Significance of day-1 viral response of hepatitis C virus in patients with chronic hepatitis C receiving direct-acting antiviral therapy.

BACKGROUND AND AIM: On-treatment response of serum hepatitis C virus (HCV) is reportedly less useful to predict the outcome of anti-HCV therapy with interferon (IFN)-free regimen with direct-acting antivirals than with IFN-based regimens in clinical trials. We evaluated the significance of very early viral response after the start of therapy, which indicates direct HCV response to the drugs, on therapeutic outcome. METHODS: Reductions in serum HCV-RNA levels were measured at 1 day after the start of therapy in 544 patients who underwent IFN-free direct-acting antiviral regimens. The association between these reductions and the achievement or failure of sustained virologic response (SVR) was evaluated. RESULTS: Patient characteristics did not influence 1-day reduction in serum HCV-RNA except for liver fibrosis. There was no difference in 1-day HCV reduction between SVR and non-SVR patients treated with a 24-week regimen. In contrast, in patients treated with a 12-week regimen, 1-day reduction was significantly greater in SVR than in non-SVR patients (P = 0.0013) and was predictive of SVR versus non-SVR (area under the receiver-operating characteristics curve: 0.80). CONCLUSIONS: Whereas the reduction in serum HCV-RNA levels at 1 day after the start of therapy was not associated with treatment outcomes in patients who underwent a 24-week regimen of IFN-free therapy, there was an association in patients receiving a 12-week regimen, and this reduction was predictive of SVR, thus potentially serving as a factor to identify patients at risk of treatment failure.

Differences in the impact of prognostic factors for hepatocellular carcinoma over time.

The aim of the present study was to evaluate the prognostic significance of serum markers that reflect tumor progression, liver function, or liver fibrosis in patients with hepatocellular carcinoma (HCC), focusing on how their impact changes over time after diagnosis. Alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), albumin-bilirubin (ALBI) score, aspartate aminotransferase to platelet ratio index (APRI), and FIB-4 index were measured at the time of initial non-recurrent HCC diagnosis in 1669 patients between 1997 and 2016. Survival rates after diagnosis were compared after stratifying patients by these markers. Time-dependent receiver-operating characteristics (ROC) analysis was carried out to assess how these markers predict patient survival or death. Serum AFP and DCP levels, ALBI score, and APRI and FIB-4 index were strongly correlated with HCC progression, liver function, and degree of liver fibrosis, respectively. Survival rates after diagnosis were significantly different when patients were stratified by these markers. In the time-dependent ROC analysis, AFP and DCP had a high prognostic impact within 3 years of diagnosis but the impact decreased thereafter. In contrast, APRI and FIB-4 index had higher prognostic impact 10 years after diagnosis. ALBI score had a high prognostic impact throughout the study period. Time-dependent ROC analysis clearly showed changes in the prognostic importance of serum markers based on the duration after diagnosis. Whereas the prognostic impact of tumor progression markers was strong in the short term, liver fibrosis markers had higher prognostic impact long after diagnosis. Liver function had constant prognostic impact on patient survival after diagnosis.

Viral eradication reduces all-cause mortality, including non-liver-related disease, in patients with progressive hepatitis C virus-related fibrosis.

BACKGROUND AND AIM: Eradication of hepatitis C virus (HCV) with interferon (IFN)-based therapy has been reported to reduce all-cause mortality in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality and causes of death has not been sufficiently investigated in patients with progressive HCV-related fibrosis. METHODS: We enrolled 784 chronic HCV patients with progressive liver fibrosis (aspartate aminotransferase to platelet ratio index >1). Cause of death, incidence of hepatocellular carcinoma, and all-cause mortality including non-liver-related mortality were analyzed. RESULTS: Of these 784 patients, 170 achieved sustained virological response (SVR) (eradication of HCV) with IFN-based therapy (IFN-SVR), and 614 did not receive IFN-based therapy (non-IFN patients, chronic HCV infection). The median follow-up duration was 10.3 years. Two hundred seventy-three patients died during follow-up (liver-related death, n = 171; non-liver-related death, n = 102). The mortality rate from non-liver-related disease was 63.6% (7/11) in IFN-SVR patients and 36.3% (95/262) in non-IFN patients, respectively. In multivariate analysis, the eradication of HCV associated with not only hepatocellular carcinoma incidence (hazard ratio (HR), 0.162; 95% confidence interval (CI), 0.092-0.284), and all-cause mortality (HR, 0.094; 95% CI, 0.047-0.187), but non-liver-related mortality (HR, 0.286; 95% CI, 0.127-0.644) as well. CONCLUSIONS: Eradication of HCV reduced both liver-related and non-liver-related mortality in patients with progressive HCV-related fibrosis.

Post-treatment levels of α-fetoprotein predict long-term hepatocellular carcinoma development after sustained virological response in patients with hepatitis C.

AIM: The rate of hepatocellular carcinoma (HCC) development is reportedly lower in patients with chronic hepatitis C virus (HCV) who have achieved a sustained virological response (SVR) than in patients who were unresponsive to therapy. However, the development of HCC is sometimes observed in patients with SVR. Therefore, we clarified the predictive power of clinical factors for HCC incidence in patients with SVR using receiver operating characteristic (ROC) curve analysis that takes time dependence into account. METHODS: A total of 571 patients with HCV who achieved SVR with interferon-based therapy were enrolled. Univariate and multivariate Cox proportional hazards models and time-dependent ROC curves were used to analyze clinical factors associated with the development of HCC. RESULTS: Twenty-four patients developed HCC during the follow-up period (median duration, 9.0 years). The 5-, 10-, 15-, and 20-year cumulative incidence rates for HCC were 1.7%, 4.8%, 5.8%, and 6.6%, respectively. Multivariate Cox proportional hazards models showed that older age (hazard ratio [HR], 3.648), male sex (HR, 7.560), lower platelet count at 24 weeks after the end of treatment (SVR24) (HR, 3.939), and higher α-fetoprotein (AFP) at SVR24 (HR, 3.630) were independently associated with HCC development. In addition, time-dependent ROC analysis showed that, compared to platelet count at SVR24, AFP at SVR24 had higher predictive power for HCC incidence approximately 7 years after SVR. CONCLUSIONS: Elevated AFP at SVR24 is a risk factor for HCC in patients with HCV, even those who achieve SVR. α-Fetoprotein is a good predictor of HCC development.

HBcrAg predicts hepatocellular carcinoma development: An analysis using time-dependent receiver operating characteristics.

BACKGROUND & AIMS: Several hepatitis B virus (HBV) markers have been identified as factors associated with the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We clarified the predictive power of HBV markers for the development of HCC using receiver operating characteristic (ROC) analysis with a consideration of time dependence. METHODS: A total of 1031 CHB patients who were not treated with nucleos(t)ide analogue therapy were enrolled. Univariate, multivariate, and time-dependent ROC curves for HBV markers associated with the development of HCC were analyzed. RESULTS: Seventy-eight patients developed HCC during the follow-up period (median duration 10.7years). Different levels or statuses of several HBV markers (HBV genotype, HBV DNA, HBV core-related antigen (HBcrAg), hepatitis B e antigen (HBeAg), and basal core promoter (BCP)), but not hepatitis B surface antigen, were significantly associated with the incidence of HCC by univariate analysis using the log-rank test. Cox proportional hazards models using the covariates of HBV genotype status, HBV DNA levels, HBcrAg levels, HBeAg status, and BCP status indicated that HBcrAg >2.9logU/ml (hazard ratio (HR), 5.05; 95% confidence interval (CI), 2.40-10.63) and BCP mutation (HR, 28.85; 95% CI, 4.00-208.20) were independently associated with the incidence of HCC. Additionally, time-dependent ROC analysis showed that HBcrAg was superior to HBV DNA in terms of predictive power for HCC development throughout the follow-up period. CONCLUSIONS: Elevation of HBcrAg levels in CHB patients is associated with the development of HCC. HBcrAg is an excellent predictor of HCC development. LAY SUMMARY: Hepatitis B virus (HBV) core-related antigen (HBcrAg) is an excellent predictor of hepatocellular carcinoma (HCC) development in chronic hepatitis B patients without nucleos(t)ide analogue therapy. HBcrAg was superior to HBV DNA in terms of predictive power for HCC development by time-dependent receiver operating characteristic analysis.

Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: a propensity score analysis.

BACKGROUND & AIMS: Eradication of hepatitis C virus (HCV) by interferon (IFN)-based therapy has been reported to reduce all-cause mortality rates in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality including the causes of death has not been sufficiently investigated in patients with chronic HCV infection. METHODS: We enrolled 2743 patients with chronic HCV infection. Causes of death, incidence of hepatocellular carcinoma (HCC), and all-cause mortality including non-liver-related diseases, were analysed. RESULTS: Of these 2743 patients, 587 achieved sustained virological response (SVR) (eradication of HCV) by IFN-based therapy (IFN-SVR), 475 did not (without HCV eradication) (IFN-non-SVR), or 1681 did not receive IFN-based therapy (non-IFN patients) (Cohort 1); of these, 309 were selected from IFN-SVR and non-IFN groups using propensity score matching (Cohort 2).The median follow-up duration was 11.4 years. In Cohort 1 patients, mortality rates from non-liver-related diseases were 71.0% (22/31) in IFN-SVR patients, 34.9% (37/106) in IFN-non-SVR patients and 50.0% (248/496) in non-IFN patients respectively. In Cohort 2 patients, mortality rates from non-liver-related diseases were 72.2% (13/18) in IFN-SVR patients and 46.8% (29/62) in non-IFN patients respectively. The eradication of HCV reduced all-cause mortality (hazard ratio (HR), 0.265; 95% confidence interval (CI), 0.058-0.380) including non-liver-related mortality (HR, 0.439; 95% CI, 0.231-0.834) and the incidence of HCC (HR, 0.275; 95% CI, 0.156-0.448). CONCLUSIONS: Eradication of HCV reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV.

Long-term prognosis of patients with chronic hepatitis C who did not receive interferon-based therapy: causes of death and analysis based on the FIB-4 index.

BACKGROUND: Interferon (IFN)-based therapy has been reported to reduce the liver-related mortality rate in patients with chronic hepatitis C virus (HCV) infection. However, predictors of survival and causes of death, including non-liver-related causes, have not been sufficiently investigated in chronic HCV patients who have not received IFN-based therapy. METHODS: A total of 1723 patients with chronic HCV infection who were not treated with IFN-based therapy were enrolled. Survival from liver-related diseases and non-liver-related diseases and causes of death were analyzed on the basis of the fibrosis-4 (FIB-4) index, an index of liver fibrosis. RESULTS: The median follow-up duration was 10.3 years. Of 465 patients who died during the follow-up period, 48.4 % died of liver-related diseases; of the remainder, 51.6 % died of non-liver-related diseases. On the basis of FIB-4 index, the liver-related mortality rate increased as the FIB-4 index increased: 16.1 % in the FIB-4 index < 1.45 group, 36.7 % in the 1.45 ≤ FIB-4 index ≤ 3.25 group, and 58.7 % in the FIB-4 index > 3.25 group (p < 0.001). Conversely, the non-liver-related mortality rate decreased as the FIB-4 index increased: 83.9, 63.3, and 41.3 %, respectively (p = 0.001). In the multivariate analysis, a FIB-4 index greater than 3.25 was identified as a risk factor independently associated with both liver-related death (hazard ratio 13.020; 95 % confidence interval 4.155-40.770) and non-liver-related death (hazard ratio 1.667; 95 % confidence interval 1.188-2.340). CONCLUSIONS: Patients with chronic HCV infection and an elevated FIB-4 index may benefit from monitoring not only for the development of liver-related diseases but also for the development of non-liver-related diseases.

A case of mucinous cystic neoplasm of the pancreas misdiagnosed as a pancreatic pseudocyst at the initial exam and resected after a 2-year follow-up.

A 44-year-old woman was referred to our hospital because of a cystic lesion in the pancreatic body that was found by computed tomography (CT) as a result of a screening for impaired liver function after the patient presented with a high fever in 2011. Trans-abdominal ultrasonography (US) revealed a 33-mm unilocular cyst within the pancreatic body and a 5-mm hypoechoic mass in the pancreatic neck. Contrast-enhanced CT showed a slight enhancement around the cyst and a mild dilation of the main pancreatic duct, but neither septum nor nodule was detected inside. Contrast-enhanced endoscopic ultrasonography (CE-EUS) revealed a hyperechoic elevated lesion inside the cystic lesion without enhancement in the pancreatic body; CE-EUS also revealed a 5-mm homogeneous hypoechoic mass with a remarkable enhancement in the pancreatic neck with the use of Sonazoid(®) as a contrast medium. These lesions were diagnosed as a pancreatic pseudocyst and a neuroendocrine tumor (NET), respectively, and were followed up with periodic examinations. The cystic lesion showed contraction 6 months after the initial exam. However, US revealed an enlargement of the cystic lesion to 40 mm in diameter 2 years after the initial exam, and EUS showed irregular thickening of the wall with a cyst-in-cyst appearance. The diagnoses of a mucinous cystic neoplasm (MCN) and a concomitant small NET were made after a distal pancreatectomy. We herein report a rare case of MCN that showed various morphological changes over 2 years of observation.

Impact of the branched-chain amino acid to tyrosine ratio and branched-chain amino acid granule therapy in patients with hepatocellular carcinoma: A propensity score analysis.

BACKGROUND AND AIM: It has been reported that the branched-chain amino acid (BCAA) to tyrosine ratio (BTR) is a useful indicator of liver function and BCAA therapy is associated with a decreased incidence of hepatocellular carcinoma (HCC). However, there has not been sufficient research on the relationship between BTR and the effects of BCAA therapy after initial treatment of HCC. We investigated the impact of BTR and BCAA therapy on survival in patients with HCC. METHODS: A total of 315 patients with HCC who were treated (n = 66) or not treated (n = 249) with BCAA were enrolled; of these, 66 were selected from each group using propensity score matching. Survival from liver-related mortality was analyzed. RESULTS: In patients who did not receive BCAA therapy (n = 249), multivariate analysis for factors associated with survival indicated that low BTR (≤ 4.4) was independently associated with poor prognosis in patients with HCC (hazard ratio, 1.880; 95% confidence interval, 1.125-3.143; P = 0.016). In addition, among patients selected by propensity score matching (n = 132), multivariate analysis indicated that BCAA therapy was independently associated with good prognosis in patients with HCC (hazard ratio, 0.524; 95% confidence interval, 0.282-0.973; P = 0.041). BTR was not significantly associated with survival. CONCLUSIONS: Intervention involving BCAA therapy improved survival in patients with HCC versus untreated controls, regardless of BTR. In addition, low BTR was associated with poor prognosis in patients who did not receive BCAA therapy.

[A case of type 2 autoimmune pancreatitis associated with Crohn disease].

A 45-year-old woman visited our hospital due to upper left quadrant pain and melena. Colonoscopy revealed longitudinal ulcers in the transverse colon. The endoscopic findings and pathological examination of a biopsy specimen led to diagnosis of Crohn disease, and mesalazine was administered. Although the colorectal lesions showed improvement with mesalazine, a blood test revealed elevation of biliary enzymes. Endoscopic retrograde cholangiopancreatography showed diffuse narrowing of the main pancreatic duct and smooth stricture of the distal bile duct. Steroid therapy improved the pancreatic lesion, which was diagnosed as type 2 autoimmune pancreatitis.

[Acute pancreatitis associated with the administration of ceftriaxone in an adult patient].

We report a case of a 35-year-old patient with acute pancreatitis after administration of ceftriaxone. She was given ceftriaxone (2g/day) for 9 days because of diverticulitis of the colon. She was admitted to our hospital again because of epigastralgia 12 days after the first administration of ceftriaxone. Laboratory examination showed markedly elevated serum amylase, and CT scan demonstrated findings consistent with acute pancreatitis, in addition to sludge in the common bile duct and gall bladder, which was not identified before the administration of ceftriaxone. We should be aware of the fact that administration of ceftriaxone sometimes results in the formation of biliary sludge and can cause severe adverse events such as cholecystitis and pancreatitis, not only in children, but also in adult patients.