The course of hepatitis C virus (HCV) infection carriers with normal/near-normal aminotransferases (NALT) is usually mild; however, in a few, fibrosis progression occurs. We aimed to verify whether monitoring by liver biopsy might be replaced by noninvasive methods and to identify factors associated with fibrosis progression in patients with persistently normal alanine aminotransferases. We studied 40 untreated HCV-RNA-positive subjects (22 male; median age, 44 years), who underwent two liver biopsies, with a median interval of 78.5 months, during which alanine aminotransferase concentrations (median number of determinations: 12) never exceeded 1.2 times the upper normal limit. Within 9 months from the second biopsy, they were tested by the shear elasticity probe (Fibroscan) and the artificial intelligence algorithm FibroTest. METAVIR fibrosis scores were analyzed in relationship to demographic, clinical, and viral parameters. Weighted kappa analysis was used to verify whether the results of noninvasive methods agreed with histology. Significant fibrosis (>F2), present at the first biopsy in only one patient (2.5%), was observed at the second biopsy in 14 patients (35%). At multivariate analysis, excess alcohol consumption in the past (>20 g/d; P ‫؍‬ .017) and viral load (>8.0 ؋ 10 6 copies/mL; P ‫؍‬ .021) were independent predictors of progression. In identifying patients with significant fibrosis, inter-rater agreement was excellent for Fibroscan (weighted kappa ‫؍‬ 1.0), and poor for FibroTest (weighted kappa ‫؍‬ ؊0.041). In conclusion, among HCV carriers with NALT, Fibroscan is superior to the FibroTest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors. S erum alanine aminotransferase (ALT) concentration, the most widely used indirect marker for liver disease activity, remains within the normal range in approximately 25% to 30% of chronic hepatitis C virus (HCV) carriers, and another 40% have ALT levels less than 2 times the upper limit of normal. 1,2 Although the exact definition of what is meant by persistent "normality" of ALT is discussed, 3 it is generally accepted that the natural history of the subgroup of HCV carriers who have persistently normal or minimally elevated ALT levels (NALT) is characterized by a slower progression rate. 4 Nevertheless, these patients can have progressive liver disease and develop advanced fibrosis or cirrhosis. 5 Thus, to decide whether and when to start antiviral treatment might require watchful waiting with periodic liver biopsy, a strategy unlikely to meet patients' favor. Besides, according to a recent study, such a strategy would lead to higher costs, increased cumulative incidence of cirrhosis, and decreased survival in comparison with "empiric" treatment, though allowing avoidance of treatment in many patients. 6 Reliable and inexpensive noninvasive methods to assess fibrosis progression could not be better appreciated than in this setting.

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Liver transplantation (LT) recipients are at risk for early and delayed adrenal insufficiency for multiple reasons. Although early adrenal insufficiency is known to occur in a high proportion of recipients maintained on steroid-free immunosuppressive regimens, the prevalence and risk factors associated with delayed functional adrenal gland atrophy (FAGA) are unknown because routine evaluation for this condition is not standard practice among LT centers. We investigated a group of 87 patients (64 males) transplanted for end-stage liver disease related to different etiologies. All underwent a standard corticotropin stimulation test (CST) when, after gradual steroid tapering, they had been maintained for at least 1 week on oral prednisone at a daily dose of 5 mg. FAGA, defined by a serum cortisol concentration that, 60 minutes after corticotropin administration, did not double the baseline level and remained Ͻ20 g/dL, was diagnosed in 23/87 patients (26.4%). Stepwise logistic regression analysis selected as significant predictors of FAGA the cumulative dosage of corticosteroids administered (P Ͻ 0.01), the increase in the body mass index after LT (P Ͻ 0.01), a low serum cholesterol concentration (P ϭ 0.005), and a high adrenocorticotropin hormone (ACTH) serum level (P Ͻ 0.05) at the time CST was performed. In conclusion, FAGA is a common condition among LT recipients who are maintained on prolonged corticosteroid immunosuppressive treatment. Relative adrenal insufficiency (RAI) is an uncommon clinical condition that can develop after conventional surgery, with an incidence of approximately 0.5%. 1,2 Previous studies have shown that RAI occurs more frequently in critically ill patients with severe infection, trauma, or aggressive surgery. 3,4 Moreover, RAI has been recently described in patients with end-stage liver disease, a setting for which the definition of hepatoadrenal syndrome has been proposed. 5 Although the mechanisms responsible for RAI in patients with advanced liver diseases have not been fully elucidated, decreased availability of cholesterol 6 and high levels of endotoxin and proinflammatory cytokines, such as tumor necrosis factor alpha, 7,8 may play a major role.Factors able to induce an adrenal crisis, such as hypotension, infection, and severe blood loss, may all complicate liver transplantation (LT) in the early postoperative period. Glucocorticoids, included in the majority of immunosuppressive protocols adopted after LT, prevent LT recipients from developing early RAI after LT but greatly increase the risk of late functional adrenal gland atrophy (FAGA). Indeed, the prolonged use of corticosteroids is a major cause of adrenal suppression, and corticosteroid discontinuation can therefore trigger overt FAGA. 9 LT recipients are therefore at risk for adrenal insufficiency in their first year after the transplant operation for multiple reasons. However, routine evaluation for this condition is not standard Abbreviations: ACTH, adrenocorticotropin hormone; BMI, body mass index; CI, confidence inter...

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Chronic hepatitis B virus (HBV) infection is a global health problem that presents as a spectrum of liver disease, reflecting an interplay between the virus and the host immune system. HBV genomes exist as episomal covalently closed circular DNA (cccDNA) or chromosomal integrants. The relative contribution of these genomes to the viral transcriptome in chronic hepatitis B (CHB) is not well-understood. We developed a qPCR method to estimate the abundance of HBV cccDNA- and integrant-derived viral transcripts and applied this to a cohort of patients diagnosed with CHB in the HBe antigen negative phase of disease. We noted a variable pattern of HBV transcripts from both DNA templates, with preS1/S2 mRNAs predominating and a significant association between increasing age and the expression of integrant-derived mRNAs, but not with inflammatory status. In contrast, cccDNA-derived transcripts were associated with markers of liver inflammation. Analysis of the inflammatory hepatic transcriptome identified 24 genes significantly associated with cccDNA transcriptional activity. Our study uncovers an immune gene signature that associates with HBV cccDNA transcription and increases our understanding of viral persistence.