant defenses in paired pre- and posttreatment liver biopsies from 13 PBC patients by immunodetection of 8-hydroxydeoxyguanosine (8-OHdG), Nrf2-, and Nrf2-mediated antioxidant proteins. After UDCA treatment, the number of 8-OHdG-positive hepatocytes or bile duct cells decreased with improvement of hepatic injury. The hepatic levels of both total and phosphorylated Nrf2 protein were increased, along with upregulation of nuclear phosphorylated Nrf2 expression in bile duct cells. In addition, the levels of both thioredoxin (TRX) and thioredoxin reductase 1 (TrxR1) protein were increased in the liver after UDCA. The upregulation of hepatic TRX or TrxR1 protein expression positively correlated with that of total Nrf2 protein expression. In conclusion, UDCA treatment can enhance hepatic Nrf2 activation and upregulate hepatic TRX and TrxR1 protein expression. Hepatic Nrf2 activation may play a role in the therapeutic response to UDCA in PBC.

A significant reduction in serum alanine aminotransferase levels after 3-month iron reduction therapy for chronic hepatitis C: a multicenter, prospective, randomized, controlled trial in Japan.

BACKGROUND: Increasing evidence indicates that iron cytotoxicity plays an important role in the pathogenesis of chronic hepatitis C (CHC). However, the biochemical effects of iron reduction therapy on CHC remain to be confirmed in a controlled study. This study aimed to test whether iron removal by repeated phlebotomy improves serum alanine aminotransferase (ALT) levels in patients with CHC. METHODS: Patients were randomly assigned to an iron reduction therapy or control group. The patients in the treatment group received 3-month iron reduction therapy by biweekly phlebotomy, while the patients in the control group were followed up for 3 months with regular blood tests alone. RESULTS: Thirty-three patients completed the 3-month treatment, while 29 patients received the complete follow-up. The serum ALT levels were reduced from 118 +/- 79 to 73 +/- 39 IU/L in the treatment group, but did not change in the control group (106 +/- 45 versus 107 +/- 48 IU/L). Posttreatment enzyme activity was decreased significantly from the baseline. Furthermore, it was significantly lower than the 3-month control level. Although 5 patients withdrew from the study, none was affected by any side effects of repeated phlebotomy that required them to discontinue the treatment. CONCLUSIONS: This short-term controlled trial demonstrated the biochemical efficacy and safety of iron reduction therapy for patients with CHC.