Off-treatment durability of antiviral response to nucleoside analogues in patients with chronic hepatitis B.

BACKGROUND: Off-treatment durability of nucleoside analogue (NA) therapy in patients with chronic hepatitis B has not been well investigated. In this study we monitored antiviral effect of NA therapy and evaluated off-treatment durability after NA cessation in patients with chronic hepatitis B. PATIENTS AND METHODS: A total of 94 consecutive patients (39 HBeAg-negative and 55 HBeAg-positive patients) who received NA therapy were followed up for approximately 9 years. We discontinued NA according to the following criteria; undetectable serum HBV-DNA by polymerase chain reaction (PCR) on three separate occasions at least 6 months apart in HBeAg-negative patients (APASL stopping recommendation), and seroconversion from HBeAg-positive to HBeAb-positive and undetectable serum HBV-DNA by PCR for at least 12 months in HBeAg-positive patients. RESULTS: The cumulative rate of relapse after NA cessation was 48 % and 40 % in HBeAg-negative and -positive patients, respectively. Higher baseline serum alanine aminotransferase level was the only significant predictor for maintaining remission. No patients experienced decompensation after relapse. HBsAg loss occurred at an annual rate of 1.4 % and 0.4 % in HBeAg-negative and -positive patients, respectively. Hepatocellular carcinoma developed at an annual rate of 0.6 % in both HBeAg-negative and -positive patients. CONCLUSIONS: Almost half of the patients did not relapse after cessation of NA therapy in both HBeAg-negative and -positive patients. Therefore, NA therapy could be discontinued with close monitoring if the APASL stopping recommendation is satisfied even in HBeAg-negative patients.

Meloxicam as an adjuvant to peginterferon-α-2a and ribavirin treatment for genotype 1 chronic hepatitis C: A randomized trial.

AIM: In this multicenter, randomized trial, we evaluated the effectiveness of meloxicam - a non-steroidal anti-inflammatory drug - as an adjuvant for enhancing antiviral efficacy and preventing neutropenia during the treatment of patients with genotype 1 chronic hepatitis C using peginterferon and ribavirin. METHODS: A total of 60 patients were randomly assigned, in a 1:1 ratio, to either the meloxicam or the control group after stratification by neutrophil count. Both groups received weekly peginterferon-α-2a (180 µg) and a weight-based dose of ribavirin for 48 weeks. The meloxicam group received meloxicam (10 mg/day) for the first 8 weeks after initiation of treatment. RESULTS: Through intent-to-treat analysis, we found that the sustained virological response rate in the meloxicam group (19/30, 63.3%) was significantly higher than in the control group (11/30, 36.7%, P < 0.05). The relapse rate was more than twice as high (45%) in the control group than in the meloxicam group (19.0%); however, this difference was not statistically significant. The rate of neutrophil decrease, calculated by dividing the lowest value observed during the first 8 weeks by pretreatment count, was significantly smaller in the meloxicam group (55.1 ± 14.3%) than in the control group (62.3 ± 9.6%, P < 0.05). CONCLUSION: Meloxicam enhanced antiviral efficacy and reduced the decline in neutrophil counts for the peginterferon and ribavirin treatment of genotype 1 chronic hepatitis C. This drug could be a reasonable adjuvant for the treatment of patients with chronic hepatitis C. The present study including a small number of patients warrants larger clinical trials.

Carbon dioxide (CO2) vs iodinated contrast digital subtraction angiography during balloon-occluded retrograde transvenous obliteration (BRTO) using foam sclerosant for gastric varices.

PURPOSE: To compare the visualization of the target gastric varices (GV) on balloon-occluded retrograde transvenous venography (BRTV) using iodinated contrast material vs carbon dioxide (CO(2)) in preparation for subsequent balloon-occluded retrograde transvenous obliteration (BRTO) using foam sclerotherapy. MATERIALS AND METHODS: In 16 consecutive patients with nonruptured GV, BRTV was performed first using iodinated contrast material and then with CO(2). BRTV was repeated whenever there were changes in the catheter or patient position or when coil embolization of collaterals was needed. Each visualization grade of GV (grade 1 = GV only; grade 2 = GV > collaterals; 3 = GV < collaterals; grades 4-5 = collaterals only) was determined by two observers in consensus. During foam BRTO, the GV visualization grade was recorded again and confirmed by C-arm computed tomography (CT). RESULTS: In 38 pairs of BRTV, GV grades were significantly (P < .0001) lower (ie, favoring BRTO) on CO(2) BRTV (mean ± standard deviation, 1.8 ± 0.8) than on iodine BRTV (3.4 ± 0.8). GV grades on foam BRTO (1.4 ± 0.7) were similar to the grades obtained on the most recent CO(2) BRTV (1.3 ± 0.5) but were significantly smaller (P < .0001) than on iodinated BRTV (3.1 ± 0.9). GV were opacified by foam on initial C-arm CT in 14 patients (87.5%), and complete thrombosis of GV was obtained without any complication in all 16 patients (100%). CO(2) reached the GV even when iodinated contrast material could not (grade 4) in seven of our 16 patients (43.8%), leading to successful BRTO. CONCLUSIONS: CO(2) BRTV visualized GV better than did iodine BRTV and changed the management of more than 40% of patients by enabling successful foam BRTO in patients in which conventional liquid BRTO could not be performed.

Eight-week oral administration of meloxicam, a non-steroidal anti-inflammatory drug, prevents dose reduction of pegylated interferon alpha-2a in the treatment of chronic hepatitis C.

AIM: We conducted a trial to evaluate whether eight-week oral administration of meloxicam, a non-steroidal anti-inflammatory drug, would decrease the rate of the patients who required dose reduction of pegylated interferon alpha-2a in the treatment of chronic hepatitis C. METHODS: Sixty patients given weekly subcutaneous administration of pegylated interferon alpha-2a at a dose of 180 mug for 48 weeks were allocated into the meloxicam group (n = 22) and the control group (n = 38) before interferon treatment. Meloxicam was given orally at a dose of 10 mg once a day for eight weeks from the start of interferon treatment. RESULTS: The cumulative rate of dose-reduction-free patients was significantly higher in the meloxicam group (P < 0.05). Until week eight, 44.7% of the control group and 9.1% of the meloxicam group required dose reduction. Dose was modified by neutropenia in 31.6% and 18.2% of the control and meloxicam groups, respectively. Meloxicam relieved a declineof neutrophil count within the first eight weeks from 54.2% to 44.2% (P < 0.05). Multivariate analysis revealed that greater pretreatment neutrophil count and the use of meloxicam were independent factors associated with avoiding dose reduction. Sustained virological response was obtained in 52.6% of the patients. The multivariate logistic analysis revealed that viral serotype and viral load were the only independent factors associated with sustained virological response. CONCLUSION: Eight-week administration of meloxicam prevented dose reduction of pegylated interferon by relieving a decline of neutrophil count in the treatment of chronic hepatitis C.

A liver-derived immunosuppressive factor is an arginase: identification and mechanism of immunosuppression.

We found a substance in culture medium of neonatal pig liver fragments, which suppresses an immune response monitored by (3)H-thymidine incorporation using phytohemagglutinin (PHA)-stimulated lymphocytes. We named it as an immunosuppressive factor (ISF). To purify ISF, ammonium sulfate fractionation, DE52, SP-Sephadex, hydroxyapatite, blue Sepharose, heparin Sepharose and Superdex gel filtration columns were used. Using these purification procedures, ISF was purified 1,254-fold, with 9.2% recovery, from the culture medium of neonatal pig liver fragments, and was identified as arginase by its biochemical characteristics including molecular size, amino acid sequences of digested peptides and expression of arginase activity. The addition of ISF caused to decrease in arginine concentration in culture medium and at the same time DNA synthesis was suppressed dose-dependently, both of which were recovered by the addition of NOHA (N(G)-hydroxy-L-arginine), an arginase inhibitor. In addition, the depletion of arginine in culture medium also led to the inhibition of DNA synthesis. These results led us to the conclusion that immunosuppressive effect of ISF was due to arginase activity that decreased arginine concentration in culture medium, not to another function of ISF.

Taurolithocholate impairs bile canalicular motility and canalicular bile secretion in isolated rat hepatocyte couplets.

AIM: To investigate the effects of taurolithocholate (TLC) on the canalicular motility in isolated rat hepatocyte couplets (IRHC). METHODS: TLC was added to IRHC at concentrations of 10 and 50 mumol/L, respectively. In each group, five time-lapse movies containing 3 representative bile canaliculi were taken under phase-contrast microscopy for 12 h. The number of bile canalicular contractions and the intervals between consecutive canalicular contractions were calculated. Furthermore, the effects of TLC on IRHC were examined by transmission electron microscopy. RESULTS: The bile canalicular contractions were spontaneous and forceful in the controls. Active vesicular movement was observed in the pericanalicular region. Immediately after the addition of TLC, the bile canaliculi were deformed, and canalicular bile was incorporated into the vacuoles. The canaliculi were gradually dilated, and canalicular contractions were markedly inhibited by TLC. The vesicular movements became extremely slow in the pericanalicular region. The number of canalicular contractions significantly decreased in the TLC-treated groups, as compared with that in the controls. The time intervals were prolonged, as the TLC dosage increased, indicating that bile secretion into the canaliculi was impaired with TLC. Transmission electron microscopy revealed the lamellar transformation of the canalicular membranes in IRHC treated with TLC. CONCLUSION: TLC impairs both the bile canalicular contractions and the canalicular bile secretion, possibly by acting directly on the canalicular membranes in TLC-induced cholestasis.

Effect of in vitro interferon-beta administration on hepatitis C virus in peripheral blood mononuclear cells as a predictive marker of clinical response to interferon treatment for chronic hepatitis C.

AIM: To test whether in vitro incubation of peripheral blood mononuclear cells (PBMC) with interferon (IFN) could efficiently decrease hepatitis C virus-RNA (HCV-RNA) amount and to analyze whether this effect was associated with clinical response to IFN. METHODS: Twenty-seven patients with histologically proven chronic hepatitis C were given intravenous administration of 6 million units (MU) IFN-beta daily for 6 weeks followed by three times weekly for 20 weeks. PBMC collected before IFN therapy were incubated with IFN-beta and HCV-RNA in PMBC was semi-quantitatively determined. RESULTS: Twenty-five patients completed IFN therapy. Eight patients (32%) had sustained loss of serum HCV-RNA with normal serum ALT levels after IFN therapy (complete responders). HCV-RNA in PBMC was detected in all patients, whereas it was not detected in PBMC from healthy subjects. In vitro administration of IFN-beta decreased the amount of HCV-RNA in PMBC in 18 patients (72%). Eight of these patients obtained complete response. On the other hand, none of the patients whose HCV-RNA in PBMC did not decrease by IFN-beta was complete responders. Multiple logistic regression analysis revealed that the decrease of HCV-RNA amount in PBMC by IFN-beta was the only independent predictor for complete response (P<0.05). CONCLUSION: The effect of in vitro IFN-beta on HCV in PBMC reflects clinical response and would be taken into account as a predictive marker of IFN therapy for chronic hepatitis C.

A case of small bowel ulcer caused by NSAIDs and detected after capsule endoscope retention.

We recently detected an annular ulcer thought to have been caused by non-steroidal anti-inflammatory drugs (NSAIDs) when we performed small bowel capsule endoscopy on a patient with suspected small-bowel bleeding and a history of frequent use of oral NSAIDs. The patient was a 64-year-old woman who complained of bloody stools and abdominal pain. The annular ulcer showed concentric stenosis, which caused retention of the capsule endoscope. NSAIDs are some of the most frequently used anti-inflammatory analgesics, and even more frequent use can be expected with the aging of society. No reports to date appear to have described retention of a capsule endoscope due to annular ulceration caused by NSAIDs. We report herein our experience with a patient showing small-bowel ulcer caused by NSAIDs.

Weight-based high- and low-dose ribavirin in combination with peginterferon α-2b therapy for genotype 2 chronic hepatitis C: A randomized trial.

AIM: The optimal ribavirin dose in the treatment of patients infected with hepatitis C virus (HCV) genotype 2 remains to be elucidated. We aimed to seek the optimal ribavirin dose required for this genotype in a randomized trial. METHODS: We compared the efficacy and tolerability of the 24-week peginterferon α-2b (1.5 µg/kg/week) therapy in combination with a weight-based higher dose (600-1000 mg) and lower dose (400-800 mg) of ribavirin for genotype 2 patients. Noninferior margin was set at 10%. RESULTS: A total of 120 patients were randomized to a higher-dose or a lower-dose group. Sustained virological response (SVR) by intention-to-treat analysis was achieved in 47/58 (81.0%, 90% confidential interval [CI]: 72.6-89.5) patients in the higher-dose group and 41/60 (68.3%, 90% CI: 58.5-78.2) patients in the lower-dose group (difference, -12.7%; 90% CI, -25.7 to 0.3). Relapse rates were 10% and 21.6% in the higher-dose and the lower-dose groups, respectively. Multiple logistic regression analysis showed that ribavirin dose/kg body weight was the only significant predictor of SVR (≥9.5 mg/kg per day vs <9.5 mg/kg per day; odds ratio = 3.34; 95% CI, 1.41-7.92; P = 0.006). Twenty-one (36.2%) in the higher-dose group required ribavirin dose reduction because of anemia, whereas seven patients (11.7%) did in the lower-dose group (P < 0.01). Three of the higher-dose group and two of the lower-dose group required premature termination of therapy. CONCLUSIONS: Weight-based lower-dose ribavirin regimen was not equivalent to the higher-dose counterpart in the treatment of HCV genotype 2. We discourage treating these patients with low-dose ribavirin regimens. The peginterferon therapy in combination with ribavirin at a weight-based higher dose (600-1000 mg) remains the standard-of-care treatment for this genotype.

Transcatheter arterial chemoembolization plus radiofrequency ablation therapy for early stage hepatocellular carcinoma: comparison with surgical resection.

BACKGROUND: Radiofrequency ablation (RFA) is becoming a well-known local therapy for hepatocellular carcinoma (HCC). Transcatheter arterial chemoembolization (TACE) is expected to enhance the effects of subsequent RFA by reducing arterial blood flow. However, the long-term efficacy of this combined therapy has not been elucidated. In this study, the survival rates of patients who received TACE combined with RFA (TACE + RFA) were compared with those of patients treated surgically. METHODS: The study included consecutive patients who received TACE+RFA or surgical resection as the initial curative treatment for HCC between 2000 and 2005 at Tokai University Hospital. Inclusion criteria were a single HCC

Differential impact of adherence to pegylated interferon and ribavirin in the treatment of genotype 1 high viral titer chronic hepatitis C.

To clarify the impact of adherence, we treated 122 genotype 1 high viral titer chronic hepatitis C patients with pegylated interferon (peg-IFN) and ribavirin for 48 weeks at nine referral hospitals, and evaluated the prognostic factors with a focus on the adherence to the treatment. This study included 68 (55.7%) treatment-naïve patients and 54 (44.3%) patients who did not respond to the previous treatment. Multivariate analysis revealed adherence to peg-IFN and ribavirin as the only significant predictor. Sustained virological response (SVR) rate was 72.2%, 19.0%, and 27.3% in patients given ≥80%, 60%-80%, and <60% dose peg-IFN, respectively, and was 68.6%, 41.2%, and 5.3% in those given ≥80%, 60%-80%, and <60% dose ribavirin, respectively. SVR rate sharply fell when exposure to peg-IFN was below 80% whereas it decreased in a stepwise manner as for ribavirin. Therefore, ≥80% of peg-IFN and as much as possible dose of ribavirin are desired to achieve SVR in the treatment of genotype 1 high viral titer chronic hepatitis C.

Ultrasonographic diagnosis of adult intussusception caused by pedunculated colon carcinoma.

Adult intussusception is clinically rare. We report a case with colon intussusception caused by a pedunculated polyp of the sigmoid colon in a 54-year-old male. Abdominal ultrasonographic screening for hematochezia showed intussusception in the sigmoid colon, demonstrating a multiple concentric ring sign and a mobile leading colon polyp. Histological examination of a biopsy specimen of the polyp revealed adenoma. This report suggests that ultrasound imaging is a modality of choice for differential diagnosis of intestinal intussusception with hematochezia in adults.

Clinical significance of serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in chronic liver disease.

OBJECTIVE: We have attempted to determine serum levels of type IV collagen (IV-C), laminin (LM), prolylhydroxylase (PH), metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in chronic liver disease to elucidate the clinical significance of MMPs and TIMPs in the process of hepatic fibrosis. METHODS: Serum samples were collected from 60 patients with chronic liver disease caused by hepatitis B or C. Serum levels of IV-C, LM, PH, MMP-1, 2 and 3, and TIMP-1 and 2 were measured by a one-step sandwich enzyme immunoassay using monoclonal antibodies. The values were correlated with Histology Activity Index (HAI) scores of liver biopsy specimens. RESULTS: LM and IV-C levels markedly increased in parallel with the progression of the chronic liver disease. The MMP-2 and MMP-3 levels tended to increase in chronic active hepatitis (CAH), and significantly elevated in liver cirrhosis (LC). There was a positive correlation between the IV-C and MMP-2 levels, and the ratio of IV-C to MMP-2 levels was significantly elevated in LC. Both TIMP-1 and TIMP-2 levels were markedly increased in LC. The HAI scores were positively correlated with the serum IV-C and MMP-2 levels. CONCLUSIONS: Serum IV-C and MMP-2 levels may be useful diagnostic markers for hepatic fibrosis, since they increased in parallel with the progression of chronic liver disease. In addition, the imbalances between IV-C, LM, and TIMP-1 and 2 as fibrogenic factors and MMP-2 and 3 as fibrolytic factors may lead to fibrosis in chronic viral liver disease, especially in cirrhosis.

Assessment of a difference in ALDH2 heterozygotes and alcoholic liver injury.

We have speculated that the degree of liver dysfunction in alcoholic liver disease with ALDH2*1/2*2 may be less pronounced than that with ALDH2*1/2*1. In the present study, outpatients with alcoholic liver injury were examined for ALDH2 genotype and biochemical data. The number of patients was 29 cases of nonspecific changes, 16 cases of fatty liver, 5 cases of liver fibrosis, and 44 cases of liver cirrhosis. Biochemical data were evaluated with ALDH2 heterozygotes data obtained by PCR-SSCP. The ALDH2*1/2*1 and ALDH2*1/2*1 genotypes accounted for 90% and 10%, respectively. As for ALDH2*1/2*2, there were three patients with nonspecific changes, three with fatty liver, one with liver fibrosis, and two with liver cirrhosis. In alcoholic liver disease patients, when the ALDH2*1/2*2 genotype was compared with the ALDH2*1/2*1 genotype with biochemical data, the gamma-GTP value in patients with ALDH2*1/2*2 was significantly higher than with ALDH2*1/2*1 ( < 0.005). When the frequency of ALDH2 genotype was determined in patients with alcoholic liver injury, ALDH2 heterozygotes accounted for 15% for the non-cirrhosis group, and 5% for the cirrhotic group. When a relationship between the amount of ethanol intake and biochemical data were determined in patients with alcoholic liver injury who have ALDH2 heterozygotes, the glutamic oxaloacetic transaminase (GOT) and gamma-GTP values were significantly higher at an ethanol intake amount of ethanol more than 100 g per day than intake less than 100 g per day ( < 0.05). The alcoholic patients with ALDH2*1/2*2 drink a slight amount of ethanol, the liver injury is found to be stronger than those with ALDH2*1/2*1 when they drink more than 100 g ethanol per day.

Sonographic evaluation of the anterior liver surface in chronic liver diseases using a 7.5-MHz annular-array transducer: correlation with laparoscopic and histopathologic findings.

PURPOSE: We studied the sonographic appearance of the anterior liver surface using an ultrasound scanner equipped with a 7.5-MHz annular-array transducer to determine the accuracy of this imaging modality in monitoring the course of chronic liver diseases. METHODS: We prospectively evaluated patterns of the liver surface in the sonograms of 77 consecutive patients with chronic liver diseases who had undergone sonographic examination with a 7.5-MHz annular-array transducer and a 3.75-MHz convex-array transducer over a 2-year period and compared these findings with those of laparoscopy (using previously described categories) and histopathology. RESULTS: Histopathologically confirmed disease prevalences for inactive chronic hepatitis, active chronic hepatitis, liver cirrhosis, and others were 10% (8/77), 56% (43/77), 29% (22/77), and 5% (4/77), respectively. The sonographic appearance of the liver surface with the 3.75-MHz transducer was classified as either a regular or an irregular pattern. The regular pattern corresponded to 69% (34/50) of the cases in laparoscopic category 200 or 300 and the irregular pattern with 85% (23/27) of the cases in category 400 or 500. The sonographic appearance of the liver surface with the 7.5-MHz transducer was classified as regular, unevenly irregular, diffusely irregular, or nodular. These 4 patterns detected 75% (24/32), 78% (14/18), 52% (12/23), and 75% (3/4) of the cases of laparoscopic categories 200, 300, 400, and 500, respectively. In a comparison of the sonographic patterns of the liver surface with the differential histopathologic findings, the regular sonographic pattern corresponded to 88% (7/8) of the cases of inactive chronic hepatitis, the unevenly irregular pattern with 35% (15/43) of the cases of active chronic hepatitis, and the diffusely irregular and nodular patterns (considered as 1 group) with 68% (15/22) of the cases of liver cirrhosis. CONCLUSIONS: Our results suggest that sonographic evaluation of the liver surface with a 7.5-MHz annular-array transducer using this classification provides detailed information on the evolution of chronic liver diseases that correlates with the laparoscopic and histopathologic findings and thus is a useful noninvasive method for monitoring the disease course to cirrhosis.