Clinical assessment of hepatic de novo lipogenesis in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is heralded as the next big global epidemic. Hepatic de novo lipogenesis (DNL), the synthesis of new fatty acids from non-lipid sources, is thought to play a pivotal role in the development of NAFLD. While there is currently no NAFLD-specific therapeutic agent available, pharmaceutical drugs aimed at reducing hepatic fat accretion may prove to be a powerful ally in the treatment and management of this disease. With a focus on NAFLD, the present review summarizes current techniques examining DNL from a clinical perspective, and describes the merits and limitations of three commonly used assays; stable-label isotope tracer studies, fatty acid indexes and indirect calorimetry as non-invasive measures of hepatic DNL. Finally, the application of DNL assessments in the pharmacological and nutraceutical treatment of NAFLD/NASH is summarized. In a clinical research setting, measures of DNL are an important marker in the development of anti-NAFLD treatments.

Diagnostic performance of circulating biomarkers for non-alcoholic steatohepatitis.

There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78-0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.

The Nimble Stage 1 Study Validates Diagnostic Circulating Biomarkers for Nonalcoholic Steatohepatitis.

Background There are no approved noninvasive tests (NIT) for the diagnosis of nonalcoholic steatohepatitis (NASH) and its histological phenotypes. Methods The FNIH-NIMBLE consortium tested 5 serum-based NIT panels for the following intended uses: NIS4: At-risk NASH, a composite of NASH with NAFLD activity score (NAS) ≥ 4 and fibrosis stage ≥ 2, OWLiver: NASH and NAS ≥ 4, enhanced liver fibrosis (ELF), PROC3 and Fibrometer VCTE: fibrosis stages ≥ 2, ≥ 3 or 4. Aliquots from a single blood sample obtained within 90 days of histological confirmation of NAFLD were tested. The prespecified performance metric tested for was a diagnostic AUROC greater than 0.7 and superiority to ALT for diagnosis of NASH or NAS ≥ 4 and to FIB-4 for fibrosis. Results A total of 1073 adults including NASH (n = 848), at-risk NASH (n = 539) and fibrosis stages 0-4 (n = 222, 114, 262, 277 and 198 respectively) were studied. The AUROC of NIS4 for at-risk NASH was 0.81 and superior to ALT and FIB4 (p < 0.001 for both). OWliver diagnosed NASH with sensitivity and specificity of 77.3% and 66.8% respectively. The AUROCs (95% CI) of ELF, PROC3 and Fibrometer VCTE respectively for fibrosis were as follows: ≥ stage 2 fibrosis [0.82 (0.8-0.85), 0.8 (0.77-0.83), and 0.84 (0.79-0.88)], ≥ stage 3 [0.83 (0.8-0.86), 0.76 (0.73-0.79), 0.85 (0.81-0.9), stage 4 [0.85 (0.81-0.89), 0.81 (0.77-0.85), 0.89 (0.84-0.95)]. ELF and Fibrometer VCTE were significantly superior to FIB-4 for all fibrosis endpoints (p < 0.01 for all). Conclusions These data support the further development of NIS4, ELF and Fibrometer VCTE for their intended uses.

Adding to the spectrum of insulin sensitive populations for mixed meal tolerance test glucose reliability assessment.

As a measure of insulin sensitivity, the mixed meal tolerance test (MMTT) is a simple technique that can provide robust results. The assay consists of examining plasma glucose, insulin and C-peptide prior to and following the consumption of a test meal. While this procedure has been used in clinical research for several years, there is no set standard protocol, and only until recently has the reliability of this assay been thoroughly evaluated in prediabetes and type 2 diabetes subjects. Interestingly, the results from this recent study demonstrated stronger MMTT reliability for the prediabetes and diabetes cohorts compared to obese controls. This finding suggests that the obese control group may have more inherent variability in glucose response during a meal challenge likely due to compensatory influences typically observed in non-diabetic insulin-resistant subjects. Furthermore, this study raises the question whether the MMTT assay is reliable in a non-obese cohort. Therefore, to promote the standardization of this technique and contribute to the band of insulin sensitive populations, we employed the same methodology and test meal as the reference study to evaluate the MMTT reliability in healthy and overweight men. Indeed, the interclass coefficient revealed high glucose response repeatability during the MMTT in insulin-sensitive men. Overall, the MMTT is a reliable test across a range of insulin sensitivity including healthy men. However, we propose further investigation may be required to fully define the utility of this methodology in obese non-diabetic insulin-resistant populations.