BACKGROUNDHepatic steatosis is one of the histopathologic features of chronic hepatitis C. It was reported recently that the expression of hepatitis C virus (HCV) core protein in transgenic mice induced hepatocellular carcinoma (HCC) in association with steatosis. The objective of this study was to determine the relation between hepatic steatosis and hepatocarcinogenesis in patients with chronic HCV infection.METHODSThe authors studied 161 patients with chronic HCV infection who were diagnosed at Nagasaki University Hospital, Nagasaki, Japan, between January 1980 and December 1999. Age, gender, body mass index (BMI), habitual drinking, diabetes mellitus, serum alanine aminotransferase (ALT) level, HCV serotype, serum level of HCV core protein, interferon (IFN) treatment, hepatic fibrosis inflammation, and hepatic steatosis were studied with regard to their significance in the development of HCC using univariate and multivariate analyses.RESULTSThe cumulative incidence rates of HCC were 24%, 51%, and 63% at 5 years, 10 years, and 15 years, respectively. Multivariate analysis identified hepatic steatosis, together with aging, cirrhosis, and no IFN treatment, as independent and significant risk factors for HCC (P = 0.0135, P = 0.0390, P = 0.0068, and P = 0.0142, respectively). In addition, hepatic steatosis was correlated with BMI, serum ALT levels, and triglyceride levels.CONCLUSIONSThe findings of the current study indicate that hepatic steatosis is a risk factor for HCC in patients with chronic HCV infection. Patients with chronic HCV and hepatic steatosis should be monitored carefully for HCC. Cancer 2003;97:3036–43. © 2003 American Cancer Society.DOI 10.1002/cncr.11427

Abstract. This clinical practice guideline of the diagnosis and treatment of adrenal insufficiency (AI) including adrenal crisis was produced on behalf of the Japan Endocrine Society. This evidence-based guideline was developed by a committee including all authors, and was reviewed by a subcommittee of the Japan Endocrine Society. The Japanese version has already been published, and the essential points have been summarized in this English language version. We recommend diagnostic tests, including measurement of basal cortisol and ACTH levels in combination with a rapid ACTH (250 µg corticotropin) test, the CRH test, and for particular situations the insulin tolerance test. Cut-off values in basal and peak cortisol levels after the rapid ACTH or CRH tests are proposed based on the assumption that a peak cortisol level ≥18 µg/ dL in the insulin tolerance test indicates normal adrenal function. In adult AI patients, 15-25 mg hydrocortisone (HC) in 2-3 daily doses, depending on adrenal reserve and body weight, is a basic replacement regime for AI. In special situations such as sickness, operations, pregnancy and drug interactions, cautious HC dosing or the correct choice of glucocorticoids is necessary. From long-term treatment, optimal diurnal rhythm and concentration of serum cortisol are important for the prevention of cardiovascular disease and osteoporosis. In maintenance therapy during the growth period of patients with 21-hydroxylase deficiency, proper doses of HC should be used, and long-acting glucocorticoids should not be used. Education and carrying an emergency card are essential for the prevention and rapid treatment of adrenal crisis.Key words: Adrenal insufficiency, Adrenal crisis, Cortisol, Hydrocortisone, Congenital adrenal hyperplasia Summary of Recommendations I. Chronic adrenal insufficiency (AI) I-1.0 SymptomsWe recommend suspecting AI in patients who have the following symptoms.

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inert 11keto-glucocorticoids to active 11beta-hydroxy forms, thereby amplifying intracellular glucocorticoid action. Up-regulation of 11beta-HSD1 in adipose tissue and liver is of pathogenic importance in metabolic syndrome. However, the mechanisms controlling 11beta-HSD1 transcription are poorly understood. Glucocorticoids themselves potently increase 11beta-HSD1 expression in many cells, providing a potential feed-forward system to pathology. We have investigated the molecular mechanisms by which glucocorticoids regulate transcription of 11beta-HSD1, exploiting an A549 cell model system in which endogenous 11beta-HSD1 is expressed and is induced by dexamethasone. We show that glucocorticoid induction of 11beta-HSD1 is indirect and requires new protein synthesis. A glucocorticoid-responsive region maps to between -196 and -88 with respect to the transcription start site. This region contains two binding sites for CCAAT/enhancer-binding protein (C/EBP) that together are essential for the glucocorticoid response and that bind predominantly C/EBPbeta, with C/EBPdelta present in a minority of the complexes. Both C/EBPbeta and C/EBPdelta are rapidly induced by glucocorticoids in A549 cells, but small interfering RNA-mediated knockdown shows that only C/EBPbeta reduction attenuates the glucocorticoid induction of 11beta-HSD1. Chromatin immunoprecipitation studies demonstrated increased binding of C/EBPbeta to the 11beta-HSD1 promoter in A549 cells after glucocorticoid treatment. A similar mechanism may apply in adipose tissue in vivo where increased C/EBPbeta mRNA levels after glucocorticoid treatment were associated with increased 11beta-HSD1 expression. C/EBPbeta is a key mediator of metabolic and inflammatory signaling. Positive regulation of 11beta-HSD1 by C/EBPbeta may link amplification of glucocorticoid action with metabolic and inflammatory pathways and may represent an endogenous innate host-defense mechanism.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in a variety of cancer cells with little or no effect on normal cells. Human hepatoma cells, however, are resistant to TRAIL-induced apoptosis. Since interferon-a (IFN-a) is capable of enhancing TNF-ainduced apoptosis in certain cancer cells, we evaluated the effect of IFN-a on TRAIL-induced apoptosis of human hepatoma cells. IFN-a pretreatment enhanced TRAILinduced apoptosis of HuH-7 and Hep3B cells, in which IFN-a upregulated the expression of DR5, a death receptor of TRAIL, and downregulated the expression of survivin, which has an antiapoptotic function. In contrast, IFN-a did not enhance TRAIL-induced apoptosis of HepG2 cells, in which expression of DR5 and survivin was not affected by IFN-a. On the other hand, TRAIL activated NF-jB composed of RelA-p50 heterodimer, a key transcription factor regulating cell survival, in HuH-7 and HepG2 cells. However, IFN-a pretreatment repressed the TRAIL-mediated activation of NF-jB and decreased its transcriptional activity in HuH-7 but not in HepG2 cells. Moreover, IFN-a pretreatment clearly augmented TRAIL-mediated caspase-8 activation in HuH-7 cells. Our results suggest that IFN-a could sensitize certain human hepatoma cells to TRAIL-induced apoptosis by stimulating its death signaling and by repressing the survival function in these cells.

Excess tissue glucocorticoid action may contribute to the hyperglycemia and insulin resistance associated with type 2 diabetes, but the associated mechanisms are poorly understood. 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1) converts inactive 11-dehydrocorticosterone into active corticosterone, thus amplifying glucocorticoid receptor-mediated tissue glucocorticoid action, particularly in the liver. To examine the role of tissue glucocorticoid action in type 2 diabetes, we analyzed expression of glucocorticoid receptor and 11␤-HSD1 and their regulation by endogenous hormones in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). We observed positive relations between expression of both glucocorticoid receptor and 11␤-HSD1 in liver and insulin sensitivity and expression of PEPCK mRNA in db/db mice and db/؉ controls. Increased expression of glucocorticoid receptor and 11␤-HSD1 in the liver of db/db mice was correlated with elevated circulating levels of corticosterone, insulin, and blood glu-cose. Treatment of db/db mice with glucocorticoid antagonist RU486 reversed the increases in the expression of glucocorticoid receptor and 11␤-HSD1 within the liver and attenuated the phenotype of type 2 diabetes. Addition of corticosterone to db/db mouse primary hepatocytes activated expression of glucocorticoid receptor, 11␤-HSD1, and PEPCK, and these effects were abolished by RU486. Incubation of primary hepatocytes with increasing concentrations of glucose caused dose-dependent increases in glucocorticoid receptor and 11␤-HSD1 expression, whereas insulin did not affect the expression of 11␤-HSD1 and glucocorticoid receptor in primary hepatocytes. These findings suggest that activation of glucocorticoid receptor and 11␤-HSD1 expression within the liver may contribute to the development of type 2 diabetes in db/db mice. Diabetes 54:32-40, 2005