Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C.

BACKGROUND: Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established. METHODS: We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera. RESULTS: Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p<0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation. CONCLUSIONS: Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients. TRIAL REGISTRATION NUMBER: UMIN 000001031.

Aberrant Expression of Keratin 7 in Hepatocytes as a Predictive Marker of Rapid Progression to Hepatic Failure in Asymptomatic Primary Biliary Cirrhosis.

A predictive marker of the rapid progression to hepatic failure is desired for patients with asymptomatic primary biliary cirrhosis (aPBC). We performed a systematic cohort analysis of 101 patients diagnosed as having aPBC and the rapid progression to liver failure in some, by focusing on cholestasis. Cholestasis was assessed by aberrant keratin7 (K-7) expressions in the patients' hepatocytes. Intralobular expressions of K-7 were found in 9 of the 101 patients. The grades of K-7 expression were significantly associated with the levels of alanine aminotransferase, alkaline phosphatase, and total bilirubin at the time of diagnosis, but not with bile duct loss or cholestasis. Stepwise logistic regression analysis revealed that high grades of K-7 expression correlated positively with high levels of total bilirubin. During the follow-up period, 8 patients developed jaundice, and the mean period until the development of jaundice was 5.2 years. The proportional hazards models for the risk of developing jaundice identified a high grade of aberrant K-7 expression in hepatocytes as the only significant risk factor. Aberrant K-7 expression in hepatocytes can be used as an additional marker to predict rapid progression to liver failure in patients with aPBC at the time of diagnosis.

Necessity for reassessment of patients with serogroup 2 hepatitis C virus (HCV) and undetectable serum HCV RNA.

We encountered a patient positive for anti-hepatitis C virus (HCV) whose serum HCV RNA was undetectable with the Roche AmpliPrep/Cobas TaqMan HCV assay (CAP/CTM) version 1 but showed a high viral load with the Abbott RealTime HCV assay (ART). Discrepancies in the detectability of serum HCV RNA were investigated among 891 consecutive patients who were positive for anti-HCV. Specific nucleotide variations causing the undetectability of HCV RNA were determined and confirmed by synthesizing RNA coding those variations. Serum samples with the discrepancies were also reassessed by CAP/CTM version 2. Among the 891 anti-HCV-positive patients, 4 patients had serum HCV RNA levels that were undetectable by CAP/CTM version 1 despite having levels of >5 log IU/ml that were detected by ART. All four patients had HCV genotype 2a and high titers of anti-HCV. Sequencing of the HCV 5' noncoding regions revealed 2 common variations, A at nucleotide (nt) 145 and T at nt 151. Synthesized RNAs of the HCV 5' noncoding region with standard (NCR145G151C) and variant nucleotides at nt 145 and nt 151 were quantified with CAP/CTM. RNAs of NCR145G151C and NCR145G151T were quantifiable with CAP/CTM version 1, while those of NCR145A151T and NCR145A151C went undetected. The substitution from G to A at nt 145 specifically conferred this undetectability, while this undetectability was reverted in synthesized HCV RNA with correction of this variation. Reassessment of these samples by CAP/CTM version 2 resulted in similar levels of HCV RNA being detected by ART. We conclude that HCV patients with undetectable HCV RNA by CAP/CTM version 1 should be reassessed for viral quantification.

Assessment of health-related quality of life and how it predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C.

BACKGROUND AND AIM: Chronic infection with hepatitis C virus (HCV) decreases health-related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin (RBV), in addition to IL28B polymorphisms. METHODS: The present study enrolled 228 CHC patients and assessed their HRQOLs prospectively with the 36-item short-form health survey. RESULTS: The patients with CHC have lower physical HRQOL status than the general population (P = 0.037, the Z-test). The patients with advanced liver diseases exhibited further decreases in HRQOL (P = 0.036, Spearman's rank correlation coefficient). The score of total HRQOL was significantly lower in the group with sustained virological response (SVR) to the therapy with pegylated interferon and RBV than the non-SVR group (P = 0.031, the Mann-Whitney U-test), with significantly lower scores of mental component and its comprising subscales in the SVR group. Stepwise multivariate logistic regression analysis showed that low HRQOL score ≤ 400 points was significantly associated with SVR (odds ratio = 2.4, P = 0.013), independently from high platelet counts, low HCV RNA, favorable single-nucleotide polymorphism type of IL28B, and HCV serotype 2. The patients with low HRQOL score will have significantly less decrease in HRQOL score by 4 weeks of the treatment than those with high HRQOL score at baseline (P = 0.0045). CONCLUSION: HRQOL is one of the significant predictor of the outcomes of therapy with pegylated interferon and RBV independently from IL28B polymorphism.

[Cerebral sinus thrombosis complicating ulcerative colitis].

A 40-year-old woman with ulcerative colitis (UC) was admitted to our hospital because of diminution of consciousness and left palsy. UC had been diagnosed 6 years before, but had not been treated. MRI revealed complete obstruction of the superior sagittal sinus. Cerebral sinus thrombosis, as a complication of UC, was diagnosed. We started anticoagulant therapy, but she passed away 5 days later. UC has been reported to show hypercoagulation status, leading to deep vein thrombosis within the body which sometimes causes pulmonary infarction, but occurrence of cerebral sinus thrombosis is rare.

[A case of gangliocytic paraganglioma with lymphoid metastasis].

We report a 67-year-old woman who had stiff shoulders and anemia. Upper gastrointestinal endoscopy revealed a pedunclated nodular submucosal tumor with erosions and surface ulcers in the second portion of the duodenum. These endoscopic findings were thought to be characteristic of gangliocytic paraganglioma. CT scan revealed suspected lymph node metastasis, thus the tumor was resected with pancreaticoduodenectomy and was found to be a gangliocytic paraganglioma associated with lymph nodal metastasis. Due to the rarity of the disease there is no consensus regarding treatment. Although this tumor is considered benign, the possibility exists for regional lymph nodal spread. The treatment should be well planned with continuous careful evaluation.

Carbon dioxide insufflation is useful for obtaining clear images of the bile duct during peroral cholangioscopy (with video).

BACKGROUND: Peroral cholangioscopy (POCS) is useful for the diagnosis of various bile duct lesions. However, it is often difficult to obtain clear images because of bile or biliary sludge in the bile duct, even after vigorous irrigation of the bile duct with saline solution. Therefore, this study investigated whether inflation with carbon dioxide (CO(2)) yields clearer images of the bile duct than conventional saline solution irrigation during POCS. OBJECTIVE: To evaluate the clinical utility and safety of CO(2) insufflation into the bile duct to obtain clear images in POCS observations by comparing this method with conventional saline solution irrigation. SETTING: A single center. DESIGN: Case-control study. PATIENTS: Nineteen patients with suspected biliary diseases. INTERVENTIONS: CO(2) insufflation into the bile duct during POCS. MAIN OUTCOME MEASUREMENTS: The quality and safety of this method. RESULT: The quality of the images of the bile duct lumen with CO(2) insufflation (10 patients) was significantly superior to those with saline solution irrigation (9 patients) in both clarity (P < .05) and color (P < .05). In particular, extremely clear images could be obtained from the middle part of common bile duct to the right and left hepatic duct. No serious POCS-related complications occurred. There was no significant change in the venous partial pressure of the CO(2) level during the procedure. LIMITATIONS: The number of patients examined was small. CONCLUSIONS: CO(2) insufflation is useful for obtaining clear images of the bile duct during POCS, which makes it possible to determine the qualitative diagnosis and the extent of various bile duct lesions.

[Flail chest rescued by mechanicalventilation with early tracheotomy and physiotherapy; report of a case].

A 73-year-old man hit his fore-chest accidentally when he rode his motorcycle. A huge flail chest was observed on his central fore-chest, and multiple fractures of costal cartilage were suspected. He developed pneumonia on the 4th hospital day, and he was intubated and mechanical ventilation was initiated. Because frequent sputum aspiration was necessary and aggressive physiotherapy was desirable, a tracheotomy was performed on the same day of intubation. He recovered from respiratory failure with conservative therapy and the mechanical ventilation was disconnected 13 days later. Tracheotomy in the early phase of respiratory failure with flail chest was very effective and the surgical fixation of flail segment would not be necessary even in the case of 'stove-in chest' like the present case.