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.

Valuable antiviral therapeutic options for the treatment of chronic hepatitis C patients with thrombocytopenia.

Thrombocytopenia in patients with chronic hepatitis C may represent an obstacle for the initiation of antiviral treatment. The aim of this study was to evaluate factors predictive of successful pegylated interferon (PEG-IFN) α2b and ribavirin (RBV) treatment for patients with thrombocytopenia with no history of splenectomy or partial splenic embolization. One hundred and fifty-one chronic hepatitis C patients (genotype 1: n = 110, genotype 2: n = 41) with TCP (<100 × 10(9) /L) at baseline were enrolled. Pretreatment variables included interleukin 28B (IL28B) genotype (rs8099917) and homoeostasis model assessment of insulin resistance score (HOMA-IR). The kinetics of haemoglobin and platelets according to the inosine triphosphatase (ITPA) genotype (rs1127354) were investigated. Sustained virological response (SVR) was significantly more frequent in hepatitis C virus (HCV) genotype 2 (65.9%) than in genotype 1 (34.5%) patients (P < 0.0001). Multiple logistic regression analysis of HCV genotype 1 extracted IL28B TT genotype [odds ratio (OR) 5.97, P = 0.006] and HOMA-IR <2.5 (OR 7.14, P = 0.0016) as significant independent pretreatment predictors of SVR. The analyses of HCV genotype 2 showed that HOMA-IR was significantly related to SVR, but IL28B genotype was not. Patients with ITPA CC genotype showed a significant haemoglobin reduction and lower degree of platelets decrease than those with ITPA CA/AA genotypes. The most common reason for premature discontinuation of treatment was the development of hepatocellular carcinoma (n = 8, 5.3%). In conclusion, HOMA-IR is a useful predictor of SVR for patients with thrombocytopenia infected with HCV genotype 1 or 2 treated with PEG-IFNα2b and RBV. The inclusion of IL28B, ITPA genotypes and HOMA-IR adds valuable therapeutic information.

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.

Role of bursin in the development of B lymphocytes in chicken embryonic Bursa of Fabricius.

Localization and role of bursin during Bursa of Fabricius (BF) ontogeny were examined by immunohistochemical staining and by in ovo injection with anti-bursin antibody. Mouse monoclonal anti-bursin antibody HU2 was generated by immunization with synthetic bursin. It recognized reticular cells (REC), follicular associated epithelium (FAE), FAE-supporting cells, and the basal layer of interfollicular epithelium (IFE) in the mature BF. Bu-1(+) cells were first detectable in the mesenchyme area at 13 days of embryogenesis (E13) before bud formation, then lined up along the bud, and homed into the bud at around E15. IgM(+) cells were detected in the bud after E13. Bursin was first observed at the under edge of the bud. Injection of HU2 into embryonal vein at E13 suppressed the appearance of IgM(+) cells in the Bursa at E17. These results indicate that bursin exists beneath the bud and may act on the appearance of IgM(+) cells during BF ontogeny.

Adult T-cell leukemia/lymphoma in which the pathohistological diagnosis was identical to that of Ki-1 positive anaplastic large cell lymphoma.

A 65-year-old man developed severe lumbago and a loss of appetite two months before presentation. A computerized tomograph at admission revealed soft tissue masses destroying the Th12, L4 and L5 vertebral bones. We diagnosed the lesions to be metastatic bone tumors, but the primary focus could not be determined. Just after the irradiation treatment, abnormal lymphocytes were detected in the peripheral blood cells. Under the suspicion of adult T-cell leukemia/ lymphoma (ATL), we thus performed a lymph node biopsy. The specimens were histologically composed of Ki-1 positive anaplastic large cell lymphoma (ALCL). The lymphoma cells demonstrated a biclonal integration of HTLV-1 proviral DNA. After 6 cycles of chemotherapy, the patient has demonstrated a partial and favorable remission from ATL.

Ileal varices associated with recurrent bleeding in a patient with liver cirrhosis.

We report a rare case of massive and recurrent bleeding from ileal varices in a patient with hepatitis C virus-positive liver cirrhosis. A 66-year old woman, who had undergone laparotomy and blood transfusion 36 years before (because of an extrauterine pregnancy) and endoscopic sclerotherapy for esophageal varices 1 year previously, was admitted to our hospital with loss of bright red blood per rectum. The bleeding was massive and recurrent, and frequent blood transfusions were required. Endoscopic studies failed to find the bleeding site. In the venous phase of selective superior mesenteric angiography, mesenteric varices in the lower part of the abdominal cavity were observed. Laparotomy was performed to control the repeated bleeding which had lasted for more than 1 month. Varices communicating with the right ovarian vein were found on the ileal wall and segmental resection of the ileum was performed. Histological examination demonstrated a massive varicose vein and several dilated veins in the submucosa. The patient's postoperative course was favorable, with no hemorrhagic events during a follow-up of more than 6 months after surgery. Ileal varices should be considered in the diagnosis of a patient who presents with lower gastrointestinal bleeding and portal hypertension.

Parallel evolution in radiation of Ohomopterus ground beetles inferred from mitochondrial ND5 gene sequences.

Molecular phylogenetic analyses using mitochondrial NADH dehydrogenase subunit 5 (ND5) gene sequences representing all 15 species and the majority of subspecies or races of the Ohomopterus ground beetles from all over the Japanese archipelago have uncovered a remarkable evolutionary history. Clustering of the species in the molecular phylogenetic tree is linked to their geographic distribution and does not correlate with morphological characters. Taxonomically the "same" species or the members belonging to the same species-group fall out in more than two different places on the ND5 tree. Evidence has been presented against a possible participation of ancestral polymorphism and random lineage sorting or of hybrid individuals for the observed distribution of mitochondrial DNA haplotypes. The most plausible explanation of our results is that parallel evolution took place in different lineages. Most notably, O. dehaanii, O. yaconinus, and O. japonicus in a lineage reveal almost identical morphology with those of the "same" species (or subspecies) but belonging to the phylogenetically remote lineages.

Evidence for an immunological pathogenesis of thrombocytopenia in chronic liver disease.

OBJECTIVES: To elucidate the role of platelet-associated IgG (PA-IgG) in the mechanism of thrombocytopenia associated with chronic liver disease. METHODS: Platelet count in blood, PA-IgG, and scintigraphic spleen/liver ratio as a marker of splenomegaly was examined in 214 individuals, including 16 controls showing nonspecific reactive change in liver biopsy and 198 patients with chronic liver disease. RESULTS: The mean blood platelet count decreased significantly according to severity of liver disease, from control to liver cirrhosis. PA-IgG levels increased significantly in relation to severity of liver disease, as did spleen/liver ratio. In chronic hepatitis or liver cirrhosis, an inverse correlation was found between platelet counts and PA-IgG levels. An inverse correlation was also observed between platelet count and spleen/liver ratio in liver cirrhosis. The splenic embolization resulted in a significant rise in platelet count and a significant fall in PA-IgG in the 14 cirrhotic patients. CONCLUSIONS: These results may give support to evidence for an immunological mechanism mediated by PA-IgG for the thrombocytopenia occurring in chronic liver disease. In the case of liver cirrhosis, this mechanism would act in addition to platelet pooling in the spleen on thrombocytopenia. PA-IgG may also have an important role in thrombocytopenia associated with chronic hepatitis, in which splenic platelet pooling is less marked.

[An autopsy case of severe portal hypertensive gastropathy associated with a large shunt from superior mesenteric to left renal vein in a patient with alcoholic liver cirrhosis].

We report an autopsy case of severe portal hypertensive gastropathy with a large shunt from the superior mesenteric to left renal vein in a patient with alcoholic liver cirrhosis. A 60-year-old man with alcoholic cirrhosis was admitted for tarry stool and ascites. Endoscopic finding revealed multiple red spots and hemorrhagic gastritis at prepylorus of the stomach. Angiography showed a large shunt vessel originating from the superior mesenteric to left renal vein. He died of hepatic failure and DIC following frequent gastrointestinal bleeding. At autopsy, the stomach showed marked congestion of the capillary vessels in the tunica propria mucosa. This finding showed that the gastropathy resulted in the congestion of the gastric veins connecting with the large shunt vessel.

Exposure to hepatitis B virus in the general population of Hisayama, Japan: significance of isolated antibody to hepatitis B surface antigen in general population.

Cross-sectional survey on the prevalence of hepatitis B serological markers was performed in 2,411 residents who accounted for 74.4% of the population aged 40 and over and living in Hisayama Town, Japan, in 1983. Overall prevalences were 40.7% for both anti-HBs and anti-HBc, 6.1% for isolated anti-HBs and 5.4% for isolated anti-HBc. The condition with isolated anti-HBs was different from those with isolated anti-HBc and both anti-HBc and anti-HBs as follows. The titer of anti-HBs in isolated anti-HBs positive samples was significantly lower than that in both anti-HBs and anti-HBc positive ones (46.2 +/- 5.4 vs. 83.2 +/- 2.8, mean +/- SE, p less than 0.001). The presence of isolated anti-HBs was neither significantly more frequent in males nor related to the risk of liver damages in contrast with that of anti-HBc with or without anti-HBs. These findings suggest that isolated anti-HBs pattern with the absence of anti-HBc in general population was not due to prior HBV infection, but due to natural immunization with HBsAg.

Prevalences of hepatitis B surface antigen carriers and liver damages in the general population of Hisayama, Japan.

The prevalences of hepatitis B surface antigen (HBsAg) carriers and liver damages were studied in 2,411 residents aged 40 and over and living in Hisayama, Japan in 1983. Hepatitis B virus (HBV) associated markers were all measured by radioimmunoassay. HBsAg carriers were found in 2.3 per cent of the residents. Hepatitis B e antigen and antibody to hepatitis B e antigen were positive in 8.9 per cent and 80.4 per cent, respectively, of HBsAg carriers. The prevalences of liver damages in HBsAg carriers were compared with 1095 who had none of HBV markers (neither anti-HBc nor anti-HBs). The prevalences of abnormal aminotransferase level in sera were not different between HBsAg carriers and those who had none of HBV markers. A history of jaundice and/or hepatitis was evident in 32.3 per cent of male carriers and 24.0 per cent of female ones, being significantly more than those without HBV markers (13.1 per cent and 5.8 per cent, p less than 0.05 and p less than 0.005, respectively). These results indicate that, among HBsAg carriers aged 40 and over, few have active clinical signs of hepatitis, although about 20 per cent of them have histories of symptomatic hepatitis due to hepatitis B.

[The effect of partial splenic embolization (PSE) on liver function test in patients with liver cirrhosis].

Five patients with hypersplenism associated with liver cirrhosis were treated by PSE and the changes of peripheral blood cells and liver function tests were observed. After PSE, all patients had a high fever and abdominal pain continued for a few weeks without severe complications. Peripheral blood cell counts improved soon after PSE and liver function tests (hepaplastin test and ICGR15) grew transiently worse, but they also improved within two months. During 4.5 to 10 months, the levels of albumin and total cholesterol of three patients increased, although the changes of bilirubin level and HPT were not shown. For other two patients, it was difficult to estimate the effect of PSE, because one patient was treated at the same time with lipiodol chemoembolization for HCC and another patient had a progress of nephrotic syndrome. On the other hand, ICG levels were stable after PSE but RI-uptake on liver scintigram increased in the liver. These results suggest that PSE may be able to improve not only hypersplenism but also liver function in the patients with compensated liver cirrhosis without severe complication.

Low activity of gamma-glutamyl transpeptidase in serum of acute intrahepatic cholestasis.

Low gamma-glutamyl transpeptidase (gamma-GTP) activity in serum was observed in 11 patients with acute intrahepatic cholestasis (cholestatic hepatitis and fulminant hepatitis), despite a marked increase in bilirubin levels. Inhibitors of gamma-GTP were not detected in sera of these patients. Their gamma-GTP levels in the liver were significantly higher than those in chronic liver diseases. An electrophoretic study of liver gamma-GTP in acute intrahepatic cholestasis showed the same mobility as in chronic liver diseases. These results suggest that the low serum gamma-GTP activity in acute intrahepatic cholestasis is due to factors inhibiting the release of the enzyme from the liver.

Biochemical properties of media conditioned by simian virus 40-induced hamster tumor cells: correlation with distinct cell phenotypes but not with oncogenicity.

Hamster cells, transformed in vitro by SV40, have been reported to secrete an unidentified factor(s) that inhibits thymidine uptake (TU) by various normal cell types, including activated lymphocytes. It has been postulated that this apparent antiproliferative effect may play an in vivo role in the high tumorigenic capacity of SV40-transformed hamster cells. In keeping with this hypothesis, Adenovirus type 2-transformed hamster cells, which are only weakly tumorigenic, do not inhibit TU by indicator cells in vitro. To study the biological relevance of this phenomenon, we assayed 11 cell lines derived from different fibrosarcomas, induced in Syrian hamsters by SV40, for their ability to inhibit TU by normal rabbit kidney indicator cells. In contrast to cells transformed in vitro by SV40, media conditioned by 6 of 11 tumor-derived cell lines did not inhibit TU. Our results do not support the hypothesis that an antiproliferative factor secreted by SV40-transformed cells promotes the tumor-inducing capacity of these cells. Furthermore, inhibition of TU does not appear to be due to the production of a specific antimitotic peptide, but rather to other biochemical properties of the media conditioned by transformed cells. Finally, these biochemical properties do appear to correlate with specific morphological and growth characteristics of the tumor cells, but probably as an effect and not a cause.

Prevalence and long-term prognosis of mild hypertensives and hypertensives in a Japanese community, Hisayama.

The prognosis and outcome for mild hypertensives (90 mmHg less than or equal to diastolic pressure less than or equal to 104 mmHg) and hypertensives (diastolic pressure greater than or equal to 105 mmHg) was prospectively studied in Hisayama, Japan, and compared between 1621 subjects aged 40 years or over, recruited in 1961, and 2053 subjects recruited in 1974. Each cohort was studied in a follow-up which lasted 10 years. The pharmacological treatment of hypertension proved effective among residents recruited in 1974: the survival rate had favorably improved, and the rates of mortality from cerebral stroke and morbidity from intracerebral stroke and morbidity from intracerebral hemorrhage declined significantly in mild hypertensives and hypertensives in the more recently recruited population. The management of mild hypertension was considered more likely to be effective in reducing stroke than in reducing coronary heart disease in the Japanese general population.

Thyroid function in "yusho" patients exposed to polychlorinated biphenyls (PCB).

Thyroid function was investigated in 123 yusho patients who were exposed to toxic levels of polychlorinated biphenyls (PCBs) 16 years ago. In yusho patients, compared with the patients without evidence of yusho or normal controls, the serum triiodothyronine (T3) and thyroxine (T4) levels were significantly higher, while thyroid stimulating hormone (TSH) levels measured by sensitive assay were normal. There was no difference in serum levels of albumin, alkaline phosphatase, total cholesterol, and thyroxine binding globulin (TBG) between the two groups and the prevalence of positive antithyroid autoantibodies was almost the same, suggesting that hyperthyroxinemia in yusho patients was not due to increased TBG binding or abnormal autoimmune mechanism. Serum free T4 levels, however, were not elevated, although T4/TBG ratio was significantly higher. The thyroid hormone levels were higher than normal value in 4 of 123 yusho patients but only 1 case had clinical symptoms such as excessive perspiration. Despite higher serum PCBs in yusho patients, there was no correlation between PCB levels and levels of T3, T4, or TSH. The present results suggest hyperthyroxinemia without obvious clinical symptoms in yusho patients long after exposure to PCBs.