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Treatment of chronic hepatitis C virus (HCV) infection remains a priority in the veterans affairs (VA) health care system nationwide, as there is a high burden of liver disease due to HCV infection among US veterans. The combination of sofosbuvir and simeprevir was the first all-oral antiviral regimen used in clinical practice to treat veterans with HCV infection. In this study, we report a single-center experience showing both the feasibility and effectiveness of this all-oral combination to treat HCV genotype 1 infection. One hundred patients with HCV genotype 1 infection were treated between December 2013 and June 2014. Eighty-six patients were treated with sofosbuvir and simeprevir, with or without ribavirin, for 12 weeks; 12 patients were treated with sofosbuvir, pegylated interferon, and ribavirin for 12 weeks; and 2 patients were treated with sofosbuvir and ribavirin for 24 weeks. Overall, treatment was well tolerated and feasible, with compliance rates over 95% in patients treated with all-oral therapy. The sustained virologic response (SVR) rate for sofosbuvir and simeprevir (88.4%) was superior to the rate for sofosbuvir, pegylated interferon, and ribavirin (50.0%). Subgroup analysis showed diminished SVR rates in cirrhotic patients vs noncirrhotic patients. There were no significant differences in SVR when comparing treatment with or without ribavirin or among genotype subtypes. In conclusion, this study demonstrated excellent completion rates for all-oral treatment of veterans with chronic HCV infection. Additionally, treatment was highly effective, nearing a 90% cure rate. Thus, we recommend that the VA health care system continue to incorporate new HCV medications into its formulary so as to expand HCV treatment for US veterans.

Background: Elastography is a noninvasive method to assess liver fibrosis by measuring liver stiffness. Studies have compared elas-tography to percutaneous biopsy. Laparoscopic biopsy is associated with decreased sampling error compared to percutaneous biopsy, as laparoscopic biopsies are obtained from both liver lobes and gross nodu-larity can be visualized., Methods: Patients undergoing laparoscopic liver biopsy were enrolled. Gross liver appearance was assessed, and biopsy specimens were blindly evaluated by a pathologist. Elastography (FibroScan) was used to measure liver stiffness., Results: 101 patients were examined. Fibrosis was related to elasticity (Spearman correlation r=0.63; P<.0001). Elasticity was strongly associated with advanced stages of fibrosis (stages 3 and 4; Spearman correlation r(2)=0.44; P<.001). Significant fibrosis was associated with an irregular liver surface, nodularity, and thickened edge (multiple regression r(2)=0.41; P<.001). Increased elasticity was associated with a fatty-appearing liver, irregular surface, firmness, and nodularity (multiple regression r(2)=0.46; P<.001). Receiver operating characteristic curve for elasticity for identifying patients with a liver fibrosis stage of at least 3 or of 4 had an area under the curve (AUC) of 0.85 or 0.86, respectively. AUC was 0.857 when gross nodularity was used as the gold standard for cirrhosis and 0.875 when nodularity/histology were used. Elasticity of at least 7 kPa, at least 9.5 kPa, and at least 11.8 kPa had the highest accuracy for identifying patients with a fibrosis stage of at least 2, at least 3, and 4, respectively. In hepatitis C patients, AUC was 0.921, 0.882, and 0.925 when histology, gross nodularity, and nodularity/histology, respectively, were used as the gold standard for cirrhosis., Conclusion: FibroScan could be useful for detecting advanced stages of fibrosis when validated against laparoscopic liver biopsy.

Microcephalin (MCPH1/BRIT1) forms ionizing radiation-induced nuclear foci (IRIF) and is required for DNA damage-responsive S and G(2)-M-phase checkpoints. MCPH1 contains three BRCT domains. Here we report the cloning of chicken Mcph1 (cMcph1) and functional analysis of its individual BRCT domains. Full-length cMcph1 localized to centrosomes throughout the cell cycle and formed IRIF that colocalized with gamma-H2AX. The tandem C-terminal BRCT2 and BRCT3 domains of cMcph1 were necessary for IRIF formation, while the N-terminal BRCT1 was required for centrosomal localization in irradiated cells. Centrosomal targeting of cMcph1 was independent of ATM, Brca1 or Chk1. cMcph1 formed IRIF in ATM- and Brca1-deficient cells, but not in H2AX-deficient cells. Inability to form cMcph1 IRIF impaired the cellular response to DNA damage. These results suggest that the role of microcephalin in the vertebrate DNA damage response is controlled by interaction of the C-terminal BRCT domains with gamma-H2AX.

Serum markers of liver fibrosis are difficult to validate, due to the sampling error and observer variability associated with percutaneous liver biopsies. Laparoscopic biopsy decreases sampling error and increases the reliability of histopathologic assessment. We prospectively evaluated the FIBROSpect(SM) II serum marker test for viral liver fibrosis against laparoscopic biopsies by studying 145 patients with chronic hepatitis B or C who underwent laparoscopy in a tertiary care setting. Serum samples obtained at biopsy were tested with FIBROSpect II to assess the degree of fibrosis. Multiple biopsies were obtained from each patient and scored blindly using the Batts-Ludwig system. An average biopsy stage was calculated and the performance of the test panel assessed. FIBROSpect II was able to rule in significant fibrosis (stages 2-4), with a likelihood ratio of 2.6. It correctly indicated absence of disease in 74% of stages 0-1 patients and correctly predicted significant disease in 67% of stages 2-4 patients. Test correlation was highest with Batts-Ludwig stages 3 (77%) and 4 (96%) and lowest with stage 2 (43%). Multiple biopsies from 52% of patients differed by at least 1 stage. In 13 patients (9%), cirrhosis was detected by laparoscopy but not histologically; in 4 (3%), a stage of 4 was obtained, but cirrhosis was not evident by laparoscopy. FIBROSpect II provided valuable additional information for assessing fibrosis. The discordance in fibrosis stage seen in multiple biopsies from the same patient underscores the need to consider all available information when assessing fibrosis. This study confirms and extends results of previous studies evaluating FIBROSpect II using percutaneous liver biopsy.

Background & Aims: Compared with Caucasian Americans (CA), African Americans (AA) with chronic hepatitis C are less likely to respond to interferon-based antiviral therapy., Methods: In a multicenter treatment trial, 196 AA and 205 CA treatment-naive patients with hepatitis C virus (HCV) genotype 1 infection were treated with peginterferon alfa-2a (180 microg/wk) and ribavirin (1000-1200 mg/day) for up to 48 weeks. The primary end point was sustained virologic response (SVR)., Results: Baseline features were similar among AA and CA, including HCV-RNA levels and histologic severity, but AA had higher body weights, a higher prevalence of diabetes and hypertension, and lower alanine transaminase levels (P < .001 for all). The SVR rate was 28% in AA and 52% in CA (P < .0001). Racial differences in viral responses were evident as early as treatment week 4. Breakthrough viremia was more frequent among AA than CA (13% vs 6%, P = .05); relapse rates were comparable (32% vs 25%, P = .30). Proportions of patients with serious adverse events and dose modifications and discontinuations were similar among AA and CA. In multiple regression analyses, CA had a higher SVR rate than AA (relative risk, 1.96; 95% confidence interval, 1.48-2.60; P < .0001). Other factors independently associated with higher SVR included female sex, lower baseline HCV-RNA level, less hepatic fibrosis, and more peginterferon taken., Conclusions: AA with chronic hepatitis C genotype 1 have lower rates of virologic response to peginterferon and ribavirin than CA. These differences are not explained by disease characteristics, baseline viral levels, or amount of medication taken.

Background & Aims: Variceal bleeding refractory to medical treatment with beta-blockers and endoscopic therapy can be managed by variceal decompression with either surgical shunts or transjugular intrahepatic portal systemic shunts (TIPS). This prospective randomized trial tested the hypothesis that patients receiving distal splenorenal shunts (DSRS) would have significantly lower rebleeding and encephalopathy rates than TIPS in management of refractory variceal bleeding., Methods: A prospective randomized controlled clinical trial at 5 centers was conducted. One hundred forty patients with Child-Pugh class A and B cirrhosis and refractory variceal bleeding were randomized to DSRS or TIPS. Protocol and event follow-up for 2-8 years (mean, 46 +/- 26 months) for primary end points of variceal bleeding and encephalopathy and secondary end points of death, ascites, thrombosis and stenosis, liver function, need for transplant, quality of life, and cost were evaluated., Results: There was no significant difference in rebleeding (DSRS, 5.5%; TIPS, 10.5%; P = .29) or first encephalopathy event (DSRS, 50%; TIPS, 50%). Survival at 2 and 5 years (DSRS, 81% and 62%; TIPS, 88% and 61%, respectively) were not significantly different (P = .87). Thrombosis, stenosis, and reintervention rates (DSRS, 11%; TIPS, 82%) were significantly (P < .001) higher in the TIPS group. Ascites, need for transplant, quality of life, and costs were not significantly different., Conclusions: DSRS and TIPS are similarly efficacious in the control of refractory variceal bleeding in Child-Pugh class A and B patients. Reintervention is significantly greater for TIPS compared with DSRS. Because both procedures have equivalent outcomes, the choice is dependent on available expertise and ability to monitor the shunt and reintervene when needed.

Centrosomes are the principal microtubule organising centres in somatic cells. Abnormal centrosome number is common in tumours and occurs after gamma-irradiation and in cells with mutations in DNA repair genes. To investigate how DNA damage causes centrosome amplification, we examined cells that conditionally lack the Rad51 recombinase and thereby incur high levels of spontaneous DNA damage. Rad51-deficient cells arrested in G2 phase and formed supernumerary functional centrosomes, as assessed by light and serial section electron microscopy. This centrosome amplification occurred without an additional DNA replication round and was not the result of cytokinesis failure. G2-to-M checkpoint over-ride by caffeine or wortmannin treatment strongly reduced DNA damage-induced centrosome amplification. Radiation-induced centrosome amplification was potentiated by Rad54 disruption. Gene targeting of ATM reduced, but did not abrogate, centrosome amplification induced by DNA damage in both the Rad51 and Rad54 knockout models, demonstrating ATM-dependent and -independent components of DNA damage-inducible G2-phase centrosome amplification. Our data suggest DNA damage-induced centrosome amplification as a mechanism for ensuring death of cells that evade the DNA damage or spindle assembly checkpoints.

Background/aims: It has been reported that hepatic iron concentration (HIC) may influence response to therapy in chronic viral hepatitis. The aim of this study was to determine the relationship between HIC and response to interferon alfa therapy in patients with chronic hepatitis C., Methods: HIC was measured in liver biopsy specimens from 58 patients with chronic hepatitis C treated at three centers. Three patients had mild chronic hepatitis C, 35 had moderate to severe chronic hepatitis C, and 20 had active cirrhosis. Serum ferritin levels were measured in 51 of these 58 patients. Response to therapy was defined as normalization of alanine aminotransferase levels at the end of treatment., Results: Twenty-four patients (41%) responded to therapy. HICs were generally within the normal range (< 1500 micrograms/g). The mean HIC in nonresponders (860 +/- 100 micrograms/g; range, 116-2296 micrograms/g) was significantly higher than in responders (548 +/- 85 micrograms/g; range, 29-1870 micrograms/g) (P < 0.05). Eighty-eight percent of patients with an HIC of > 1100 micrograms/g and 87% of patients with an elevated serum ferritin concentration did not respond to interferon alfa therapy., Conclusions: HIC seems to influence response to interferon alfa therapy among patients with chronic hepatitis C. A subgroup of patients with chronic hepatitis C has been identified for which an HIC of > 1100 micrograms/g predicted nonresponse in 88% of patients.

A 54-year-old man with chronic B hepatitis was treated with interferon alfa. Despite resolution of the hepatitis B viral infection, he experienced severe jaundice, ascites, and encephalopathy. Further work-up showed hyperglobulinemia, chiefly immunoglobulin G, and positive smooth muscle and anti-nuclear antibodies. Because of these "autoimmune" features, the patient was treated with prednisone. One month later, a significant clinical and biochemical improvement was observed. A possible autoimmune mechanism induced by interferon alfa is proposed as the cause for the perpetuation of the necroinflammatory activity.

A cholestatic syndrome caused by sclerosing cholangitis and papillary stenosis has been described in patients with the acquired immunodeficiency syndrome and hepatobiliary cryptosporidiosis and cytomegalovirus infection. The case of a 41-year-old homosexual man with the acquired immunodeficiency syndrome who presented with abdominal pain, diarrhea, fever, and cholestasis is reported. A percutaneous transhepatic cholangiogram showed that the extrahepatic and right-sided intrahepatic ducts were normal. Computerized tomography of the abdomen showed multiple hypodense lesions in the liver. Guided needle biopsies of several of these lesions showed severe confluent necrotizing pericholangitis with cytomegalovirus-infected cells. Numerous cryptosporidia were seen attached to biliary epithelium. The unique histopathologic and radiographic features of this case should be added to the spectrum of hepatobiliary manifestations of the acquired immunodeficiency syndrome.

A healthy 39-year-old man who had clinical findings consistent with sclerosing cholangitis was found to have systemic protothecosis at surgery. Severe granulomatous inflammation and palpable nodules were found in the gallbladder, on the surface of the liver, and in the duodenum. Prototheca wickerhamii was detected in biopsied specimens and stool; the titer of indirect fluorescent antibody to this organism was 1:2,000. The patient recovered after a short course of treatment with amphotericin B and 3 months of oral therapy with ketoconazole. He had no other concurrent illness and had no abnormality in his immune system. This is the second reported human case of systemic protothecosis. An elevated IgG level, an elevated erythrocyte sedimentation rate, eosinophilia, and abnormal levels of enzymes in the liver were found in both cases. Protothecosis should be considered in the differential diagnosis of hepatic and biliary inflammatory diseases of uncertain etiology.

We determined the prevalence of antibodies to the hepatitis C virus (anti-HCV) in 90 patients and 37 staff members of two hemodialysis units utilizing a recently developed anti-HCV recombinant based assay. Eleven patients (12%) were anti-HCV(+). Of these, eight (73%) had antibodies to the hepatitis B core antigen (anti-HBc) indicating prior hepatitis B infection; one patient was hepatitis B surface antigen (HBsAg)(+). All staff members were anti-HCV(-), although seven (19%) of them were anti-HBc(+). Alanine aminotransferase elevations were present at the time of the study in four anti-HCV(-) patients and in only one anti-HCV(+) patient. All anti-HCV(+) (mean 59 +/- 74; range 3 to 269 units) and 85% of anti-HCV(-) patients (mean 16 +/- 27; range 0 to 204 units) had received multiple blood transfusions (P = 0.348). Among 50 patients tested for human immunodeficiency virus (HIV), 43% of anti-HCV(+) as compared to only 7% anti-HCV(-) were positive (P = 0.003). There was a history of intravenous drug abuse (IVDA) in eight (72%) of the anti-HCV(+) patients and in only seven (9%) of the anti-HCV(-) group (P = 0.00001). The results of this serologic survey suggests that anti-HCV positivity is prevalent, although much less than anti-HBc, among our dialysis patients, whereas it was not detected among staff members. The prevalence rate of anti-HCV was statistically significantly higher among anti-HIV(+) and IVDA patients but not in multi-transfused patients.

A 37-yr-old white woman from Australia presented with ascending cholangitis and jaundice and was found to have multiple brown, "earthy" pigment stones in the biliary tree, including the segmental ducts. Removal of these stones was accomplished via a subcutaneously placed afferent jejunal limb of a choledochojejunostomy using balloon dilators. The jejunal conduit also served as an access for periodic removal of newly formed stones. This combined surgical and radiologic approach is an effective way of removing recurring pigment stones. The afferent jejunal limb can also be used to perfuse dissolution agents, if necessary, via catheters placed in the biliary tree.

Gallium-67 scintigraphy is a valuable test together with other screening tests such as alpha feto-protein (AFP) and other imaging modalities in following up recurrent hepatocellular carcinoma (HCC). Three patients were followed in our institution for intervals varying from 2-24 mo after successful resection of uninodular localized hepatomas. In the first patient, gallium scan showed abnormal localized activity while the computed tomography (CT) scan and the magnetic resonance imaging were negative. Liver function tests and AFP were also normal and the patient was operated upon only on the basis of the gallium scan. The second patient had a follow-up gallium scan 2 mo after the first operation that showed an area of increased activity along the inferior aspect of the right lobe. A CT scan done after that showed no evidence of recurrence, but subsequently became positive when repeated 4 mo later. The third patient had abnormal simultaneous gallium scan and CT scan demonstrating a recurrence in the left adrenal gland while both AFP and carcinoembryonic antigen were normal. This has led us to consider every patient a candidate for a baseline and follow-up gallium scan for evaluation for recurrence following HCC.