With the increasing incidence of non-alcoholic fatty liver disease (NAFLD) and the aging of the population, sarcopenia is attracting attention as one of the pathological conditions involved in the development and progression of NAFLD. In NAFLD, sarcopenia is closely associated with insulin resistance and results from the atrophy of skeletal muscle, an insulin target organ. In addition, inflammatory cytokines that promote skeletal muscle protein breakdown, low adiponectin levels leading to decreased insulin sensitivity, and hyperleptinemia are also involved in NAFLD pathogenesis. The presence of sarcopenia is a prognostic factor and increases the risk of mortality in patients with cirrhosis and post-treatment liver cancer. Sarcopenia, the presence of which mainly occurs due to decreased muscle mass, combined with increased visceral fat, can lead to sarcopenia-associated obesity, which increases the risk of NASH, liver fibrosis, and cardiovascular disease. In order to treat sarcopenia, it is necessary to properly evaluate sarcopenia status. Patients with high BMI, as in sarcopenic obesity, may improve with caloric restriction. However, inadequate oral intake may lead to further loss of muscle mass. Aerobic and resistance exercise should also be used appropriately.

Non-invasive imaging techniques have greatly advanced the assessment of liver fibrosis and steatosis but are not fully evaluated in overweight patients. We evaluated the diagnostic performance of vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE) to assess fibrosis and controlled attenuation parameter (CAP) and MR imaging (MRI)-proton density fat fraction (MRI-PDFF) to assess steatosis in overweight and obese patients with non-alcoholic fatty liver disease (NAFLD). We included 163 biopsy-proven patients with NAFLD who underwent VCTE, MRE/MRI-PDFF, and liver biopsy (years 2014–2020) who were classified according to their body mass index (BMI) as normal (BMI < 25 kg/m2, n = 38), overweight (25 ≤ BMI < 30 kg/m2, n = 68), and obese (BMI ≥ 30 kg/m2, n = 57). VCTE and MRE detected fibrosis of stages ≥ 2, ≥ 3, and 4 with an area under the receiver operating curve (AUROC) of 0.83–0.94 (VCTE) and 0.85–0.95 (MRE) in all groups, without considerable differences. MRI-PDFF detected steatosis of grades ≥ 2 and 3 with high AUROC in all groups (0.81–1.00). CAP’s diagnostic ability (0.63–0.95) was lower than that of MRI-PDFF and decreased with increasing BMI compared to MRI-PDFF. VCTE and MRE similarly accurately assess fibrosis, although MRI-PDFF is more accurate than CAP in detecting steatosis in overweight and obese patients with NAFLD.

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A 2-step approach, Fibrosis-4 index (FIB-4) followed by vibration-controlled transient elastography (VCTE), has been proposed to predict advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to develop a novel 3-step approach for predicting advanced fibrosis. We enrolled 284 biopsy-confirmed NAFLD patients from two tertiary care centers and developed subgroups (n = 190), including 3.7% of patients with advanced fibrosis, assuming a primary care setting. In the 3-step approach, patients with intermediate-to-high FIB-4 in the first step underwent an enhanced liver fibrosis test or measurement of type IV collagen 7S domain as the second step, and VCTE was performed if the second step value was higher than the cutoff. In 284 cases, a tertiary care cohort with 36.3% advanced fibrosis, the 3-step approach showed significantly higher specificity and positive predictive value than the 2-step approach. In the subgroup with 3.7% advanced fibrosis, the 3-step approach significantly reduced the referral rate to specialists, the number of high-risk patients (i.e., liver biopsy candidates), and healthcare costs by 12.5% to 15.8%. The 3-step approach may improve the diagnostic performance to predict advanced fibrosis in NAFLD, which could lower rates of referrals to specialists, liver biopsies, and medical costs.

IntroductionNon-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related to hyperglycaemic and hyperlipidaemia. The prevalence of NAFLD is increasing worldwide. However, currently, there is no consensus regarding the efficacy and safety of drugs used to treat patients with NAFLD/non-alcoholic steatohepatitis (NASH). Guanabenz acetate, a selective α2-adrenoceptor stimulator used in the treatment of hypertension, binds at a high-affinity constant to a nuclear transcriptional coregulator, helicase with zinc finger 2 (Helz2) and inhibits Helz2-medaited steatosis in the liver; chronic oral administration of guanabenz acetate produces a dose-dependent inhibition of lipid accumulation by inhibiting lipogenesis and activating fatty acid Β-oxidation in the liver of obese mice, resulting in improvement of insulin resistance and hyperlipidaemia. Taken all together, guanabenz acetate has a potentially effective in improving the development of NAFLD/NASH and metabolic abnormalities. In this randomised, open label, parallel-group, phase IIa study, we made attempts to conduct a proof-of-concept assessment by evaluating the efficacy and safety of guanabenz acetate treatment in patients with NAFLD/NASH.Methods and analysisA total of 28 adult patients with NAFLD or NASH and hypertension complications meeting the inclusion/exclusion criteria will be enrolled. Patients will be randomised to receive either 4 or 8 mg guanabenz acetate (n=14 per group). Blood tests and MRI will be performed 16 weeks after commencement of treatment. The primary endpoint will be the percentage reduction in hepatic fat content (%) measured using MRI-proton density fat fraction from baseline by at least 3.46% at week 16 after treatment initiation.Ethics and disseminationEthics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment (YCU021001). The results of this study will be submitted for publication in international peer-reviewed journals, and the key findings will be presented at international scientific conferences. Participants wishing to know the results of this study will be contacted directly on data publication.Trial registration numberThis trial is registered with ClinicalTrials.gov (number: NCT05084404).Protocol versionV.1.1, 19 August 2021.