Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Assessment of Lifestyle Factors Helps to Identify Liver Fibrosis Due to Non-Alcoholic Fatty Liver Disease in Obesity.

Only some individuals with obesity develop liver fibrosis due to non-alcoholic fatty liver disease (NAFLD-fibrosis). We determined whether detailed assessment of lifestyle factors in addition to physical, biochemical and genetic factors helps in identification of these patients. A total of 100 patients with obesity (mean BMI 40.0 ± 0.6 kg/m2) referred for bariatric surgery at the Helsinki University Hospital underwent a liver biopsy to evaluate liver histology. Physical activity was determined by accelerometer recordings and by the Modifiable Activity Questionnaire, diet by the FINRISK Food Frequency Questionnaire, and other lifestyle factors, such as sleep patterns and smoking, by face-to-face interviews. Physical and biochemical parameters and genetic risk score (GRS based on variants in PNPLA3, TM6SF2, MBOAT7 and HSD17B13) were measured. Of all participants 49% had NAFLD-fibrosis. Independent predictors of NAFLD-fibrosis were low moderate-to-vigorous physical activity, high red meat intake, low carbohydrate intake, smoking, HbA1c, triglycerides and GRS. A model including these factors (areas under the receiver operating characteristics curve (AUROC) 0.90 (95% CI 0.84-0.96)) identified NAFLD-fibrosis significantly more accurately than a model including all but lifestyle factors (AUROC 0.82 (95% CI 0.73-0.91)) or models including lifestyle, physical and biochemical, or genetic factors alone. Assessment of lifestyle parameters in addition to physical, biochemical and genetic factors helps to identify obese patients with NAFLD-fibrosis.

Increased resting energy expenditure, fat oxidation, and food intake in patients with highly active antiretroviral therapy-associated lipodystrophy.

Highly active antiretroviral therapy (HAART) is associated with metabolic adverse events such as lipodystrophy in human immunodeficiency virus (HIV)-infected patients. The objective of the present study was to evaluate the effects of HAART-associated lipodystrophy on resting energy expenditure and caloric intake. In this cross-sectional study we compared resting energy expenditure (REE) and energy intake in 30 HAART-treated patients with lipodystrophy (HAART+LD+) with 13 HAART-treated patients without lipodystrophy (HAART+LD-). REE was measured using indirect calorimetry, and energy intake was recorded as a 3-day diary of food intake. REE (5,180+/-160 vs. 4,260+/-150 J/min, P<0.01) and also REE expressed per fat-free mass (86+/-1 vs. 78+/-2 J.kg fat-free mass-1.min-1, P<0.01) were significantly higher in the HAART+LD+ than the HAART+LD- group. Rate of lipid oxidation was significantly higher in the HAART+LD+ than the HAART+LD- group. Total energy and fat intakes were significantly increased in the HAART+LD+ compared with the HAART+LD- group. These results imply that HAART-associated lipodystrophy is associated with increased REE and lipid oxidation and with increased caloric and fat intake.

Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens.

OBJECTIVES: Despite evidence for the role of adipokines such as adiponectin in the metabolic toxicities of protease inhibitor (PI)-treated patients, little is known about their role in nucleoside reverse transcriptase inhibitor (NRTI)-induced lipoatrophy (LA). We analyzed the relations between mitochondrial toxicity, adipokine expression, and clinical LA in peripheral blood mononuclear cells (PBMCs) and adipose samples from individuals treated with stavudine (d4T) or zidovudine (ZDV) in comparison to patients undergoing highly active antiretroviral therapy (HAART) as well as HIV-negative individuals. METHODS: In this cross-sectional analysis, we studied 18 PI-naive HIV-infected patients with LA treated with d4T (d4T+LA+ [n = 12]) or zidovudine (ZDV+LA+ [n = 6]) in comparison to HAART-treated patients with (HAART+LA+ [n = 8]) and without (HAART+LA- [n = 8]) LA as well as HIV-negative controls (n = 12). Adipose samples were assessed for protein and/or messenger RNA (mRNA) levels of adiponectin, tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, and sterol regulatory element-binding protein (SREBP) 1a/c in all groups, whereas adipose and PBMC samples from the d4T+LA+, ZDV+LA+, and HIV-negative subgroups were assessed for mitochondrial DNA (mtDNA) depletion and cytochrome c-oxidase (COX) II/COX IV ratios. RESULTS: There was no change in mtDNA levels in adipose or PBMC samples in NRTI-treated patients with LA, although patients treated with d4T had reduced COX II/COX IV ratios in adipose and PBMC samples. Adipose tissue adiponectin mRNA and plasma levels were reduced in the d4T- and ZDV-treated patients regardless of the use of PIs. Tissue SREBP1c mRNA levels were also significantly reduced in both NRTI groups when compared with the HIV-negative controls. Significant reductions in SREBP1c levels were also evident with the HAART+LA+ group when compared with HAART+LA- controls. CONCLUSIONS: Patients with LA on d4T-based regimens show evidence of mitochondrial respiratory chain dysfunction, whereas the d4T- and ZDV-based regimens also demonstrated reduced SREBP1c and adiponectin levels, findings that have previously been shown with PIs.