The accuracy of the report of hepatic steatosis on ultrasonography in patients infected with hepatitis C in a clinical setting: A retrospective observational study

BACKGROUND: Steatosis is occasionally reported during screening ultrasonography in patients with hepatitis C virus (HCV). We conducted a retrospective observational study to assess the factors associated with steatosis on ultrasonography and the relationship between steatosis on ultrasound versus biopsy in patients infected with HCV in a clinical setting. Our hypothesis was ultrasonography would perform poorly for the detection of steatosis outside of the context of a controlled study, primarily due to false-positive results caused by hepatic fibrosis and inflammation. METHODS: A retrospective review of ultrasound reports was conducted on patients infected with HCV in a tertiary care gastroenterology clinic. Reports were reviewed for the specific documentation of the presence of steatosis. Baseline clinical and histologic parameters were recorded, and compared for patients with vs. without steatosis. Multiple logistic regression analysis was performed on these baseline variables. Liver biopsies were reviewed by two pathologists, and graded for steatosis. Steatosis on biopsy was compared to steatosis on ultrasound report, and the performance characteristics of ultrasonography were calculated, using biopsy as the gold standard. RESULTS: Ultrasound reports were available on 164 patients. Patients with steatosis on ultrasound had a higher incidence of the following parameters compared to patients without steatosis: diabetes (12/49 [24%] vs. 7/115 [6%], p < 0.001), fibrosis stage >2 (15/48 [31%] vs. 16/110 [15%], p = 0.02), histologic grade >2 (19/48 [40%] vs. 17/103 [17%], p = 0.002), and ALT (129.5 ± 89.0 IU/L vs. 94.3 ± 87.0 IU/L, p = 0.01). Histologic grade was the only factor independently associated with steatosis with multivariate analysis. When compared to the histologic diagnosis of steatosis (n = 122), ultrasonography had a substantial number of false-positive and false-negative results. In patients with a normal ultrasound, 8/82 (10%) had >30% steatosis on biopsy. Among patients with steatosis reported on ultrasound, only 12/40 (30%) had >30% steatosis on biopsy review. CONCLUSION: Steatosis on ultrasound is associated with markers of inflammation and fibrosis in HCV-infected patients, but does not consistently correlate with steatosis on biopsy outside of the context of a controlled study. Clinicians should be skeptical of the definitive diagnosis of steatosis on hepatic ultrasonography

Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines

Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFα is an apoptotic inducer in some cancer cells, it activates NFκB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFκB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFα, thus converting TNFα from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTα, FasL, and TRAIL. Mechanistically, CCNs function through integrin α6β1 and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding α6β1-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an α6β1-HSPG-binding defective CCN1 are blunted in TNFα- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFα and related cytokines

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field