Ken Takehara

Thrombocytopenia associated with hepatitis C viral infection

BACKGROUND/AIMSnWe investigated whether chronic hepatitis C infection is associated with thrombocytopenia.nnnMETHODS/RESULTSnThrombocytopenia (<15 x 10(4) platelets/mu l) was diagnosed in 151 of 368 patients (41.0%) with chronic hepatitis C, a significantly higher proportion than that observed in patients with chronic hepatitis B (18.9%, p < 0.01). Elevated titers of platelet-associated immunoglobulin G were observed in 88.1% of patients with chronic hepatitis C and in 47.1% of patients with chronic hepatitis B. Platelet-associated immunoglobulin G titers were significantly higher in patients with chronic hepatitis C (87.3 +/- 10.1 ng/10(7) cells) vs. those with chronic hepatitis B (30.3 +/- 6.4) or the control subjects (p < 0.01). There was a significant negative correlation between platelet-associated immunoglobulin G titers and platelet counts in both chronic hepatitis C and B cases. Platelet-associated immunoglobulin G titers were significantly higher in patients with type C cirrhosis than in those with type B cirrhosis. Interestingly, HCV-RNA was detected by RT-PCR in the platelets from 11 of 14 patients with hepatitis C virus.nnnCONCLUSIONSnThese data indicate that chronic infection with hepatitis C virus may produce a significant autoimmune reaction to platelets, leading to thrombocytopenia.

Accidental transmission of HCV and treatment with interferon

Accidental transmission of contagious pathogens, especially hepatitis C virus (HCV), by needlestick or other means as an occupational hazard for medical staff is of concern. We retrospectively analysed cases of work‐related accidental injury with pathogens such as hepatitis B virus (HBV), HCV, syphilis and human immunodeficiency virus (HIV) reported to the centres for disease control at 15 hospitals (total 5776 beds) in the Gunma prefecture, Japan, from December 1990 to August 1993 (24.7 months). There were 416 such cases (16.8 cases/month), with an incidence of 0.2–3.5 accidents per month per hospital. Such accidents occurred in 297 (71.2%) nurses, 98 (23.5%) medical doctors, 13 (3%) laboratory technicians, four (1.0%) hospital maintenance workers, one (0.2%) assistant nurse, one secretary and two others. There were 323 (77.6%) injuries caused by needlestick, 42 (10.1%) from suture needles or surgical knife cuts, 17 (4.1%) from blood splatters from patients into the eyes or mouth, 10 (2.4%) from contact with injured skin and 24 (5.8%) simple skin contacts. Of the pathogens, 60.3% were HCV, 22.6% HBV, 5.8% syphilis, 0.7% HIV and 10.6% were of unknown origin. Four cases (1.6%) of HCV infection were found and treated with one or two courses of interferon therapy, and HCV was subsequently cleared. All four patients were cured with interferon therapy. None of the HBV‐injured cases resulted in infection, possibly because of prophylaxis with HB immunoglobulin and HB vaccine. No HIV or syphilis infection was contracted. In summary, chronic HCV infection acquired as an occupational hazard can be cured by appropriate treatment, such as with interferon, after early detection of the infection.

Biotinidase Activity in Patients with Liver Disease

To investigate whether biotinidase deficiency may occur in liver disease, we determined biotinidase activity, biotin levels, and organic acids in patients with liver disease. Serum biotinidase activity in patients with liver disease (2.63 +/- 1.40 nmol/min/ml) was significantly lower than in the control group (5.43 +/- 1.06 nmol/min/ml). Serum biotinidase activity in decompensated liver cirrhosis (LC) and hepatoma was significantly lower than in acute viral hepatitis (AVH), chronic viral hepatitis (CVH), and compensated LC. The mean serum level of biotin in decompensated LC (1.8 +/- 0.6 microgram/ml) and hepatoma (1.7 +/- 0.8 microgram/ml) was significantly lower than in the control group (2.5 +/- 1.0 microgram/ml), and urinary excretion of biotin was increased in patients with liver disease, particularly in decompensated LC. Biotinidase activity correlated positively with serum biotin level and correlated negatively with urinary biotin level. Moreover, in four of five patients with severe liver disease the excretion of propionate, lactate, and 3-hydroxybutyrate decreased after biotin supplementation. The data for patients with severe liver disease so resembled those for late-onset multiple carboxylase deficiency that biotinidase deficiency is likely in patients with severe liver disease.

Clinical evaluation of biotin-binding immunoglobulin in patients with Graves' disease.

Biotin-binding immunoglobulin (BBI) was recently identified in human serum and has been suggested to have a significant association with allergic and autoimmune disorders. Attempts were made to evaluate the clinical significance of BBI in autoimmune thyroid disorders. Prevalence of BBI was significantly higher in Graves disease (47%) than in Hashimotos disease (8%) and healthy controls (10%). The BBI consisted of heterogeneous subtypes with respect to binding of several immunoglobulin classes. Sera in Graves disease showed predominantly IgG-binding BBI, whereas healthy subjects had IgM-binding BBI. Thyroid stimulating hormone receptor antibody (TRAb) level was significantly higher in the BBI non-detected group than in the detected group. There was no significant relationship between BBI prevalence and thyroid hormone concentrations, anti-thyroglobulin antibody (TGAb) or anti-thyroid microsomal antibody (McAb) titers. In addition, biotin levels in peripheral blood and red blood cells and biotinidase activity did not differ in the BBI detected and non-detected groups. The present results suggest that BBI is associated with autoimmune dysfunction in Graves disease.

Evaluation of the therapeutic effect of TAE on primary liver cancer

The therapeutic effect of transcatheter arterial chemoembolization (TAE) performed on 31 patients with primary liver cancer was evaluated using the following procedures: (1) the alpha-fetoprotein (AFP) reduction rates and prognoses were analyzed according to the tumor reduction rates (TR), and (2) the AFP reduction rates and prognoses were also analyzed according to the tumor necrosis rates (TN) estimated by regarding every region with Lipiodol retention as being necrotic. The following results were obtained. The AFP level was 400 ng/ml or higher in 15 patients (48%). Their AFP reduction rates were as favorably high as 65.4%–99.8% (mean, 88.1%), and the AFP level was normalized in 3 patients. The cumulative survival rates after the initial treatment were relatively high, i.e., 78.4% in the 1 st year, 58.1% in the 2nd year, and 38.7% in the 3rd year. These results suggested the effectiveness of the TAE treatment undertaken in this study. Regarding the TR, the tumor was reduced in size by 50% or more in only 5 patients (16%), and most patients had a TR of less than 25%. On the other hand, the majority, 25 patients (81%), had a TN ranging between 50% and less than 100%, including 7 who had a TN ranging between 50% and less than 90% and 18 who had a TN ranging between 90% and less than 100%. There was no significant correlation between the AFP reduction rate and the TN or TR. Regarding evaluation of the cumulative survival rates by TR and TN, the 1-year survival rate was lower in patients having a TR of less than 25% than in those having a TR of 25% or more. Patients having a TN of less than 50% showed a poor outcome as compared with those having a TN of 50% or more. Although the TR was found to be less than 50% in a majority of the patients when the therapeutic effect of TAE on the liver cancer was evaluated according to the TR, many of these patients showed a good outocome. Thus, the conventional efficacy evaluation, in which a tumor reduction of 50% or more is considered to be effective, should be reconsidered. On the other hand, the TN was found to be 50% or more in most of the patients suggesting the necessity of a more detailed classification of TN. In relation to the survival rate patients having a TN of less than 50% showed a poor outcome.

Effect of biotin on ammonia intoxication in rats and mice

The effects of biotin on ammonia concentration in blood and brain were evaluated in hyperammonemic rats and mice. Rats were injected with 5 mmol/kg BW of ammonium acetate, and mice were injected with 10 mmol/kg BW. Increases in blood ammonia levels in rats 15–30 min after ammonia loading were prevented by treatment with 0.2 ml/100 g BW of biotin or 0.04 ml/100g BW of arginineglutamate with statistical significance. Blood ammonia levels after ammonia loading were lower, although not significantly, in the arginine glutamate-treated rats than in the biotin-treated animals. In mice also, increases in blood and brain ammonia levels after ammonia loading were prevented by the administration of biotin. The decrease in brain glutamate and aspartate after ammonia loading was lower and the brain glutamine level was higher in biotin-treated mice than in the controls. These findings indicate the protective effect of biotin against ammonia intoxication.