Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment.

BACKGROUND: With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR). AIM: To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC. METHODS: This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n = 152) or without previous HCC (n = 1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC. RESULTS: During the follow-up period (median: 17 months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P < 0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0 ng/mL and ≥ 9.0 ng/mL groups (cut-off value) respectively (log-rank test: P < 0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P = 0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence. CONCLUSIONS: For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.

Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure.

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.

Telaprevir-based triple therapy for chronic hepatitis C patients with advanced fibrosis: a prospective clinical study.

BACKGROUND: Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis-related complications. AIM: To evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy for patients with advanced fibrosis in a clinical practice setting. METHODS: This prospective, multicentre study consisted of 102 patients with advanced fibrosis (METAVIR score F3-4) who were infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin (RBV). RESULTS: The sustained virological response (SVR) rate was 69.6% (71 of 102). Notably, for treatment-naïve and prior relapse patients the SVR rate was over 80%. Previous treatment response, interleukin 28B polymorphism (rs8099917) and rapid virological response (undetectable HCV RNA at week 4) were independently associated with SVR. To achieve SVR, an adequate dosage of PEG-IFNα2b (≥1.2 µg/kg/week) and RBV (≥7.5 mg/kg/day) is preferable; however, the mean weight-adjusted TVR dosage had little impact on treatment outcome. Although severe blood cytopaenia and a dermatological disorder were frequently found, the rate of discontinuation due to adverse effects was 12.7%. The inosine triphosphatase CC allele (rs1127354) was independently associated with the development of severe anaemia, and lower serum albumin level (<35 g/L) was associated with the occurrence of infection. CONCLUSIONS: The great gain in the SVR rate by telaprevir-based triple therapy offsets the problems with adverse effects; thus, it should be considered as a potent treatment protocol for patients with advanced fibrosis, especially for those with treatment-naïve and prior relapse.

Ultrasound evaluation of the fibrosis stage in chronic liver disease by the simultaneous use of low and high frequency probes.

A liver biopsy is currently considered the definitive diagnostic modality for establishing the severity of hepatic fibrosis. We analysed the diagnostic sensitivity and accuracy of ultrasound (US) using both low frequency and high frequency probes as a repeatable, inexpensive, and reliable method to determine the fibrosis stage in chronic liver disease and then compared our results with the histological findings. A total of 103 patients with chronic liver disease (60 males and 43 females, average age 51 years old) who had undergone both a liver biopsy and US with 2-5 MHz frequency and 5-12 MHz frequency probes were prospectively evaluated in this study. An US scoring system using both the low frequency and high frequency probes was performed by evaluating the edge, surface and parenchymal texture of the liver. Each score was obtained by evaluating three parameters; the bluntness of the liver edge, the irregularity of the surface and the coarseness of the parenchymal texture were evaluated and then compared with the histological findings. The US scores of the liver edge (rs: 0.6668), liver surface (rs: 0.9007) and liver parenchymal texture (rs: 0.8853) correlated significantly with the fibrosis stage obtained based on the biopsy findings. The accumulated US scores of these three parameters, however, was found to be the most reliable indicator (rs: 0.9524). Patients with an accumulated score of 6.5 or more were all found to have fibrosis stage 4 in which the accuracy of our scoring system for correctly predicting cirrhosis was found to be 100% sensitive. When an accumulated US score of 3 was interpreted to indicate mild fibrosis (a fibrosis score of 0 or 1), all 42 patients with stage 0 or 1 fibrosis were found to have an accumulated US score of 3 or less (a probability of 100%) and 42 of 53 patients with a score of 3 or less were found to have stage 0 or 1 fibrosis (specificity of 79.2%). An ultrasound evaluation of the liver fibrosis stage based on the scoring system using both low and high frequency probes was found to be a reliable and effective alternative to the histological staging in chronic liver diseases.

Cutting edge: a critical role for IL-10 in induction of nasal tolerance in experimental autoimmune myocarditis.

Appropriate treatment of autoimmune myocarditis following virus infection remains a major clinical problem. Induction of nasal tolerance may provide a new approach to treatment. However, the exact mechanism of nasal tolerance is unknown. To assess the mechanism of nasal tolerance, we examined the role of IL-10 in the induction and suppression of autoimmune myocarditis. First we showed that blocking IL-10 concurrent with nasal administration of Ag abolished the disease-suppressing effect of nasal tolerization. It also led to increased cardiac myosin-specific IL-1 and TNF-alpha production. Then we demonstrated that blocking IL-10 during the effector phase increased not only the incidence and severity of disease but also Ag-specific IL-2, IL-4, and TNF-alpha production as well as cardiac myosin-specific IgG1 and IgG2b production, whereas blocking IL-10 during the induction phase had no effect. This study implicates IL-10 in the induction of nasal tolerance and in limiting inflammation later during the disease process.

Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-gamma-independent pathway.

BACKGROUND: Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses. This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-gamma. Methods and Results- We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization. Both IL-12Rbeta1-deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN-gamma is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN-gamma suppresses EAM. Lack of IFN-gamma due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-gamma-deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2-producing cells; and heightened ability to produce cytokines on stimulation in vitro. Treatment of mice with recombinant IFN-gamma suppressed the development of myocarditis. CONCLUSIONS: IL-12/IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN-gamma plays a protective role. The disease-limiting effects of IFN-gamma might be explained by its ability to control the expansion of activated T lymphocytes.

Transcatheter arterial chemoembolization therapy combined with percutaneous ethanol injection for unresectable large hepatocellular carcinoma: an evaluation of the local therapeutic effect and survival rate.

BACKGROUND/AIMS: This study was undertaken to evaluate the effectiveness of combination therapy with transcatheter arterial chemoembolization followed by percutaneous ethanol injection in patients with unresectable large hepatocellular carcinoma by comparing the use of this combined regimen with transcatheter arterial chemoembolization alone. METHODOLOGY: Six hundred and thirty-one consecutive patients with hepatocellular carcinoma lesions observed from Jan 1989 to Dec 1999 (11 years) at the Internal Medicine Department, Saga Prefectural Hospital Koseikan were retrospectively enrolled in the study. The series included 120 patients with large unresectable hepatocellular carcinoma lesions, the largest of which were greater than 3 cm in largest dimension. Fifty-two patients underwent a single transcatheter arterial chemoembolization followed by percutaneous ethanol injection, which were compared with 68 patients treated by transcatheter arterial chemoembolization alone. Both groups of patients with hepatocellular carcinoma did not differ regarding the base-line characteristics. The overall survival rates and recurrence ratio of initially treated lesions were compared in both groups. RESULTS: On overall survival rates by the Kaplan-Meier method, three- and five-year survival in the transcatheter arterial chemoembolization and percutaneous ethanol injection group (59.0%, 32.1%) proved to be significantly longer than those in the transcatheter arterial chemoembolization group (27.1%, 17.0%). In addition, during the follow-up local recurrence in the combination group (23.1%) was significantly lower than that in the transcatheter arterial chemoembolization group (50.0%). CONCLUSIONS: The combined treatment with transcatheter arterial chemoembolization and percutaneous ethanol injection proved to be more effective and safer. Furthermore, a lower incidence of local recurrence was observed than transcatheter arterial chemoembolization alone which resulted in an increased survival of the patients associated with unresectable large hepatocellular carcinoma lesions.

Contribution of the innate immune system to autoimmune myocarditis: a role for complement.

Myocarditis is a principal cause of heart disease among young adults and is often a precursor of heart failure due to dilated cardiomyopathy. We show here that complement is critical for the induction of experimental autoimmune myocarditis and that it acts through complement receptor type 1 (CR1) and type 2 (CR2). We also found a subset of CD44(hi)CD62L(lo) T cells that expresses CR1 and CR2 and propose that both receptors are involved in the expression of B and T cell activation markers, T cell proliferation and cytokine production. These findings provide a mechanism by which activated complement, a key product of the innate immune response, modulates the induction of an autoimmune disease.

Gender differences in pharmacokinetics of alcohol.

BACKGROUND: The enhanced vulnerability of women to develop alcohol-related diseases may be due to their higher blood alcohol levels after drinking, but the mechanism for this effect is debated. METHODS: Sixty-five healthy volunteers of both genders drank 0.3 g of ethanol/kg of body weight (as 5%, 10%, or 40% solutions) postprandially. Blood alcohol concentrations were monitored by breath analysis and compared with those after intravenous infusion of the same dose. First-pass metabolism was quantified (using Michaelis-Menten kinetics) as the route-dependent difference in the amount of ethanol reaching the systemic blood. Gastric emptying was assessed by nuclear scanning after intake of 300 microCurie of technetium-labeled diethylene triamine pentacetic acid in 10% ethanol. The activities of alcohol dehydrogenase isozymes were assessed in 58 gastric biopsies, using preferred substrates for gamma-ADH (acetaldehyde) and for final sigma-ADH (m-nitrobenzaldehyde) and a specific reaction of chi-ADH (glutathione-dependent formaldehyde dehydrogenase). RESULTS: Women had less first-pass metabolism than men when given 10% or 40%, but not 5%, alcohol. This was associated with lower gastric chi-ADH activity; its low affinity for ethanol could explain the greater gender difference in first-pass metabolism with high rather than with low concentrations of imbibed alcohol. Alcohol gastric emptying was 42% slower and hepatic oxidation was 10% higher in women. A 7.3% smaller volume of alcohol distribution contributed to the higher ethanol levels in women, but it did not account for the route-dependent effects. CONCLUSIONS: The gender difference in alcohol levels is due mainly to a smaller gastric metabolism in females (because of a significantly lesser activity of chi-ADH), rather than to differences in gastric emptying or in hepatic oxidation of ethanol. The concentration-dependency of these effects may explain earlier discrepancies. The combined pharmacokinetic differences may increase the vulnerability of women to the effects of ethanol.

Manifestation of cutaneous polyarteritis nodosa during interferon therapy for chronic hepatitis C associated with primary biliary cirrhosis.

Interferon alpha-2b was administered to a 50-year-old Japanese woman with chronic hepatitis C associated with primary biliary cirrhosis. Two months after the beginning of the interferon alpha-2b therapy a systemic nodular, erythematous rash developed. Histological analysis of the skin revealed typical features of necrotizing arteritis. Because there was no microhematuria, and no microaneurysms were detected on abdominal angiography, a diagnosis of cutaneous polyarteritis nodosa was made. A good outcome was achieved after interferon alpha-2b was discontinued and prednisolone was administered instead. The cutaneous polyarteritis nodosa in this patient is thus considered to have occurred as an adverse effect of interferon administration. To our knowledge, this is the first reported case of cutaneous polyarteritis nodosa which developed because of interferon therapy for chronic hepatitis C associated with primary biliary cirrhosis.

Differences in survival based on the type of follow-up for the detection of hepatocellular carcinoma: an analysis of 547 patients.

The aim of this study was to identify any significant variables in the prognosis of 547 cases with hepatocellular carcinoma (HCC), and simultaneously confirm the survival among the different surveillance modalities for the initial detection of HCC in a closely followed-up group (regular periodic follow-up with monthly alpha-fetoprotein (AFP) and ultrasonography at least every 4 months), a not closely followed-up group (neither performed with AFP nor ultrasonography regularly) and an incidental group (incidentally discovered due to related symptoms). Five hundred and forty-seven consecutive patients with HCC diagnosed at the Internal Medicine Department of Saga Prefectural Hospital Koseikan from January 1989 to December 1998 were retrospectively analyzed. The 1-, 3- and 5-year survivals in all 547 cases were 69.7, 42.4 and 26.9%, respectively. The 1-, 3- and 5-year survivals in the cases found to have solitary HCC measuring 2 cm or less in diameter at the time of diagnosis were 97.3, 76.2 and 52.3%, respectively. Forty-seven point one percent of the closely followed-up group, which was the high-risk group were found to have solitary HCC measuring 2 cm or less in diameter (48 out of the 102 followed-up cases), while only 18.5 and 11.8% were found in the not closely followed-up group (46 out of 248 cases) and the incidental group (22 out of 186 cases), respectively. The 5-year survival in the closely followed-up, the not closely followed-up and the incidental groups were 42.9, 26.1 and 15.3%, respectively. The significant factors obtained in the closely followed-up group compared to those from the not closely followed-up group included AFP, tumor size, tumor number and portal thrombosis. These findings indicate the importance of a close follow-up for high-risk groups in order to identify HCC at an early stage, and thereby have a positive influence on survival.

Colour Doppler ultrasound for the evaluation of bowel wall thickening.

We performed colour Doppler ultrasound to evaluate bowel wall thickening and to determine the effectiveness of this modality. 42 patients (aged 8-83 years old, mean age 43.5 years) with bowel disease underwent both grey scale and colour Doppler ultrasound examinations. The diagnoses were classified into three categories: inflammation, vasculitis or ischaemia. The bowel wall thickness, wall echotexture and location of the involved portion were all recorded by grey scale ultrasound, while the presence of an intramural colour Doppler flow and arterial signal was evaluated by colour Doppler ultrasound. The colour Doppler flow was graded as "absent", "mild", or "abundant", and the resistive index was also calculated. Bowel wall thickening was observed in the bowel diseases demonstrating inflammation, vasculitis and ischaemia. Patients with ischaemia were significantly older than those with inflammation. The difference in bowel wall thickness was not significant among the disease categories. Differences in bowel wall echotexture, colour Doppler flow, arterial signal and resistive index among the disease categories were significant. The absence of a colour Doppler flow and of an arterial signal suggested ischaemia, while in younger patients, an abundant colour Doppler flow and a stratified echotexture suggested inflammation. The mean resistive index in the ischemic group was significantly higher than that in the inflammatory group. In conclusion, both grey scale and colour Doppler ultrasound are considered to provide useful information for evaluating and differentiating bowel wall thickening in various bowel diseases.

The value of colour Doppler ultrasonography for small bowel involvement of adult Henoch-Schönlein purpura.

Three patients presented with a non-thrombocytopenic purpuric rash on their upper and lower limbs, abdominal pain, diarrhoea, and arthralgia. Grey scale ultrasound showed abnormally thickened walls of the small bowel. Colour Doppler showed blood flow signals in the diseased bowel wall in all patients. Subsequent barium and endoscopic studies showed oedematous bowel loops with petechial lesions. Biopsy from the purpuric rash of the skin demonstrated vasculitis of subdermal small vessels. The clinical diagnosis of Henoch-Schönlein purpura was made in each case. This paper describes the efficacy of grey scale and colour Doppler ultrasonography in the assessment of the small bowel involvement of Henoch-Schönlein purpura.

Obstructive jaundice due to multiple hepatic abscesses.

A 63-year-old Japanese male with diabetes mellitus developed obstructive jaundice following the onset of multiple hepatic abscesses. Percutaneous transhepatic cholangiography showed intrahepatic bile duct irregularity and dilatations accompanied by a complete obstruction of the right branch of the intrahepatic bile duct. Three kinds of organisms were cultured from the blood and the drained bile. The cholangiographic changes returned to the normal after the liver abscesses subsided following biliary drainage and the administration of intravenous antibiotics.