Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct-acting antiviral therapy.

To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon-free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co-infected patients and 765 patients with resolved HBV infection during and after treatment with direct-acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti-HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)-positive patients with an HBV DNA level <2000 IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti-HBs titres at baseline with those at post-DAA therapy in 123 patients without HBsAg. There was no significant difference in anti-HBs levels between the two points (P = .79). In conclusion, HBV reactivation was rare in HBsAg-negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV-reactivated patients with a baseline HBV DNA level <2000 IU/mL before DAA therapy.

Development of hepatocellular carcinoma in patients with chronic hepatitis C who had a sustained virological response to interferon therapy: a multicenter, retrospective cohort study of 1124 patients.

BACKGROUND: Interferon (IFN) improves hepatic inflammation/fibrosis and reduces the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CH-C). However, HCC develops in some patients who have a sustained virological response (SVR) to IFN therapy. We designed this study to establish a follow-up protocol for patients with CH-C who have SVR to IFN therapy. METHODS: We retrospectively studied 1124 patients with CH-C who received IFN. RESULTS: HCC developed in 3.5% of patients with SVR to IFN. As compared with SVR patients without HCC, SVR patients with HCC were predominantly male (P=0.003), older at the initiation of IFN therapy (P=0.002), and at a more advanced histologic stage of disease (P<0.001). However, three of the 13 SVR HCC patients had mild fibrosis. The mean interval from IFN therapy to the detection of HCC in SVR HCC patients was 5.8 years and did not differ significantly from that in non-SVR HCC patients (P=0.304). Although most patients with HCC received curative therapy, the prognosis of some SVR HCC patients was poor, probably because of insufficient follow-up, resulting in delayed detection of HCC. CONCLUSIONS: SVR patients with CH-C who are elderly, male, or have an advanced histologic stage are at a high risk for the development of HCC after IFN therapy. We recommend that SVR patients should be observed carefully for more than 10 years after the completion of IFN therapy, even if they only have early fibrosis.

Interferon reduces somatic mutation of mitochondrial DNA in liver tissues from chronic viral hepatitis patients.

SUMMARY: We recently reported that the genetic instability resulting in the high rate of mitochondrial DNA (mtDNA) mutation in noncancerous liver tissue is consistent with the multicentric hepatocarcinogenesis detected clinically. Interferon (IFN) has been reported to reduce hepatocarcinogenesis in individuals with hepatitis virus infection. Liver biopsy specimens were obtained from 26 patients with chronic hepatitis C virus (HCV) infection before and after IFN therapy (total dose: 252 million units). The mean (+/-SD) age of the study population was 45 +/- 9 years and 13 (50%) were male [mode of acquisition: blood transfusion (27%), unknown (73%); viral load: 5.2 +/- 1.1 k copies/mL; duration of infection: 17 +/- 9 years (65%), unknown (35%); genotype: I (4%), II (80%), III (8%), IV (8%); alcohol intake: positive (31%), negative (69%)]. DNA samples were extracted from the specimens and subjected to direct sequencing. The mtDNA mutation frequency in the D-loop was increased in liver specimens from individuals with HCV infection compared with 21 controls (2.5 vs 0.6, P < 0.001). IFN therapy decreased the mtDNA mutation (mean difference = 0.7, P < 0.001) and the decreased number of mtDNA mutations was positively correlated with suppression of the total histological activity index score (mean difference = 1.3, P < 0.01). These results clearly indicate that the mutational rate of mtDNA is strongly associated with IFN therapy. Thus, analysis of mtDNA could provide a new criterion for the therapeutic evaluation of the effect of IFN, and may be useful for the prediction of risk of carcinogenesis.

[A study of hypertriglyceridemia occurring in patients with chronic hepatitis C during administration of interferon beta].

The prevalence and risk factors of hypertriglyceridemia during the administration of interferon (IFN) were examined in 78 patients with chronic hepatitis C who were treated with 6 MU of IFN-beta once or 3 MU of IFN-beta twice a day for 6 weeks. Hypertriglyceridemia (serum triglyceride (TG) above 150 mg/dl) was found before the start of IFN treatment in 9% of the patients. During the administration of IFN, elevation of serum TG above 150 mg/dl was found in 82% of patients. In addition, serum TG level exceeded 500 mg/dl at least once during the administration of IFN in 13% of patients. On stepwise multiple regression analysis, three risk factors, high serum TG value before the administration of IFN, high ALT value before the administration of IFN, and divided administration of IFN-beta twice daily were found to be associated with hypertriglyceridemia during IFN administration.

Peliosis hepatis associated with idiopathic restrictive cardiomyopathy.

A rare case of peliosis hepatis associated with idiopathic restrictive cardiomyopathy is reported. A 75-year-old man was admitted for evaluation of marked edema and jaundice. Serum total bilirubin was elevated above 20 mg/dl. The liver biopsy under laparoscopy revealed marked sinusoidal dilatation and retention of red blood cells, which was consistent with a diagnosis of peliosis hepatis. Cardiac catheterization revealed right ventricular filling disturbance without specific findings on endomyocardial biopsy, suggesting idiopathic restrictive cardiomyopathy. The level of serum total bilirubin decreased in association with improvement of edema after drip infusion of furosemide therapy.

[MR imaging of hepatocellular carcinoma following microwave coagulation therapy].

MRI was performed in 13 patients who had microwave coagulation therapy (MCT) for hepatocellular carcinoma. Six of them underwent surgery after MRI. The area (including tumor) treated by MCT showed low to high intensity on T1WI, and low to isointensity on T2WI. No enhancement was obtained on dynamic MRI. Histologically, this area was supposed to be coagulation necrosis. On T1WI, only tumor showed high intensity within the MCT area in 8 patients, and nearly uniform intensity was observed in 5 patients. Histologically, residual cell nuclei were observed in the former, and nearly uniform coagulation necrosis in the latter. The marginal part of the MCT area exhibited low intensity on T1WI, and high intensity on T2WI. Strong enhancement was obtained on dynamic MRI, and histologically, granulation tissue was noted. In the hepatic parenchyma around the MCT area, a ring-or wedge-shaped high intensity part was observed in 7 patients on T2WI, and that part was enhanced on dynamic MRI. This finding was considered to reflect changes such as hepatic hyperperfusion. In terms of the capability of visualizing residual tumor after MCT, MRI was superior to CT. Furthermore, a clear distinction was seen between the MCT area and non-MCT area on T2WI and dynamic MRI. Thus, MRI was useful in the determination of additional therapy.

[Percutaneous microwave coagulation therapy for hepatocellular carcinoma--study on its therapeutic effect in surgical cases].

Six patients with hepatocellular carcinoma were subjected to percutaneous microwave coagulation therapy (PMCT) by ultrasonic guiding. The size of the main tumor in the present cases was limited to not more than 2 cm. From 18 to 48 days after PMCT, each patient was subjected to surgery and pathological examination. By macroscopic observation, the PMCT area including both non-tumor and tumor regions looked yellowish white, and the boundary was clearly recognized. In the histological examination, the coagulation area surrounded by fibrous capsule was found, and deletion of nuclei and changes in stainability were observed in the marginal region. These changes indicated obvious coagulation necrosis, but the changes became less intense toward the center in the area, and in some portions, the tissue was indistinguishable from viable cells by light microscopy. In 2 cases out of the 6, part of the tumor remained outside the coagulation area. Since only the area determined by the microwave electrode is coagulated to cause necrosis on PMCT, sufficient safety margin should be required.

Study on the mechanism of an experimental immunological intrahepatic cholestasis model.

Tuberculin-sensitized guinea pigs were intravenously injected with heat-killed Propionibacterium acnes followed by an intravenous injection of purified protein derivatives 7 day later, resulting in the induction of intrahepatic cholestasis. Using this experimental model, the following results were obtained: (1) Both uptake and release of bile acid were inhibited in the hepatocytes prepared from the cholestasis guinea pigs. (2) The results of the erythritol clearance method indicated that the decrease in bile flow observed in the cholestasis guinea pigs was mostly attributable to the reduced bile excretion from the canaliculi. (3) The decrease in the formation of bile acid independent bile flow was the cause of the decrease in bile flow observed in the cholestasis guinea pigs. (4) There was no change in the permeability of the interhepatocellular tight junction in the cholestasis guinea pigs.

[Choleretic effects of taurine on experimentally-induced intrahepatic cholestasis].

When a lymphokine, the cholestatic factor, is intravenously injected into rats through a mesenteric vein, remarkable reductions in bile flow and bile acid excretion are observed. However when taurine was injected with the cholestatic factor, the reduction in bile flow and bile acid excretion were significantly suppressed. Moreover, injection of taurine with cholestatic factor resulted in the decreases of both bile acid-dependent bile flow and vesicular transport but not bile acid-independent bile flow. Not significant choleretic effects were noted when taurine alone was administered to normal rats.

Effects of arachidonic acid metabolites and interleukin-1 on platelet activating factor production by hepatic sinusoidal endothelial cells from mice.

The effects of interleukin-1 (IL-1) and arachidonic acid metabolites, prostaglandin (PG) E1, leukotriene (LT) B4 and LTC4, on the amount of platelet activating factor (PAF) produced and released by mouse hepatic sinusoidal endothelial cells were investigated. When hepatic sinusoidal endothelial cells were incubated with 1 microgram/mL of calcium ionophore (CaI) A23187, PAF production increased until 20 min after the start of incubation, but when the cells were incubated with PGE1 and CaI A23187, PAF production was significantly suppressed. On the other hand, when hepatic sinusoidal endothelial cells were incubated with IL-1 beta, LTB4 or LTC4 alone, PAF production significantly increased compared with that of the cells incubated without these substances. However, when the cells were incubated with PGE1 alone or with IL-1 beta, LTB4 or LTC4 and CaI A23187, these effects were not observed. These results indicated that PAF produced by hepatic sinusoidal endothelial cells is affected by IL-1 and arachidonic acid metabolites, suggesting that immune and inflammatory reactions in these cells may be regulated by chemical mediators produced by the cells themselves.

Possible involvement of platelet-activating factor in the induction of liver cell injury.

In order to examine whether the platelet-activating factor (PAF) plays a role in the induction of liver cell injury, the effects of a PAF antagonist were studied in an experimental model of mice with acute liver cell injury induced by intravenous injection of heat-killed Propionibacterium acnes (P. acnes) and lipopolysaccharide. As a result, an intravenous injection of the PAF antagonist was shown to improve the histological changes in the liver, reducing the degree of focal tissue necrosis. In addition, liver adherent cells isolated from normal mice and from those pretreated with P. acnes were shown to produce PAF by stimulation with calcium ionophore A 23187. These results suggested that PAF produced by liver adherent cells may be involved in the induction of liver cell injury.

Effects of ursodeoxycholic acid on intrahepatic cholestasis.

Ursodeoxycholic acid (UDCA) was administered to 16 intrahepatic cholestasis patients with severe jaundice, and its clinical effects were studied. As a result, it was remarkably effective in 6 patients, significantly effective in 5 patients, slightly effective in 2 patients and unchanged in 3 patients. As for the dose, when 600 mg/day was administered, it was effective in all patients, but even when only 150 mg/day was administered, it was effective in one patient (50%). Duration of treatment was 15 to 177 days with a mean of 55.3 days. These results suggested that while there is no adequate treatment for intrahepatic cholestasis with severe jaundice, UDCA should be considered as a possible method of treatment.