Simple new clinical score to predict hepatocellular carcinoma after sustained viral response with direct-acting antivirals.

The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.

AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy.

BACKGROUND: An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. METHODS: Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as 'early recurrence', and recurrence more than 1 year after as 'late recurrence'. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. RESULTS: Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026-1.087, p < 0.001) and post-treatment estimated glomerular filtration rate (eGFR) (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99, p = 0.032) as a predictor of HCC recurrence in the late phase. CONCLUSION: Patients with higher post-treatment AFP in the early phase and those with lower post-treatment eGFR in the late phase had a high risk of HCC recurrence. The risk factors associated with HCC recurrence after DAA treatment were different between the early and late phases.

Sex difference in the development of hepatocellular carcinoma after direct-acting antiviral therapy in patients with HCV infection.

Sex differences in the predictors for hepatocellular carcinoma (HCC) development after direct-acting antiviral (DAA) therapy was investigated. DAA therapy was given to 1438 (663 male, 775 female) patients. Sex differences in the HCC development rate and the factors contributing to HCC development after DAA therapy were investigated. Male patients had a significantly higher cumulative HCC incidence (log-rank test, P = .007). On multivariate analysis, the fibrosis-4 index (HR = 1.11; 95%CI, 1.042-1.202, P = .002) and posttreatment α-fetoprotein (AFP) (HR = 1.11; 95%CI, 1.046-1.197, P = .001) were found to be independent factors that contributed to HCC development following DAA therapy in female patients, whereas only posttreatment AFP (HR = 1.090; 95%CI, 1.024-1.160, P = .007) was an independent factor in male patients. The optimal posttreatment AFP cut-off values were set based on receiver operating characteristic curve analyses. The optimal posttreatment AFP cut-off value was much higher in females (6.0 ng/mL) than in male (3.5 ng/mL) patients. In conclusion both in male and female patients, posttreatment AFP was an independent predictor of HCC development after DAA therapy. However, the cut-off values differed between the sexes. In male patients, HCC could be seen in patients with relatively low posttreatment AFP levels; more careful observation might be needed in such patients.

Predictors of hepatocellular carcinoma occurrence after direct-acting antiviral therapy in patients with hepatitis C virus infection.

AIM: The predictors for the development of hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment were investigated. METHODS: A total of 1174 patients with chronic hepatitis C virus infection were treated with DAA therapy (sofosbuvir and ledipasvir [n = 615], sofosbuvir and ribavirin [n = 380], and daclatasvir and asunaprevir [n = 179]) and achieved sustained virologic response (SVR). The HCC development rate and the factors that might contribute to the development of HCC after the end of DAA treatment were analyzed. RESULTS: During the median observation period of 537 days, HCC developed in 33 cases. The incidence of HCC was 1.9%, 3.2%, and 4.1% at 1, 1.5, and 2 years after the end of DAA therapy, respectively. Multivariate analysis with pre- and post-treatment factors identified the Fibrosis-4 (FIB-4) index (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.021-1.178; P = 0.011) and post-treatment α-fetoprotein (AFP) (HR = 1.11; 95% CI, 1.054-1.172; P < 0.001) as independent factors that contributed to the development of HCC after DAA therapy. Using these identified parameters, a new scoring system (0 to 2 points) was established. Patients in the high-score group (2 points) could be identified as having a significantly higher risk of HCC development, and the respective 1- and 2-year cumulative incidence rates of HCC were 6.1% and 14.4%. CONCLUSIONS: A high FIB-4 index and a high post-treatment AFP at the end of DAA treatment were the independent predictors for developing HCC after DAA treatment. For patients with these risk factors, extra attention to the possibility of HCC development is needed.

Predictors of treatment efficacy and ALT non-normalization with sofosbuvir/ribavirin therapy for patients with hepatitis C virus genotype 2.

The tolerability and efficacy of sofosbuvir and ribavirin in patients infected with hepatitis C virus (HCV) genotype 2 were investigated under actual clinical conditions. A total of 208 patients with chronic HCV genotype 2 infection were treated with sofosbuvir 400 mg and ribavirin (weight-based dosing) for 12 weeks. Treatment discontinuation and sustained virological response 12 (SVR12) were evaluated. Moreover, factors associated with SVR12, hemoglobin decreasing to less than 10 g/dL during treatment, and alanine aminotransferase (ALT) non-normalization after treatment were evaluated. In all patients, SVR12 responses were 96.1% (200/208). About 6 of 8 patients (3.8%) who did not achieve SVR12 were re-treatment patients, and eight patients who did not achieve SVR all had liver cirrhosis. Multivariate analysis also identified body mass index (OR = 0.79; P < 0.001), platelet count (OR = 0.88; P = 0.003), and estimated glomerular filtration rate (eGFR) (OR = 0.96; P = 0.007) as independent contributing factors associated with hemoglobin decreasing to less than 10 g/dL during treatment, and only Mac-2 Binding Protein Glycosylation isomer (M2BpGi) (OR = 2.46; P = 0.017) as an independent contributing factor associated with ALT non-normalization after treatment. Cirrhotic patients may have a relatively high rate of treatment failure. In patients whose M2BpGi levels are elevated, their ALT tended to not normalize after treatment completion. These patients who did not achieve normalization of ALT after sofosbuvir plus RBV treatment need more careful observation for emergence of hepatocellular carcinoma even after achievement of SVR.

Simeprevir with peginterferon/ribavirin for patients with hepatitis C virus genotype 1: high frequency of viral relapse in elderly patients.

PURPOSE: The tolerability and efficacy of simeprevir in combination with peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1 under actual clinical conditions were investigated. METHODS: A total of 176 patients with chronic HCV genotype 1 infection were treated with simeprevir for 12 weeks plus Peg-IFN/RBV for 24 weeks. Overall, 107 (60.7 %) patients were aged 60 years or more, and 16 (9 %) patients were aged 70 years or more. Treatment discontinuation, sustained virological response 12 (SVR12), and viral relapse were evaluated and compared between younger patients and elderly patients. RESULTS: The rates of undetectable HCV RNA at the end of treatment were 95.8, 100 and 93.1 % in treatment-naïve, prior relapse, and prior non-responders, respectively. However, the rates of SVR12 were 82.4, 88.2 and 69.2 %, respectively. Especially in prior non-responders, viral relapse was relatively frequent. Treatment discontinuation and SVR12 were not different between patients aged <70 and ≥70 years, but viral relapse after completing treatment was significantly more frequent in patients aged ≥70 years (p = 0.012). CONCLUSIONS: In simeprevir with peginterferon and ribavirin therapy, viral relapse was relatively frequent. Especially in elderly patients, the relapse rate was high after completing treatment, instead of low frequency of discontinuation by the adverse events.

Sustained virological response of patients with hepatitis C virus genotype 2 depends on pegylated interferon compliance.

AIM: Patients infected with hepatitis C virus (HCV) genotype 2 are more sensitive to interferon (IFN) therapy than those infected with genotype 1, but 10-20% of patients do not achieve a sustained viral response (SVR) to combination therapy with pegylated (PEG) IFN and ribavirin (RBV). This study examines the prognostic factors associated with SVR in patients infected with HCV genotype 2 treated with PEG IFN and RBV. METHODS: We treated 149 patients with chronic hepatitis C caused by HCV genotype 2. The patients received s.c. PEG IFN-α-2b (1.5 µg/kg) and a weekly weight-adjusted dose of RBV (600, 800 and 1000 mg per <60, 60-80 and >80 kg, respectively) for 24 weeks and then prognostic factors associated with the SVR were examined. RESULTS: Among the 149 patients, 138 completed the combination therapy and a sustained viral response was achieved in 71.8% of them. Univariate analysis showed that age, as well as mean RBV and PEG IFN doses were factors affecting the SVR (P = 0.012, =0.021, =0.014). Multivariate analysis identified age and mean PEG IFN dose (P = 0.021, =0.018, respectively) as factors involved in the SVR, but not mean RBV dose. CONCLUSION: The SVR of patients infected with HCV genotype 2 depended on the dosage of PEG IFN, but not of RBV. Selecting sufficient doses of PEG IFN for combination with RBV is critical for treating such patients.

[A case of parahiatal hernia with vomiting, and a review of the literature].

A parahiatal hernia, that occurs from muscular diaphragmatic defects causing separation from the esophageal hiatus, is rare. We treated a 68-year-old Japanese woman with the symptom of vomiting. Based on imaging studies (upper gastrointestinal studies, gastroscopy, contrast-enhanced computed tomography) we diagnosed parahiatal hernia. On laparoscopic surgery, the hernial orifice was separated from the esophageal hiatus and the crus of the diaphragm was between the hiatus and the orifice. We closed the hernial orifice with mesh. Parahiatal hernia is rare and is difficult to diagnose preoperatively. We present a case and the clinical discuss the characteristics and management of this rare disease.

Clinical usefulness of quantitative evaluation of visceral fat by ultrasonography.

PURPOSE: The aim of this work was to evaluate the usefulness of a proposed method for visceral fat volume assessment by ultrasonography (US) in identifying those at risk of metabolic syndrome, and also to establish the most suitable cutoff level of waist circumference for the diagnosis of visceral adiposity. METHODS: One hundred and fifty-two outpatients with metabolic diseases such as hypertension, diabetes, or dyslipidemia were studied. The total visceral fat volume (total-VFA) was measured by computed tomography (CT), the visceral fat area at the level of the umbilicus was measured by CT (CT-VFA), and the visceral fat area was also measured by US (US-VFA), as we recently proposed. RESULTS: Significant correlation coefficients were found between total-VFA and CT-VFA, US-VFA, and waist circumference in men but not in women. The correlation co-efficient between US-VFA and waist circumference was significantly positive in men and weakly positive in women. According to receiver-operator characteristic curves, the cutoff value of waist circumference yielding the maximal sensitivity plus specificity for predicting more than 100 cm(2) of US-VFA was 85 cm in men and 84 cm in women. The change in US-VFA was significantly larger than that in waist circumference after a 6-month interval. CONCLUSION: The US-measured visceral fat area is more useful than waist circumference in a clinical setting.

A technique for the measurement of visceral fat by ultrasonography: comparison of measurements by ultrasonography and computed tomography.

OBJECTIVE: This study aims to create a method of calculating intra-abdominal visceral fat volume by using ultrasound (US). The visceral fat volume measured by US was evaluated by comparison with the volume measured by computed tomography (CT). METHODS: Eighty-seven patients (52 males and 35 females) were enrolled in this study. Both US and CT were performed, and the visceral fat volume was measured. Both the distance and thickness of the parameters in US were measured as follows: 1) the distance between the internal surface of the abdominal muscle and the splenic vein, 2) the distance between the internal surface of the abdominal muscle and the posterior wall of aorta on the umbilicus, and 3) the thickness of the fat layer of the posterior right renal wall. RESULTS: The equation was calculated as follows: [visceral fat volume]=-9.008+1.191x[distance between the internal surface of the abdominal muscle and the splenic vein (mm)]+0.987x[distance between the internal surface of the abdominal muscle and the posterior wall of the aorta on the umbilicus (mm)]+3.644x[thickness of the fat layer of the posterior right renal wall (mm)]. There was a good correlation between the visceral fat volume calculated by the above equation and the volume by CT described (r=0.860, p<0.0001). CONCLUSION: The measurement of the visceral fat volume using US provided results as effectively as CT, and it was proven to be a useful method.

Therapeutic efficacy of decreased nitrite production by bezafibrate in patients with primary biliary cirrhosis.

BACKGROUND: The therapeutic efficacy of bezafibrate, a hypolipidemic drug, has been shown in patients with primary biliary cirrhosis (PBC) in some pilot studies; however, little is known regarding the mechanism of action of bezafibrate in PBC. This study was conducted to evaluate the therapeutic efficacy, as well as to gain insight about the possible mechanism of action, of bezafibrate in PBC. METHODS: Sixteen patients with PBC were administered with bezafibrate (400 mg/day) either with (n = 10) or without ursodeoxycholic acid (UDCA; n = 6). The peripheral blood of these patients was collected before and at different times after therapy commencement, and antigen-presenting dendritic cells (DCs) were then cultured. The DCs were enriched and cultured with Staphylococcus aureus Cowan strain-1 for 48 h to evaluate their capacity to produce nitrite. RESULTS: One month after the start of bezafibrate therapy, the serum levels of alkaline phosphatase (P = 0.0005), gamma-glutamyl transpeptidase (P = 0.0006), total cholesterol (P = 0.0072), and immunoglobulin M (P = 0.0281) were decreased significantly compared to those before patients started bezafibrate therapy. The levels of nitrite produced by DCs decreased in all patients with PBC within 1 month of commencement of bezafibrate therapy. Moreover, decreased nitrite production by DCs was also seen when nitrite production was evaluated 1 year after the start of bezafibrate therapy. CONCLUSIONS: This study reconfirms the therapeutic efficacy of bezafibrate in patients with PBC, including those with UDCA-resistant PBC. Downregulation of nitrite production by DCs may have some relationship with the therapeutic efficacy of bezafibrate; however, further study will be needed to clarify whether or not the antiinflammatory activity of bezafibrate is mediated through nitrite production.

Recent clinical features of Wilson's disease with hepatic presentation.

BACKGROUND: We carried out this study to evaluate recent clinical features of Wilson's disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC). METHODS: Sixteen patients with hepatic manifestations were diagnosed with WD in the period 1976-2003. We divided this period into two periods, "past" and "recent". The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital. RESULTS: Four patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects. CONCLUSIONS: Recently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication.

Change of acute hepatitis B transmission routes in Japan.

BACKGROUND: Many years have passed since various prophylactic policies for preventing hepatitis B virus (HBV) transmission were begun. We studied the chronological alterations in HBV infectious routes in patients with acute hepatitis B in the past 27 years. METHODS: Seventy-two patients with acute HBV infection who were admitted to our hospital during the period 1976 to 2002 were enrolled in this study. This study was divided into two periods (first period, 1976-1990; and second period, 1991-2002), and the HBV infectious routes were studied. RESULTS: Infectious routes have been changing. Posttransfusion hepatitis was seen only in the first period. In the second period, sexual transmission was the major infectious route (68%), followed by infection at a medical facility or occupational exposure such as needlestick injury (8%). CONCLUSIONS: Transmission from sexual contact has become the main infectious route of HBV in Japan.

Decompensated hepatitis B virus-related cirrhosis successfully treated with lamivudine allowing surgery for hepatocellular carcinoma.

A 39-year-old man was diagnosed with hepatitis B virus-related cirrhosis, and because of hepatic exacerbations with icterus and ascites, he had been repeatedly hospitalized. He was treated with lamivudine. Several months later, his ascites disappeared and his liver function was improved from class C to A according to the Child-Pugh classification. Two years later, one small hepatocellular carcinoma was detected, and he underwent a successful hepatectomy. From this case, we consider lamivudine to be useful for improving hepatic function in decompensated liver cirrhosis type B and lamivudine might enable surgical resection of hepatocellular carcinoma.

Autoimmune hepatitis associated with Graves' disease.

A 31-year-old woman with Graves' disease with a 12-month-history of propylthiouracil intake and autoantibodies in the sera was admitted to our hospital. The differential diagnosis between autoimmune hepatitis and propylthiouracil-induced hepatitis was intractable. Steroid therapy was started and she showed a complete response to the treatment. Liver biopsy demonstrated acute hepatitis and plasma cell infiltration. A second liver biopsy, which was performed 10 months after starting steroid therapy, showed some inflammatory cells in the portal tracts. These findings suggest that she had been suffering from autoimmune hepatitis.

Drug-induced hepatitis with hepatic granuloma due to saridon.

A 38-year-old Japanese woman with no past history of liver disease developed liver dysfunction associated with fever, anorexia, and general malaise following the prolonged administration of saridon. A liver biopsy demonstrated multiple noncaseating epithelioid granulomas within hepatic lobules, with an inflammatory cell infiltrate of the lobular parenchyma and portal tracts. Viral markers and autoantibodies were negative. Lymphocyte stimulation tests for saridon and for isopropylantipyrine, one of the constituents of saridon, were positive, and therefore a diagnosis of drug-induced hepatitis due to administration of saridon was made. Her symptoms resolved and liver function test results returned to normal following discontinuation of the drug. The possibility of drug-induced hepatitis must be considered when liver dysfunction or systemic symptomatology develops during saridon therapy.