Adverse muscle composition is a significant risk factor for all-cause mortality in NAFLD.

Background & Aims: Adverse muscle composition (MC) (i.e., low muscle volume and high muscle fat) has previously been linked to poor functional performance and comorbidities in non-alcoholic fatty liver disease (NAFLD). In this study we aimed to investigate associations of all-cause mortality with liver fat, NAFLD, and MC in the UK Biobank imaging study. Methods: Magnetic resonance images of 40,174 participants were analyzed for liver proton density fat fraction (PDFF), thigh fat-free muscle volume (FFMV) z-score, and muscle fat infiltration (MFI) using the AMRA® Researcher. Participants with NAFLD were sex-, age-, and BMI-matched to participants without NAFLD with low alcohol consumption. Adverse MC was identified using previously published cut-offs. All-cause mortality was investigated using Cox regression. Models within NAFLD were crude and subsequently adjusted for sex, age, BMI (M1), hand grip strength, physical activity, smoking, alcohol (M2), and previous cancer, coronary heart disease, type 2 diabetes (M3). Results: A total of 5,069 participants had NAFLD. During a mean (±SD) follow-up of 3.9 (±1.4) years, 150 out of the 10,138 participants (53% men, age 64.4 [±7.6] years, BMI 29.7 [±4.4] kg/m2) died. In the matched dataset, neither NAFLD nor liver PDFF were associated with all-cause mortality, while all MC variables achieved significance. Within NAFLD, adverse MC, MFI and FFMV z-score were significantly associated with all-cause mortality and remained so in M1 and M2 (crude hazard ratios [HRs] 2.84, 95% CI 1.70-4.75, p <0.001; 1.15, 95% CI 1.07-1.24, p <0.001; 0.70, 95% CI 0.55-0.88, p <0.001). In M3, the relationship was attenuated for adverse MC and FFMV z-score (adjusted HRs 1.72, 95% CI 1.00-2.98, p = 0.051; 0.77, 95% CI 0.58-1.02, p = 0.069) but remained significant for MFI (adjusted HR 1.13, 95% CI 1.01-1.26, p = 0.026). Conclusions: Neither NAFLD nor liver PDFF was predictive of all-cause mortality. Adverse MC was a strong predictor of all-cause mortality in individuals with NAFLD. Impact and implications: Individuals with fatty liver disease and poor muscle health more often suffer from poor functional performance and comorbidities. This study shows that they are also at a higher risk of dying. The study results indicate that measuring muscle health (the patient's muscle volume and how much fat they have in their muscles) could help in the early detection of high-risk patients and enable targeted preventative care.

Physical activity is inversely associated with hepatic fibro-inflammation: A population-based cohort study using UK Biobank data.

Background & Aims: Physical activity (PA) is recommended in the management of non-alcoholic fatty liver disease (NAFLD) given its beneficial effects on liver fat and cardiometabolic risk. Using data from the UK Biobank population-cohort, this study examined associations between habitual PA and hepatic fibro-inflammation. Methods: A total of 840 men and women aged 55-70 years were included in this cross-sectional study. Hepatic fibro-inflammation (iron-corrected T1 [cT1]) and liver fat were measured using MRI, whilst body fat was measured using dual-energy X-ray absorptiometry. PA was measured using accelerometry. Generalised linear models examined associations between PA (light [LPA], moderate [MPA], vigorous [VPA], moderate-to-vigorous [MVPA] and mean acceleration) and hepatic cT1. Models were fitted for the whole sample and separately for upper and lower median groups for body and liver fat. Models were adjusted for sociodemographic and lifestyle variables. Results: In the full sample, LPA (-0.08 ms [-0.12 to -0.03]), MPA, (-0.13 ms [-0.21 to -0.05]), VPA (-1.16 ms [-1.81 to -0.51]), MVPA (-0.14 ms [-0.21 to -0.06]) and mean acceleration (-0.67 ms [-1.05 to-0.28]) were inversely associated with hepatic cT1. With the sample split by median liver or body fat, only VPA was inversely associated with hepatic cT1 in the upper median groups for body (-2.68 ms [-4.24 to -1.13]) and liver fat (-2.33 [-3.73 to -0.93]). PA was unrelated to hepatic cT1 in the lower median groups. Conclusions: Within a population-based cohort, device-measured PA is inversely associated with hepatic fibro-inflammation. This relationship is strongest with VPA and is greater in people with higher levels of body and liver fat. Lay summary: This study has shown that people who regularly perform greater amounts of physical activity have a reduced level of inflammation and fibrosis in their liver. This beneficial relationship is particularly strong when more intense physical activity is undertaken (i.e., vigorous-intensity), and is most visible in individuals with higher levels of liver fat and body fat.

Role of Diffusion-Weighted Magnetic Resonance Imaging in the Diagnosis and Grading of Hepatic Steatosis in Patients With Non-alcoholic Fatty Liver Disease: Comparison With Ultrasonography and Magnetic Resonance Spectroscopy.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is becoming the most common cause of cirrhosis. Although magnetic resonance spectroscopy (MRS) is considered the gold standard, it has a few limitations. The role of diffusion-weighted imaging (DWI), which is a simpler sequence, in the diagnosis and grading of fatty liver is not well studied. The aim of the study was to investigate the value of DWI in the diagnosis and grading of hepatic steatosis in patients with NAFLD. MATERIALS AND METHODS: Fifty-one adults (mean age: 38 years; 28 men, 23 women) with NAFLD, diagnosed clinically and by ultrasonography (USG), were included in the study after obtaining informed consent and approval from the institute ethics committee. USG was performed for grading of hepatic steatosis in all patients, followed by magnetic resonance imaging with DWI and MRS, on a 1.5T scanner. The mean apparent diffusion coefficient (ADC) values and proton density fat fraction (PDFF) were calculated, and MRS was used as the gold standard. The mean ADC values were compared with the PDFF and USG grades. RESULTS: There was a weak correlation between ADC values and PDFF (r = -0.36; P < 0.05). In addition, there was a weak correlation between the ADC values of the liver and USG grade (r = -0.34; P < 0.05). However, an overall increase in USG grades and PDFF was associated with decrease in the mean ADC value (P < 0.001). CONCLUSION: DWI is not accurate in the diagnosis and grading of hepatic steatosis in patients with NAFLD. However, a significant increase in fat deposition in the liver lowers the ADC values.

Quantification of Liver Fat by MRI-PDFF Imaging in Patients with Suspected Non-alcoholic Fatty Liver Disease and Its Correlation with Metabolic Syndrome, Liver Function Test and Ultrasonography.

BACKGROUND: Magnetic resonance imaging (MRI)-estimated proton density fat fraction (PDFF) has emerged to be a promising tool in quantification of liver fat. Aim of this study was to quantify liver fat using MRI-PDFF in patients with suspected non-alcoholic fatty liver disease (NAFLD) and to correlate it with the presence of metabolic syndrome (MetS), ultrasonography (USG) and liver function test (LFT). METHODS: We included 111 consecutive patients who were suspected to have NAFLD on the basis of clinical, laboratory or USG findings. A 3 Tesla Phillips MRI machine was used with a software named "mDixon Quant" for quantification of the liver fat. RESULTS: MRI-PDFF revealed hepatic steatosis grading as Grade 0 in 31 patients (28%), Grade I in 40 (36%), Grade II in 19 (17.1%) and Grade III in 21 patients (18.9%). MetS patients had higher proportion of advanced steatosis (Grades II and III) as compared to those without MetS (P < 0.001). ALT (alanine transaminase) was found to be significantly elevated (>1.5 times) in the patients with advanced steatosis as compared to patients with Grades I and 0 fatty liver on MRI-PDFF (P < 0.001). The Kappa measure of agreement between USG and MRI-PDFF was found to be 0.2, which suggests a low level of agreement between the two tests. CONCLUSION: MetS patients have higher proportion of advanced steatosis (Grades II and III) at MRI-PDFF as compared to those without MetS. Patients with advanced steatosis at MRI-PDFF had higher proportion of abnormal LFTs as compared to those with Grades 0 and I hepatic steatosis. There was a dis-correlation between MRI-PDFF and USG in the evaluation of NAFLD.

Adverse muscle composition is linked to poor functional performance and metabolic comorbidities in NAFLD.

BACKGROUND & AIMS: Sarcopenia and frailty are recognised as important factors in later stages of liver disease. However, their role in non-alcoholic fatty liver disease (NAFLD) is not yet fully understood. In this study we investigate the associations of MRI-measured adverse muscle composition (AMC: low muscle volume and high muscle fat) with poor function, sarcopenia, and metabolic comorbidity within NAFLD in the large UK Biobank imaging study. METHODS: A total of 9,545 participants were included. Liver fat, fat-tissue free muscle volume, and muscle fat infiltration were quantified using a rapid MRI protocol and automated image analysis (AMRA® Researcher). For each participant, a personalised muscle volume z-score (sex- and body size-specific) was calculated and combined with muscle fat infiltration for AMC detection. The following outcomes were investigated: functional performance (hand grip strength, walking pace, stair climbing, falls) and metabolic comorbidities (coronary heart disease, type 2 diabetes). Sarcopenia was detected by combining MRI thresholds for low muscle quantity and low hand grip strength according to the European working group definition. RESULTS: The prevalence of sarcopenia in NAFLD (1.6%) was significantly lower (p <0.05) compared with controls without fatty liver (3.4%), whereas the prevalence of poor function and metabolic comorbidity was similar or higher. Of the 1,204 participants with NAFLD, 169 (14%) had AMC and showed 1.7-2.4× higher prevalence of poor function (all p <0.05) as well as 2.1× and 3.3× higher prevalence of type 2 diabetes and coronary heart disease (p <0.001), respectively, compared with those without AMC. CONCLUSIONS: AMC is a prevalent and highly vulnerable NAFLD phenotype displaying poor function and high prevalence of metabolic comorbidity. Sarcopenia guidelines can be strengthened by including cut-offs for muscle fat, enabling AMC detection. LAY SUMMARY: Today, it is hard to predict whether a patient with fatty liver disease will progress to more severe liver disease. This study shows that measuring muscle health (the patient's muscle volume and how much fat they have in their muscles) could help identify the more vulnerable patients and enable early prevention of severe liver disease.

Role of Magnetic Resonance Imaging in the Monitoring of Patients with Nonalcoholic Fatty Liver Disease: Comparison with Ultrasonography, Lipid Profile, and Body Mass Index.

AIM: The aim of this study was to study the role of magnetic resonance imaging (MRI) in monitoring hepatic fat content in cases of nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: 41 adults (mean age: 39 years, 22 males; 19 females) with NAFLD were included after obtaining approval from the institutional ethics committee. The baseline clinical (weight, body mass index [BMI]) and biochemical parameters, fatty liver grade on ultrasonography (USG), and hepatic fat signal fraction (FSF) using dual-echo chemical shift imaging and proton density fat fraction on magnetic resonance spectroscopy (MRS-PDFF) were assessed, before and after intervention (dietary and lifestyle changes and oral vitamin E for six months). They were categorized into Group A (good compliance to intervention) and Group B (poor compliance), and the clinical and imaging parameters were compared between them. RESULTS: After intervention, Group A (n = 30) showed significant reduction in BMI (28.35 ± 3.25 to 27.14 ± 3.24 kg/m2; P < 0.001), hepatic FSF (19.30 ± 9.09% to 11.18 ± 7.61%; P < 0.05), and MRS-PDFF (18.79 ± 8.53% to 10.64 ± 6.66%). In Group B (n = 11), there was significant increase in BMI (28.85 ± 2.41 to 29.31 ± 2.57 kg/m2; P < 0.001), hepatic FSF (18.96 ± 9.79% to 21.48 ± 11.80%; P < 0.05), and reduction in high-density lipoproteins (P < 0.05). Although there was good correlation between USG and MRS in quantifying liver fat (r = 0.84-0.87; P < 0.001), USG was unable to detect <5.3% change in hepatic fat. There was poor correlation between lipid profile and MRS-PDFF. Change in body weight significantly correlated with change in hepatic fat content (r = 0.76; P < 0.001). CONCLUSION: MRI is useful in accurately quantifying and in monitoring hepatic fat content and is better than clinical and biochemical parameters and USG.

Marrow adipose tissue gradient is preserved through high protein diet and bed rest. A randomized crossover study.

CONTEXT: Marrow adipose tissue (MAT) has a peripheral to central distribution in adults, higher in peripheral bones. Similarly, the spine has a caudal to cephalad MAT distribution, higher in lumbar vertebras. Diet and the level of physical activities are known modulators of MAT with significant impact on bone; however, whether these can modulate the MAT gradient is unknown. OBJECTIVE: To measure the effect of high protein diet and bed rest interventions on the lumbar MAT gradient. DESIGN PARTICIPANTS INTERVENTION: In a prospective randomized crossover trial, 10 healthy men participated in 2 consecutive campaigns of 21days head-down-tilt-bed-rest (HDTBR). They received either whey protein and potassium bicarbonate-supplemented or control diet separated by a 4-month washout period. MAIN OUTCOME MEASURES: Ten serial MRI measures of lumbar vertebral fat fraction (VFF) were performed at baseline, 10days and 20days of HDTBR and 3 and 28days after HDTBR of each bed rest campaign. RESULTS: The mean L5-L1 VFF difference of 4.2 ± 1.2 percentage point higher at L5 (p = 0.008) constituted a caudal to cephalad lumbar MAT gradient. High protein diet did not alter the lumbar VFF differences during both HDTBR campaigns (all time points p > 0.05). Similarly, 2 campaigns of 21days of HDTBR did not change the lumbar VFF differences (all time points p > 0.05). CONCLUSIONS: This pilot study established that the lumbar vertebral MAT gradient was not altered by a high protein nor by 2 × 21days bed rest interventions. These findings demonstrated that this lack of mechanical stimulus was not an important modulator of the lumbar MAT gradient. The highly preserved MAT gradient needs to be measured in more situations of health and disease and may potentially serve to detect pathological situations.

Cross-sectional correlation between hepatic R2* and proton density fat fraction (PDFF) in children with hepatic steatosis.

PURPOSE: To determine the relationship between hepatic proton density fat fraction (PDFF) and R2* in vivo. MATERIALS AND METHODS: In this Health Insurance Portability and Accountability Act (HIPAA)-compliant, Institutional Review Board (IRB)-approved, cross-sectional study, we conducted a secondary analysis of 3T magnetic resonance imaging (MRI) exams performed as part of prospective research studies in children in whom conditions associated with iron overload were excluded clinically. Each exam included low-flip-angle, multiecho magnitude (-M) and complex (-C) based chemical-shift-encoded MRI techniques with spectral modeling of fat to generate hepatic PDFF and R2* parametric maps. For each technique and each patient, regions of interest were placed on the maps in each of the nine Couinaud segments, and composite whole-liver PDFF and R2* values were calculated. Pearson's correlation coefficients between PDFF and R2* were computed for each MRI technique. Correlations were compared using Steiger's test. RESULTS: In all, 184 children (123 boys, 61 girls) were included in this analysis. PDFF estimated by MRI-M and MRI-C ranged from 1.1-35.4% (9.44 ± 8.76) and 2.1-38.1% (10.1 ± 8.7), respectively. R2* estimated by MRI-M and MRI-C ranged from 32.6-78.7 s-1 (48.4 ± 9.8) and 27.2-71.5 s-1 (42.2 ± 8.6), respectively. There were strong and significant correlations between hepatic PDFF and R2* values estimated by MRI-M (r = 0.874; P < 0.0001) and MRI-C (r = 0.853; P < 0.0001). The correlation coefficients (0.874 vs. 0.853) were not significantly different (P = 0.15). CONCLUSION: Hepatic PDFF and R2* are strongly correlated with each other in vivo. This relationship was observed using two different MRI techniques. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:418-424.

Metadoxine Versus Placebo for the Treatment of Non-alcoholic Steatohepatitis: A Randomized Controlled Trial.

OBJECTIVE AND DESIGN: The study aimed at assessing the therapeutic efficacy and safety of metadoxine versus placebo on the ultrasonographic and histological features of non-alcoholic steatohepatitis (NASH). SUBJECTS: 134 subjects with biopsy-confirmed NASH were randomized to receive metadoxine 500 mg two times daily (n = 75) or placebo (n = 59) added to the standard of care, over 16 weeks. EFFICACY ENDPOINTS: Originally, the primary efficacy endpoint was the composite of: reduction in the steatosis by ≥1 grade, reduction in hepatic necro-inflammation by ≥1 grade and ALT normalization. Since >50% of patients refused the second biopsy, it was decided to analyze only the individual parameters. RESULTS: There was no significant difference between the treatment and the placebo groups in either liver histology or ALT or AST. Overall, as expected both groups showed reduction in serum ALT and AST compared to baseline. Compared to placebo (9 out 54), patients on metadoxine (34 out of 75) had significantly higher rates of improvement in 1-point in steatosis grade on ultrasound (P-value <0.001). Safety and tolerability did not differ between treatments. CONCLUSION: Metadoxine is not effective in improvement of liver histology or serum ALT or AST in patients with NASH. However, there was significant improvement of steatosis assessed by ultrasound. To properly estimate the effects on histology and transaminases, further studies of longer duration and at higher doses are needed.