Namiki Izumi

Increased hepatotoxicity of acetaminophen by concomitant administration of caffeine in the rat

Since caffeine is frequently co-administered with acetaminophen, it is of clinical interest to study the effect of caffeine on the hepatotoxicity of acetaminophen. In male Sprague-Dawley rats fasted for 18 h, concomitant administration of caffeine (0.1 g/kg, i.p.) as judged by increased serum enzyme activities and increased incidence of hepatic necrosis. Careful observations on hepatotoxicity are suggested when acetaminophen is prescribed with caffeine.

Rapid Decrease of Plasma HCV RNA in Early Phase of Twice Daily Administration of 3 MU Doses Interferon-β in Patients with Genotype 1b Hepatitis C Infection

Virological response to interferon (IFN) is poor in patients with plasma levels of HCV RNA higher than 1 Meq/ml and genotype 1b hepatitis C viral infection. In 60 patients, a randomized control study was conducted to compare 3 MU of IFN-β twice daily for four weeks (group A) and 6 MU once a day for four weeks (group B) followed by a four-week administration of 6 MU once a day. The plasma levels of HCV RNA, determined by an amplicore-monitor method, for patients in group A were significantly lower than those for group B at the fourth and eighth day of IFN administration, and complete virological responses were noted in two patients from group A but none in group B. It is concluded that twice daily administration of 3 MU IFN-β is more effective than once a day 6 MU in the early phase of IFN therapy.

Differences of liver membrane antibody frequency in alcoholic liver disease: detection of IgG and IgA classes using radioimmunoassay

The presence of liver membrane antibody in IgG and IgA was investigated by radioimmunoassay using isolated rabbit hepatocytes as target cells. This technique was more sensitive than the immunofluorescent method. IgG liver membrane antibodies were positive in 24% of patients with alcoholic liver disease. IgA liver membrane antibodies were detected in 58% of patients with alcoholic liver disease, whereas they were detected only in 21% of those with nonalcoholic liver disease, except for cases of autoimmune chronic active hepatitis. In alcoholic liver disease, IgA liver membrane antibodies were detected at a high frequency in a group of patients with alcoholic hepatitis and active cirrhosis (94%) as compared with that of fatty liver, hepatic fibrosis, and inactive cirrhosis (42%). These results suggest that alcoholic liver disease is characterized in part by a humoral immune response of IgA liver membrane antibodies.

Possible involvement of protein kinase C and calcium in GSH efflux from Hep G2 cells

We investigated the effects of protein kinase C modulations and calcium mobilization on GSH efflux in Hep G2 cells. GSH efflux from Hep G2 cells was increased by a phorbol ester. Staurosporine, an inhibitor of protein kinase C, diminished phorbol ester-stimulated GSH efflux from the cells. GSH efflux was negatively correlated with extracellular calcium concentrations. Verapamil enhanced GSH efflux, whereas ATP decreased GSH efflux. The latter effect was diminished in the absence of extracellular calcium. Protein kinase C and calcium mobilization may be crucial factors in GSH efflux from human hepatocytes.

Reply: To PMID 23564522.

We appreciate the valuable comments made by Dr. Lo. We agree that serum a-fetoprotein (AFP) levels sometime fluctuate during serial observations. Therefore, we used the average AFP integration value in our study, as previously described, and an AFP fluctuation that may have occurred during our observation period was not likely to affect the average AFP result. We also agree that a 1-month interval between AFP measurements for lowrisk patients is too frequent. In our study, the AFP measurement interval depended on an individual patient’s risk for hepatocellular carcinoma (HCC), and in accordance with the Japanese Evidencebased Clinical Guidelines for the Diagnosis and Treatment of HCC, our AFP measurement interval was every 6 months for low-risk patients. Unlike other cross-sectional studies that examined AFP values as a tumor marker to detect current HCC, our longitudinal cohort study determined the clinical significance of posttreatment AFP values and evaluated whether AFP values could be used as a predictive risk factor for “future” HCC development. We hypothesized that the AFP values during the observation period associate with the risk for “future” HCC development because elevated serum AFP is sometimes observed in patients with advanced chronic hepatitis C virus (CHC) in the absence of HCC. The positive predictive value of AFP was low. However, the extremely high negative predictive AFP value (0.960) suggested that the postinterferon (post-IFN) treatment AFP value <6.0 ng/mL predicted a decreased likelihood of “future” HCC development. In the HALT-C study, the AFP was 20 ng/mL in 50% of patients who developed HCC, suggesting that the AFP predictive criterion of 20 ng/mL is insufficient to predict a low risk for HCC development. Therefore, post-IFN treatment predictive AFP levels should be <6.0 ng/mL to suppress the risk for “future” HCC development. The HCC incidence is largely different between Western countries and Japan (Western< Japan). Therefore, future studies are needed to determine whether our results are in agreement with long-term, large cohort studies that include various population subgroups. Nevertheless, we believe that our results have important clinical implications for clinicians considering an individual patient’s HCC surveillance and/or treatment strategy. We also appreciate the valuable comments made by Drs. Toyoda, Kumada, and Tada. We are also aware that there are two distinct patterns of HCC development after sustained virological response (SVR) has been achieved. Although we carefully ruled out the existence of HCC by imaging modalities, we agree that the limit of detection of our imaging apparatus did not allow us to detect and completely exclude minute HCC. However, this raises the question as to whether incidences of minute HCC are capable of producing detectable AFP. We agree with Dr. Toyoda et al. that an AFP fucosylated fraction (AFP-L3) may be useful to address this question. Unfortunately, pre-IFN treatment AFP-L3 levels were not available in our patients who had post-IFN AFP 10 ng/ mL and developed HCC after achieving SVR (n 5 11). AFP-L3 values were available from nine patients at the time of HCC development and were 10% in eight (89%) patients, suggesting that AFP production was unlikely specific to HCC in these patients. In addition, AFP levels at the time of HCC development were not higher than AFP levels during follow-up for 8 out of 11 patients. Therefore, although the possibility of minute undetectable HCC before IFN treatment existed, elevated AFP was unlikely associated with preexisting HCC in patients with post-IFN AFP 10 ng/mL who had HCC after SVR was achieved.

Hepatic Iron Accumulation and Incidence of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

Although hepatic iron accumulation is occasionally observed in patients with chronic hepatitis C, the pathophysiological significance has not been elucidated. Several methods for the evaluation of hepatic iron content have been utilized, but histological analysis has been most commonly carried out. Since the deposition of hepatic iron is different in the liver, direct measurement of hepatic iron by atomic absorption spectrophotometry is likely to be the most reliable method. Serum alanine aminotransferase decreases after extensive phlebotomy; thus, hepatic iron is suggested to be involved in injury to hepatocytes. The most important clinical issue is the possible relationship of hepatic iron content and the incidence of hepatocellular carcinoma (HCC), but no definite relationship has been established. Therefore, a randomized control study is necessary to clarify whether or not the development of HCC is reduced by removing hepatic iron by extensive phlebotomy in chronic hepatitis C.

Hypouricemia and renal tubular acidosis in primary biliary cirrhosis.

SummaryA 51-year-old woman with primary biliary cirrhosis developed distal renal tubular acidosis and hypouricemia (1.4mg per 100ml) in the course of hepatic injury. Her renal clearance of uric acid reached 33.7 ml/min (mean±SD in five normal age-matched women: 9.2 ±3.1 ml/min). Pyrazinamide, an inhibitor of uric acid secretion, considerably reduced the uric acid clearance, while it was not enhanced by probenecid, a blocker of uric acid reabsorption. Thus, the hypouricemia may have been due to a defect of postsecretory reabsorption of uric acid in the renal tubules. The present case emphasizes the significance of hypouricemia and hyperuricosuria as indicators of renal tubular injury in primary biliary cirrhosis.