Association of proton-density fat fraction with osteoporosis: a systematic review and meta-analysis.

This study aimed to evaluate the correlation between measuring proton-density fat fraction (PDFF) in bone marrow using multi-echo chemical shift-encoded MRI and osteoporosis, assessing its effectiveness as a biomarker for osteoporosis. A systematic review was conducted by two independent researchers using Cochrane, PubMed, EMBASE, and Web of Science databases up to December 2023. Quality assessments were evaluated using the Cochrane risk of bias tool and the Agency for Healthcare Research and Quality (AHRQ) checklist. Fourteen studies involving 1495 patients were analyzed. The meta-analysis revealed a significant difference in PDFF values between the osteoporosis/osteopenia group and the normal control group, with a mean difference of 11.04 (95% CI: 9.17 to 12.92, Z=11.52, P < 0.00001). Measuring PDFF via MRI shows potential as an osteoporosis biomarker and may serve as a risk factor for osteoporosis. This insight opens new avenues for future diagnostic and therapeutic strategies, potentially improving osteoporosis management and patient care. OBJECTIVE: This study aims to assess the correlation between measuring proton-density fat fraction (PDFF) in bone marrow using multi-echo chemical shift-encoded MRI and osteoporosis, evaluating its effectiveness as a biomarker for osteoporosis. MATERIALS AND METHODS: This systematic review was carried out by two independent researchers using Cochrane, PubMed, EMBASE, and Web of Science databases up to December 2023. Quality assessments were evaluated using the Cochrane risk of bias tool and the Agency for Healthcare Research and Quality (AHRQ) checklist. RESULTS: Fourteen studies involving 1495 patients were analyzed. The meta-analysis revealed a significant difference in PDFF values between the osteoporosis/osteopenia group and the normal control group, with a (MD = 11.04, 95% CI: 9.17 to 12.92, Z = 11.52, P < 0.00001). Subgroup analyses indicated that diagnostic methods, gender, and echo length did not significantly impact the PDFF-osteoporosis association. CONCLUSION: PDFF measurement via MRI shows potential as an osteoporosis biomarker and may serve as a risk factor for osteoporosis. This insight opens new avenues for future diagnostic and therapeutic strategies, potentially improving osteoporosis management and patient care.

Reference Values for Water-Specific T1 of the Liver at 3 T: T2*-Compensation and the Confounding Effects of Fat.

BACKGROUND: T1 mapping of the liver is confounded by the presence of fat. Multiparametric T1 mapping combines fat-water separation with T1-weighting to enable imaging of water-specific T1 (T1Water ), proton density fat fraction (PDFF), and T2* values. However, normative T1Water values in the liver and its dependence on age/sex is unknown. PURPOSE: Determine normative values for T1Water in the liver with comparison to MOLLI and evaluate a T2*-compensation approach to reduce T1 variability. STUDY TYPE: Prospective observational; phantoms. POPULATIONS: One hundred twenty-four controls (56 male, 18-75 years), 50 patients at-risk for liver disease (18 male, 30-76 years). FIELD STRENGTH/SEQUENCE: 2.89 T; Saturation-recovery chemical-shift encoded T1 Mapping (SR-CSE); MOLLI. ASSESSMENT: SR-CSE provided T1Water measurements, PDFF and T2* values in the liver across three slices in 6 seconds. These were compared with MOLLI T1 values. A new T2*-compensation approach to reduce T1 variability was evaluated test/re-test reproducibility. STATISTICAL TESTS: Linear regression, ANCOVA, t-test, Bland and Altman, intraclass correlation coefficient (ICC). P < 0.05 was considered statistically significant. RESULTS: Liver T1 values were significantly higher in healthy females (F) than males (M) for both SR-CSE (F-973 ± 78 msec, M-930 ± 72 msec) and MOLLI (F-802 ± 55 msec, M-759 ± 69 msec). T1 values were negatively correlated with age, with similar sex- and age-dependencies observed in T2*. The T2*-compensation model reduced the variability of T1 values by half and removed sex- and age-differences (SR-CSE: F-946 ± 36 msec, M-941 ± 43 msec; MOLLI: F-775 ± 35 msec, M-770 ± 35 msec). At-risk participants had elevated PDFF and T1 values, which became more distinct from the healthy cohort after T2*-compensation. MOLLI systematically underestimated liver T1 values by ~170 msec with an additional positive T1-bias from fat content (~11 msec/1% in PDFF). Reproducibility ICC values were ≥0.96 for all parameters. DATA CONCLUSION: Liver T1Water values were lower in males and decreased with age, as observed for SR-CSE and MOLLI acquisitions. MOLLI underestimated liver T1 with an additional large positive fat-modulated T1 bias. T2*-compensation removed sex- and age-dependence in liver T1, reduced the range of healthy values and increased T1 group differences between healthy and at-risk groups. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Severe hepatic steatosis promotes increased liver stiffness in the early stages of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: The predictors of progression from steatosis to more advanced stages of metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. We evaluated the association between the quantity of hepatic steatosis and longitudinal changes in liver stiffness measurements (LSMs) using magnetic resonance elastography (MRE) in patients with MASLD. METHODS: We retrospectively analysed patients with MASLD who underwent at least two serial MRE and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) examinations at least 1 year apart. Fine-Gray competitive proportional hazard regression was used to identify LSM progression and regression factors. RESULTS: A total of 471 patients were enrolled. Factors linked to LSM progression were steatosis grade 3 (MRI-PDFF ≥17.1%, adjusted hazard ratio [aHR] 2.597; 95% confidence interval [CI] 1.483-4.547) and albumin-bilirubin grade 2 or 3 (aHR 2.790; 95% CI 1.284-6.091), while the only factor linked to LSM regression was % decrease rate of MRI-PDFF ≥5% (aHR 2.781; 95% CI 1.584-4.883). Steatosis grade 3 correlated with a higher incidence rate of LSM progression than steatosis grade 1 (MRI-PDFF <11.3%) in patients with LSM stage 0 (<2.5 kilopascal [kPa]), and a % annual decrease rate of MRI-PDFF ≥5% correlated with a higher incidence rate of LSM regression than that of MRI-PDFF >-5% and <5% in patients with LSM stage 1 or 2-4 (≥2.5 kPa). CONCLUSIONS: Severe hepatic steatosis was linked to significant LSM progression in patients with MASLD and low LSM (<2.5 kPa).

Nonalcoholic Fatty Liver Disease, Bone and Muscle Quality in Prolactinoma: A Pilot Study.

OBJECTIVE: Hyperprolactinemia has negative impacts on metabolism and musculoskeletal health. In this study, individuals with active prolactinoma were evaluated for nonalcoholic fatty liver disease (NAFLD) and musculoskeletal health, which are underemphasized in the literature. METHODS: Twelve active prolactinoma patients and twelve healthy controls matched by age, gender, and BMI were included. Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) was used to evaluate hepatic steatosis and magnetic resonance elastography (MRE) to evaluate liver stiffness measurement (LSM). Abdominal muscle mass, and vertebral MRI-PDFF was also evaluated with MRI. Body compositions were evaluated by dual energy X-ray absorptiometry (DXA). The skeletal muscle quality (SMQ) was classified as normal, low and weak by using "handgrip strength/appendicular skeletal muscle mass (HGS/ASM)" ratio based on the cut-off values previously stated in the literature. RESULTS: Prolactin, HbA1c and CRP levels were higher in prolactinoma patients (p<0.001, p=0.033 and p=0.035, respectively). The median MRI-PDFF and MRE-LSM were 3.0% (2.01-15.20) and 2.22 kPa (2.0-2.5) in the prolactinoma group and 2.5% (1.65-10.00) and 2.19 kPa (1.92-2.54) in the control group, respectively and similiar between groups. In prolactinoma patients, liver MRI-PDFF showed a positive and strong correlation with the duration of disease and traditional risk factors for NAFLD. Total, vertebral and pelvic bone mineral density was similar between groups, while vertebral MRI-PDFF tended to be higher in prolactinoma patients (p=0.075). Muscle mass and strength parameters were similar between groups, but HGS/ASM tended to be higher in prolactinoma patients (p=0.057). Muscle mass was low in 33.3% of prolactinoma patients and 66.6 of controls. According to SMQ, all prolactinoma patients had normal SMQ, whereas 66.6% of the controls had normal SMQ. CONCLUSION: Prolactinoma patients demonstrated similar liver MRI-PDFF and MRE-LSM to controls despite their impaired metabolic profile and lower gonadal hormone levels. Hyperprolactinemia may improve muscle quality in prolactinoma patients despite hypogonadism.

Free-breathing MRI techniques for fat and R2* quantification in the liver.

OBJECTIVE: To review the recent advancements in free-breathing MRI techniques for proton-density fat fraction (PDFF) and R2* quantification in the liver, and discuss the current challenges and future opportunities. MATERIALS AND METHODS: This work focused on recent developments of different MRI pulse sequences, motion management strategies, and reconstruction approaches that enable free-breathing liver PDFF and R2* quantification. RESULTS: Different free-breathing liver PDFF and R2* quantification techniques have been evaluated in various cohorts, including healthy volunteers and patients with liver diseases, both in adults and children. Initial results demonstrate promising performance with respect to reference measurements. These techniques have a high potential impact on providing a solution to the clinical need of accurate liver fat and iron quantification in populations with limited breath-holding capacity. DISCUSSION: As these free-breathing techniques progress toward clinical translation, studies of the linearity, bias, and repeatability of free-breathing PDFF and R2* quantification in a larger cohort are important. Scan acceleration and improved motion management also hold potential for further enhancement.

Parameter optimization for proton density fat fraction quantification in skeletal muscle tissue at 7 T.

OBJECTIVE: To establish an image acquisition and post-processing workflow for the determination of the proton density fat fraction (PDFF) in calf muscle tissue at 7 T. MATERIALS AND METHODS: Echo times (TEs) of the applied vendor-provided multi-echo gradient echo sequence were optimized based on simulations of the effective number of signal averages (NSA*). The resulting parameters were validated by measurements in phantom and in healthy calf muscle tissue (n = 12). Additionally, methods to reduce phase errors arising at 7 T were evaluated. Finally, PDFF values measured at 7 T in calf muscle tissue of healthy subjects (n = 9) and patients with fatty replacement of muscle tissue (n = 3) were compared to 3 T results. RESULTS: Simulations, phantom and in vivo measurements showed the importance of using optimized TEs for the fat-water separation at 7 T. Fat-water swaps could be mitigated using a phase demodulation with an additional B0 map, or by shifting the TEs to longer values. Muscular PDFF values measured at 7 T were comparable to measurements at 3 T in both healthy subjects and patients with increased fatty replacement. CONCLUSION: PDFF determination in calf muscle tissue is feasible at 7 T using a chemical shift-based approach with optimized acquisition and post-processing parameters.

Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH.

BACKGROUND & AIMS: The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). METHODS: This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12. RESULTS: One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively. CONCLUSIONS: In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit. CLINICAL TRIAL NUMBER (EUDRACT): 2018-003119-22. GOV IDENTIFIER: NCT03812029. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH.

SPARCQ: A new approach for fat fraction mapping using asymmetries in the phase-cycled balanced SSFP signal profile.

PURPOSE: To develop SPARCQ (Signal Profile Asymmetries for Rapid Compartment Quantification), a novel approach to quantify fat fraction (FF) using asymmetries in the phase-cycled balanced SSFP (bSSFP) profile. METHODS: SPARCQ uses phase-cycling to obtain bSSFP frequency profiles, which display asymmetries in the presence of fat and water at certain TRs. For each voxel, the measured signal profile is decomposed into a weighted sum of simulated profiles via multi-compartment dictionary matching. Each dictionary entry represents a single-compartment bSSFP profile with a specific off-resonance frequency and relaxation time ratio. Using the results of dictionary matching, the fractions of the different off-resonance components are extracted for each voxel, generating quantitative maps of water and FF and banding-artifact-free images for the entire image volume. SPARCQ was validated using simulations, experiments in a water-fat phantom and in knees of healthy volunteers. Experimental results were compared with reference proton density FFs obtained with 1 H-MRS (phantoms) and with multiecho gradient-echo MRI (phantoms and volunteers). SPARCQ repeatability was evaluated in six scan-rescan experiments. RESULTS: Simulations showed that FF quantification is accurate and robust for SNRs greater than 20. Phantom experiments demonstrated good agreement between SPARCQ and gold standard FFs. In volunteers, banding-artifact-free quantitative maps and water-fat-separated images obtained with SPARCQ and ME-GRE demonstrated the expected contrast between fatty and non-fatty tissues. The coefficient of repeatability of SPARCQ FF was 0.0512. CONCLUSION: SPARCQ demonstrates potential for fat quantification using asymmetries in bSSFP profiles and may be a promising alternative to conventional FF quantification techniques.

Confounder-corrected T1 mapping in the liver through simultaneous estimation of T1 , PDFF, R 2 * , and B 1 + in a single breath-hold acquisition.

PURPOSE: Quantitative volumetric T1 mapping in the liver has the potential to aid in the detection, diagnosis, and quantification of liver fibrosis, inflammation, and spatially resolved liver function. However, accurate measurement of hepatic T1 is confounded by the presence of fat and inhomogeneous B 1 + $$ {B}_1^{+} $$ excitation. Furthermore, scan time constraints related to respiratory motion require tradeoffs of reduced volumetric coverage and/or increased acquisition time. This work presents a novel 3D acquisition and estimation method for confounder-corrected T1 measurement over the entire liver within a single breath-hold through simultaneous estimation of T1 , fat and B 1 + $$ {B}_1^{+} $$ . THEORY AND METHODS: The proposed method combines chemical shift encoded MRI and variable flip angle MRI with a B 1 + $$ {B}_1^{+} $$ mapping technique to enable confounder-corrected T1 mapping. The method was evaluated theoretically and demonstrated in both phantom and in vivo acquisitions at 1.5 and 3.0T. At 1.5T, the method was evaluated both pre- and post- contrast enhancement in healthy volunteers. RESULTS: The proposed method demonstrated excellent linear agreement with reference inversion-recovery spin-echo based T1 in phantom acquisitions at both 1.5 and 3.0T, with minimal bias (5.2 and 45 ms, respectively) over T1 ranging from 200-1200 ms. In vivo results were in general agreement with reference saturation-recovery based 2D T1 maps (SMART1 Map, GE Healthcare). CONCLUSION: The proposed 3D T1 mapping method accounts for fat and B 1 + $$ {B}_1^{+} $$ confounders through simultaneous estimation of T1 , B 1 + $$ {B}_1^{+} $$ , PDFF and R 2 * $$ {R}_2^{\ast } $$ . It demonstrates strong linear agreement with reference T1 measurements, with low bias and high precision, and can achieve full liver coverage in a single breath-hold.

Usefulness of controlled attenuation parameter in monitoring clinically relevant decline of hepatic steatosis for non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) is the reference standard of hepatic steatosis assessment. This study evaluates usefulness of controlled attenuation parameter (CAP) in monitoring the clinically relevant outcome by MRI-PDFF for non-alcoholic fatty liver disease (NAFLD) patients. METHODS: NAFLD patients were enrolled prospectively. Instruction was given in lifestyle modifications with exercise and control of metabolic factors. MRI-PDFF and CAP were performed at enrollment and follow-up, with the diagnostic validity of CAP in monitoring clinically relevant outcome defined as a decline of ≥30% relative to baseline value by MRI-PDFF. RESULTS: A total of 75 patients (male/female: 49/26, mean age: 53.2) were enrolled. Baseline MRI-PDFF, CAP and liver stiffness was 14.4%, 300.2 dB/m and 6.5 kPa. In a median interval of 369 days, thirteen (17.3%) patients achieved clinically relevant outcome with decline of 46.7 dB/m by CAP, compared with increase of 5.1 in the other patients. In multivariate analysis, clinically relevant outcome was associated with changes (Δ) of CAP and glucose. Assessed by area under receiver operating curve, the performances of ΔCAP in predicting clinically relevant outcome were 0.815 and 0.808, and with the specificity of >90%, the ΔCAP cutoff was -46 dB/m and -15% relative to baseline value; sensitivity was 53.8% and 46.2% with negative predictive value of 90.3% and 88.9% respectively. CONCLUSIONS: For NAFLD patients, CAP exhibited good performance in monitoring clinically relevant decline of hepatic steatosis in MRI-PDFF. With the cutoffs of -46 dB/m or -15%, ΔCAP is useful in excluding clinical relevant outcome achievement.

Deep Learning for Inference of Hepatic Proton Density Fat Fraction From T1-Weighted In-Phase and Opposed-Phase MRI: Retrospective Analysis of Population-Based Trial Data.

BACKGROUND. The confounder-corrected chemical shift-encoded MRI (CSE-MRI) sequence used to determine proton density fat fraction (PDFF) for hepatic fat quantification is not widely available. As an alternative, hepatic fat can be assessed by a two-point Dixon method to calculate signal fat fraction (FF) from conventional T1-weighted in- and opposed-phase (IOP) images, although signal FF is prone to biases, leading to inaccurate quantification. OBJECTIVE. The purpose of this study was to compare hepatic fat quantification by use of PDFF inferred from conventional T1-weighted IOP images and deep-learning convolutional neural networks (CNNs) with quantification by use of two-point Dixon signal FF with CSE-MRI PDFF as the reference standard. METHODS. This study entailed retrospective analysis of data from 292 participants (203 women, 89 men; mean age, 53.7 ± 12.0 [SD] years) enrolled at two sites from September 1, 2017, to December 18, 2019, in the Strong Heart Family Study (a prospective population-based study of American Indian communities). Participants underwent liver MRI (site A, 3 T; site B, 1.5 T) including T1-weighted IOP MRI and CSE-MRI (used to reconstruct CSE PDFF and CSE R2* maps). With CSE PDFF as reference, a CNN was trained in a random sample of 218 (75%) participants to infer voxel-by-voxel PDFF maps from T1-weighted IOP images; testing was performed in the other 74 (25%) participants. Parametric values from the entire liver were automatically extracted. Per-participant median CNN-inferred PDFF and median two-point Dixon signal FF were compared with reference median CSE-MRI PDFF by means of linear regression analysis, intraclass correlation coefficient (ICC), and Bland-Altman analysis. The code is publicly available at github.com/kang927/CNN-inference-of-PDFF-from-T1w-IOP-MR. RESULTS. In the 74 test-set participants, reference CSE PDFF ranged from 1% to 32% (mean, 11.3% ± 8.3% [SD]); reference CSE R2* ranged from 31 to 457 seconds-1 (mean, 62.4 ± 67.3 seconds-1 [SD]). Agreement metrics with reference to CSE PDFF for CNN-inferred PDFF were ICC = 0.99, bias = -0.19%, 95% limits of agreement (LoA) = (-2.80%, 2.71%) and for two-point Dixon signal FF were ICC = 0.93, bias = -1.11%, LoA = (-7.54%, 5.33%). CONCLUSION. Agreement with reference CSE PDFF was better for CNN-inferred PDFF from conventional T1-weighted IOP images than for two-point Dixon signal FF. Further investigation is needed in individuals with moderate-to-severe iron overload. CLINICAL IMPACT. Measurement of CNN-inferred PDFF from widely available T1-weighted IOP images may facilitate adoption of hepatic PDFF as a quantitative bio-marker for liver fat assessment, expanding opportunities to screen for hepatic steatosis and nonalcoholic fatty liver disease.

Effect of a combination of pemafibrate and a mild low-carbohydrate diet on obese and non-obese patients with metabolic-associated fatty liver disease.

BACKGROUND AND AIM: Recently, pemafibrate and a low-carbohydrate diet (LCD) have each been reported to improve fatty liver disease. However, it is unclear whether their combination improves fatty liver disease and is equally effective in obese and non-obese patients. METHODS: In 38 metabolic-associated fatty liver disease (MAFLD) patients, classified by baseline body mass index (BMI), changes in laboratory values, magnetic resonance elastography (MRE), and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) were studied after 1 year of combined pemafibrate plus mild LCD. RESULTS: The combination treatment resulted in weight loss (P = 0.002), improvement in hepatobiliary enzymes (γ-glutamyl transferase, P = 0.027; aspartate aminotransferase, P < 0.001; alanine transaminase [ALT], P < 0.001), and improvement in liver fibrosis markers (FIB-4 index, P = 0.032; 7 s domain of type IV collagen, P = 0.002; M2BPGi, P < 0.001). Vibration-controlled transient elastography improved from 8.8 to 6.9 kPa (P < 0.001) and MRE improved from 3.1 to 2.8 kPa (P = 0.017) in the liver stiffness. MRI-PDFF improved from 16.6% to 12.3% in liver steatosis (P = 0.007). In patients with a BMI of 25 or higher, improvements of ALT (r = 0.659, P < 0.001) and MRI-PDFF (r = 0.784, P < 0.001) were significantly correlated with weight loss. However, in patients with a BMI below 25, the improvements of ALT or PDFF were not accompanied by weight loss. CONCLUSIONS: Combined treatment with pemafibrate and a low-carbohydrate diet resulted in weight loss and improvements in ALT, MRE, and MRI-PDFF in MAFLD patients. Although such improvements were associated with weight loss in obese patients, the improvements were observed irrespective of weight loss in non-obese patients, indicating this combination can be effective both in obese and non-obese MAFLD patients.

Impact of tofogliflozin on hepatic outcomes: a systematic review.

PURPOSE: Studies have demonstrated a high prevalence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) patients. The aim was to review the effect of tofogliflozin on hepatic outcomes in T2DM patients. METHODS: A literature search in PubMed, Science Direct and Cochrane Central Register of Controlled Trials was conducted for randomised clinical trials of tofogliflozin by applying predetermined inclusion and exclusion criteria. RESULTS: A total number of four randomised clinical trials, including 226 subjects, were included in the review. There was a significant decrease in aspartate aminotransferase (AST) and alanine transaminase (ALT) levels in the tofogliflozin group as compared to the control or active comparator groups. Additionally, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) levels were also significantly decreased in the tofogliflozin group. However, no significant difference was observed in levels of adiponectin. CONCLUSION: Overall, an improvement in levels of hepatic parameters was observed in T2DM patients with concurrent liver disorders. However, a large number of clinical trials are needed to prove the efficacy of tofogliflozin on hepatic outcomes in patients with T2DM.

Osteosarcopenia in acromegaly: reduced muscle quality and increased vertebral fat deposition.

PURPOSE: Musculoskeletal disorders are among the most disabling comorbidities in patients with acromegaly. This study examined muscle and bone quality in patients with acromegaly. METHODS: Thirty-three patients with acromegaly and nineteen age- and body mass index-matched healthy controls were included in the study. Body composition was determined using dual-energy X-ray absorptiometry. The participants underwent abdominal magnetic resonance imaging (MRI) for cross-sectional evaluation of muscle area and vertebral MRI proton density fat fraction (MRI-PDFF). Muscular strength was measured using hand grip strength (HGS). Skeletal muscle quality (SMQ) was classified as weak, low, or normal, according to HGS/ASM (appendicular skeletal muscle mass) ratio. RESULTS: Groups had similar lean tissues, total body fat ratios, and total abdominal muscle areas. Acromegalic patients had lower pelvic BMD (p = 0.012) and higher vertebral MRI-PDFF (p = 0.014), while total and spine bone mineral densities (BMD) were similar between the groups. The SMQ score rate was normal only 57.5% in the acromegaly group, and 94.7% of the controls had a normal SMQ score (p = 0.01). Subgroup analysis showed that patients with active acromegaly (AA) had higher lean tissue and lower body fat ratios than controlled acromegaly (CA) and control groups. Vertebral MRI-PDFF was higher in the CA group than that in the AA and control groups (p = 0.022 and p = 0.001, respectively). The proportion of participants with normal SMQ was lower in the AA and CA groups than that in the control group (p = 0.012 and p = 0.013, respectively). CONCLUSION: Acromegalic patients had reduced SMQ and pelvic BMD, but greater vertebral MRI-PDFF. Although lean tissue increases in AA, this does not affect SMQ. Therefore, increased vertebral MRI-PDFF in controlled acromegalic patients may be due to ectopic adiposity.

A prediction model of liver fat fraction and presence of non-alcoholic fatty liver disease (NAFLD) among patients with overweight or obesity.

The global prevalence of non-alcoholic fatty liver disease (NAFLD) has attained a level of 25.24%. The prevalence of NAFLD in China has exhibited an upward trajectory in parallel with the increasing incidence of obesity over the preceding decade. In order to comprehensively assess hepatic lipid deposition in individuals with overweight or obesity, we have devised a pioneering prognostic formula that capitalizes on clinical parameters. To this end, we have conducted a cross-sectional cohort study involving 149 overweight or obese subjects. Magnetic resonance imaging proton density fat fraction (MRI-PDFF) has been employed to evaluate the extent of liver fat accumulation. Through univariate analysis, we have identified potential factors, and the definitive elements in the prediction model were selected utilizing the forward stepwise regression algorithm. The Shang Hai Steatosis Index (SHSI) incorporates alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting insulin, and 1-h postload glycaemic levels, thereby furnishing the capability to predict NAFLD with an area under the receiver operator characteristic (AUROC) of 0.87. By establishing a threshold value of 10.96, determined through Youden's index, we have achieved a sensitivity of 69.57% and a specificity of 88.24%. The Spearman correlation coefficient between liver fat fraction ascertained by MRI-PDFF and that predicted by the SHSI equation amounts to 0.74. Consequently, the SHSI equation affords a dependable means of predicting the presence of NAFLD and liver fat accumulation within the overweight and obese population.

Assessment of hepatic fat content and prediction of myocardial fibrosis in athletes by using proton density fat fraction sequence.

PURPOSE: To explore the characteristics of the hepatic fat content in athletes, and predict late gadolinium enhancement (LGE) based on magnetic resonance imaging-proton density fat fraction (MRI-PDFF). MATERIAL AND METHODS: From March 2020 to March 2021, 233 amateur athletes and 42 healthy sedentary controls were prospectively recruited. The liver fat content of four regions of interest (ROIs 1-4), the mean liver fat fraction (FF), cardiac function, and myocardium LGE were recorded, respectively. The values of ROIs 1-4 and FF were compared between athletes and controls. According to the liver fat content threshold for distinguishing athletes and controls, the cutoff total exercise time that induced a change in liver fat was obtained. The correlations among the liver fat content, cardiac function, and other parameters were analyzed. Moreover, the liver fat content was used to predict myocardium LGE by logistic regression. RESULTS: There were significant differences for the values of ROI 1, ROI 3, ROI 4, and FF between athletes and controls (allp< 0.05). The cutoff total exercise time for inducing a change in the liver fat content was 1680 h (area under the curve [AUC] = 0.593, specificity = 83.3,p< 0.05). Blood indexes, cardiac function, and basic clinical parameters were related to liver fat content (allp< 0.05). The prediction model for LGE had an AUC value of 0.829 for the receiver operator characteristic curve. CONCLUSION: MRI-PDFF could assess liver fat content and predict cardiac fibrosis in athletes for risk stratification and follow-up.

MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis.

BACKGROUND & AIMS: Among the large population of patients with non-alcoholic fatty liver disease (NAFLD), identifying those with fibrotic non-alcoholic steatohepatitis (Fibro-NASH) is a clinical priority, as these patients are at the highest risk of disease progression and will benefit most from pharmacologic treatment. MRI-based proton density fat fraction (MRI-PDFF) and MR elastography (MRE) can risk-stratify patients with NAFLD by assessing steatosis and fibrosis, respectively. We developed a highly specific MRI-based score to identify patients with Fibro-NASH. METHODS: This analysis included derivation (n = 103) and validation (n = 244) cohorts of patients who underwent MRI, liver biopsy, transient elastography, and laboratory testing for NAFLD from 2016-2020 in 2 tertiary care centers. To identify Fibro-NASH, a formula was developed based on MRI-PDFF, MRE, and a third variable with highest balanced accuracy per logistic regression. The MRI-aspartate aminotransferase (MAST) score was created and compared to NAFLD fibrosis (NFS), Fibrosis-4 (FIB-4), and FibroScan-aspartate aminotransferase (FAST) scores. RESULTS: The MAST score demonstrated high performance and discrimination in the validation cohort (AUC 0.93; 95% CI 0.88-0.97). In the validation cohorts, the 90% specificity cut-off of 0.242 corresponded to a sensitivity of 75.0%, positive predictive value (PPV) of 50.0% and negative predictive value (NPV) of 96.5%, whereas the 90% sensitivity cut-off of 0.165 corresponded to a specificity of 72.2%, PPV of 29.4%, and NPV of 98.1%. Compared to NFS and FIB-4, MAST resulted in fewer patients having indeterminate scores and an overall higher AUC. Compared to FAST, MAST exhibited a higher AUC and overall better discrimination. CONCLUSION: The MAST score is an accurate, MRI-serum-based score that outperforms previous scores in non-invasively identifying patients at higher risk of Fibro-NASH. LAY SUMMARY: Identifying patients with non-alcoholic steatohepatitis and significant fibrosis - who need treatment and are at risk of clinical liver-related outcomes - is a clinical priority. We developed a more accurate score using MRI-based technologies and a laboratory blood test (aspartate aminotransferase) that outperforms previous non-invasive scores for the identification of patients at higher risk of liver disease progression.

Clinical Utility of Magnetic Resonance Imaging Biomarkers for Identifying Nonalcoholic Steatohepatitis Patients at High Risk of Progression: A Multicenter Pooled Data and Meta-Analysis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence worldwide. NAFLD is associated with excess risk of all-cause mortality, and its progression to nonalcoholic steatohepatitis (NASH) and fibrosis accounts for a growing proportion of cirrhosis and hepatocellular cancer and thus is a leading cause of liver transplant worldwide. Noninvasive precise methods to identify patients with NASH and NASH with significant disease activity and fibrosis are crucial when the disease is still modifiable. The aim of this study was to examine the clinical utility of corrected T1 (cT1) vs magnetic resonance imaging (MRI) liver fat for identification of NASH participants with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage (F) ≥2 (high-risk NASH). METHODS: Data from five clinical studies (n = 543) with participants suspected of NAFLD were pooled or used for individual participant data meta-analysis. The diagnostic accuracy of the MRI biomarkers to stratify NASH patients was determined using the area under the receiver operating characteristic curve (AUROC). RESULTS: A stepwise increase in cT1 and MRI liver fat with increased NAFLD severity was shown, and cT1 was significantly higher in participants with high-risk NASH. The diagnostic accuracy (AUROC) of cT1 to identify patients with NASH was 0.78 (95% CI, 0.74-0.82), for liver fat was 0.78 (95% CI, 0.73-0.82), and when combined with MRI liver fat was 0.82 (95% CI, 0.78-0.85). The diagnostic accuracy of cT1 to identify patients with high-risk NASH was good (AUROC = 0.78; 95% CI, 0.74-0.82), was superior to MRI liver fat (AUROC = 0.69; 95% CI, 0.64-0.74), and was not substantially improved by combining it with MRI liver fat (AUROC = 0.79; 95% CI, 0.75-0.83). The meta-analysis showed similar performance to the pooled analysis for these biomarkers. CONCLUSIONS: This study shows that quantitative MRI-derived biomarkers cT1 and liver fat are suitable for identifying patients with NASH, and cT1 is a better noninvasive technology than liver fat to identify NASH patients at greatest risk of disease progression. Therefore, MRI cT1 and liver fat have important clinical utility to help guide the appropriate use of interventions in NAFLD and NASH clinical care pathways.

Development, validation, qualification, and dissemination of quantitative MR methods: Overview and recommendations by the ISMRM quantitative MR study group.

On behalf of the International Society for Magnetic Resonance in Medicine (ISMRM) Quantitative MR Study Group, this article provides an overview of considerations for the development, validation, qualification, and dissemination of quantitative MR (qMR) methods. This process is framed in terms of two central technical performance properties, i.e., bias and precision. Although qMR is confounded by undesired effects, methods with low bias and high precision can be iteratively developed and validated. For illustration, two distinct qMR methods are discussed throughout the manuscript: quantification of liver proton-density fat fraction, and cardiac T1 . These examples demonstrate the expansion of qMR methods from research centers toward widespread clinical dissemination. The overall goal of this article is to provide trainees, researchers, and clinicians with essential guidelines for the development and validation of qMR methods, as well as an understanding of necessary steps and potential pitfalls for the dissemination of quantitative MR in research and in the clinic.

Addressing concomitant gradient phase errors in time-interleaved chemical shift-encoded MRI fat fraction and R2 * mapping with a pass-specific phase fitting method.

PURPOSE: Concomitant gradients induce phase errors that increase quadratically with distance from isocenter. This work proposes a complex-based fitting method that addresses concomitant gradient phase errors in chemical shift encoded (CSE) MRI estimation of proton density fat fraction (PDFF) and R2 * through joint estimation of pass-specific phase terms. This method is applicable to time-interleaved multi-echo gradient-echo acquisitions (i.e., multi-pass acquisitions) and does not require prior knowledge of gradient waveforms typically needed to address concomitant gradient phase errors. THEORY AND METHODS: A CSE-MRI spoiled gradient echo signal model, with pass-specific phase terms, is introduced for non-linear least squares estimation of PDFF and R2 * in the presence of concomitant gradient phase errors. Cramér-Rao lower bound analysis was used to determine noise performance tradeoffs of the proposed fitting method, which was then validated in both phantom and in vivo experiments. RESULTS: The proposed fitting method removed PDFF and R2 * estimation errors up to 12% and 10 s-1 , respectively, at ±12 cm off isocenter (S/I) in a water phantom. In healthy volunteers, PDFF and R2 * bias was reduced by ~10% (12 cm off-isocenter) and ~30 s-1 (16 cm off-isocenter), respectively. An evaluation in 29 clinical liver datasets demonstrated reduced PDFF bias and variability (8.4% improvement in the coefficient of variation), even with the imaging volume centered at isocenter. CONCLUSION: Concomitant gradient induced phase errors in multi-pass CSE-MRI acquisitions can result in PDFF and R2 * estimation biases away from isocenter. The proposed fitting method enables accurate PDFF and R2 * quantification in the presence of concomitant gradient phase errors without knowledge of imaging gradient waveforms.