Assessment of Imaging Modalities Against Liver Biopsy in Nonalcoholic Fatty Liver Disease: The Amsterdam NAFLD-NASH Cohort.

BACKGROUND: Noninvasive diagnostic methods are urgently required in disease stratification and monitoring in nonalcoholic fatty liver disease (NAFLD). Multiparametric magnetic resonance imaging (MRI) is a promising technique to assess hepatic steatosis, inflammation, and fibrosis, potentially enabling noninvasive identification of individuals with active and advanced stages of NAFLD. PURPOSE: To examine the diagnostic performance of multiparametric MRI for the assessment of disease severity along the NAFLD disease spectrum with comparison to histological scores. STUDY TYPE: Prospective, cohort. POPULATION: Thirty-seven patients with NAFLD. FIELD STRENGTH/SEQUENCE: Multiparametric MRI at 3.0 T consisted of magnetic resonance (MR) spectroscopy (MRS) with multi-echo stimulated-echo acquisition mode, magnitude-based and three-point Dixon using a two-dimensional multi-echo gradient echo, MR elastography (MRE) using a generalized multishot gradient-recalled echo sequence and intravoxel incoherent motion (IVIM) using a multislice diffusion weighted single-shot echo-planar sequence. ASSESSMENT: Histological steatosis grades were compared to proton density fat fraction measured by MRS (PDFFMRS ), magnitude-based MRI (PDFFMRI-M ), and three-point Dixon (PDFFDixon ), as well as FibroScan® controlled attenuation parameter (CAP). Fibrosis and disease activity were compared to IVIM and MRE. FibroScan® liver stiffness measurements were compared to fibrosis levels. Diagnostic performance of all imaging parameters was determined for distinction between simple steatosis and nonalcoholic steatohepatitis (NASH). STATISTICAL TESTS: Spearman's rank test, Kruskal-Wallis test, Dunn's post-hoc test with Holm-Bonferroni P-value adjustment, receiver operating characteristic curve analysis. A P-value <0.05 was considered statistically significant. RESULTS: Histological steatosis grade correlated significantly with PDFFMRS (rs  = 0.66, P < 0.001), PDFFMRI-M (rs  = 0.68, P < 0.001), and PDFFDixon (rs  = 0.67, P < 0.001), whereas no correlation was found with CAP. MRE and IVIM diffusion and perfusion significantly correlated with disease activity (rs  = 0.55, P < 0.001, rs  = -0.40, P = 0.016, rs  = -0.37, P = 0.027, respectively) and fibrosis (rs  = 0.55, P < 0.001, rs  = -0.46, P = 0.0051; rs  = -0.53, P < 0.001, respectively). MRE and IVIM diffusion had the highest area-under-the-curve for distinction between simple steatosis and NASH (0.79 and 0.73, respectively). DATA CONCLUSION: Multiparametric MRI is a promising method for noninvasive, accurate, and sensitive distinction between simple hepatic steatosis and NASH, as well as for the assessment of steatosis and fibrosis severity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: 2.

Unipolar MR elastography: Theory, numerical analysis and implementation.

In MR elastography (MRE), zeroth moment balanced motion-encoding gradients (MEGs) are incorporated into MRI sequences to induce a phase shift proportional to the local displacement caused by external actuation. To maximize the signal-to-noise ratio (SNR), fractional encoding is employed, i.e., the MEG duration is reduced below the wave period. Here, gradients encode primarily the velocity of the motion-reducing encoding efficiency. Thus, in GRE-MRE, T2 * decay and motion sensitivity have to be balanced, imposing a lower limit on repetition times (TRs). We propose to use a single trapezoidal gradient, a "unipolar gradient", to directly encode spin displacement. Such gradients cannot be used in conventional sequences as they exhibit a large zeroth moment and dephase magnetization. By time-reversing a spoiled SSFP sequence, the spoiling gradient becomes an efficient unipolar MEG. The proposed "unipolar MRE" technique benefits from this approach in three ways: first, displacement encoding is split over multiple TRs increasing motion sensitivity; second, spoiler and MEG coincide, allowing a reduction in TR; third, motion sensitivity of a typical unipolar lobe is of an order of magnitude higher than a bipolar MEG of equal duration. In this work, motion encoding using unipolar MRE is analyzed using the extended phase graph (EPG) formalism with a periodic motion propagator. As an approximation, the two-transverse TR approximation for diffusion-weighted SSFP is extended to incorporate cyclic motion. A complex encoding efficiency metric is introduced to compare the displacement fields of unipolar and conventional GRE-MRE sequences in both magnitude and phase. The derived theoretical encoding equations are used to characterize the proposed sequence using an extensive parameter study. Unipolar MRE is validated against conventional GRE-MRE in a phantom study showing excellent agreement between measured displacement fields. In addition, unipolar MRE yields significantly increased octahedral shear strain-SNR relative to conventional GRE-MRE and allows for the recovery of high stiffness inclusions, where conventional GRE-MRE fails.

Ristretto MRE: A generalized multi-shot GRE-MRE sequence.

In order to acquire consistent k-space data in MR elastography, a fixed temporal relationship between the MRI sequence and the underlying period of the wave needs to be ensured. To this end, conventional GRE-MRE enforces synchronization through repeated triggering of the transducer and forcing the sequence repetition time to be equal to an integer multiple of the wave period. For wave frequencies below 100 Hz, however, this leads to prolonged acquisition times, as the repetition time scales inversely with frequency. A previously developed multi-shot approach (eXpresso MRE) to multi-slice GRE-MRE tackles this issue by acquiring an integer number of slices per wave period, which allows acquisition to be accelerated in typical scenarios by a factor of two or three. In this work, it is demonstrated that the constraints imposed by the eXpresso scheme are overly restrictive. We propose a generalization of the sequence in three steps by incorporating sequence delays into imaging shots and allowing for interleaved wave-phase acquisition. The Ristretto scheme is compared in terms of imaging shot and total scan duration relative to eXpresso and conventional GRE-MRE and is validated in three different phantom studies. First, the agreement of measured displacement fields in different stages of the sequence generalization is shown. Second, performance is compared for 25, 36, 40, and 60 Hz actuation frequencies. Third, the performance is assessed for the acquisition of different numbers of slices (13 to 17). In vivo feasibility is demonstrated in the liver and the breast. Here, Ristretto is compared with an optimized eXpresso sequence, leading to scan accelerations of 15% and 5%, respectively, without compromising displacement field and stiffness estimates in general. The Ristretto concept allows us to choose imaging shot durations on a fine grid independent of the number of slices and the wave frequency, permitting 2- to 4.5-fold acceleration of conventional GRE-MRE acquisitions.

Intrapancreatic fat deposition is unrelated to liver steatosis in metabolic dysfunction-associated steatotic liver disease.

Background & Aims: Individuals with obesity may develop intrapancreatic fat deposition (IPFD) and fatty pancreas disease (FPD). Whether this causes inflammation and fibrosis and leads to pancreatic dysfunction is less established than for liver damage in metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, the interrelations of FPD and MASLD are poorly understood. Therefore, we aimed to assess IPFD and fibro-inflammation in relation to pancreatic function and liver disease severity in individuals with MASLD. Methods: Seventy-six participants from the Amsterdam MASLD-MASH cohort (ANCHOR) study underwent liver biopsy and multiparametric MRI of the liver and pancreas, consisting of proton-density fat fraction sequences, T1 mapping and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Results: The prevalence of FPD was 37.3%. There was a clear correlation between pancreatic T1 relaxation time, which indicates fibro-inflammation, and parameters of glycemic dysregulation, namely HbA1c (R = 0.59; p <0.001), fasting glucose (R = 0.51; p <0.001) and the presence of type 2 diabetes (mean 802.0 ms vs. 733.6 ms; p <0.05). In contrast, there was no relation between IPFD and hepatic fat content (R = 0.03; p = 0.80). Pancreatic IVIM diffusion (IVIM-D) was lower in advanced liver fibrosis (p <0.05) and pancreatic perfusion (IVIM-f), reflecting vessel density, inversely correlated to histological MASLD activity (p <0.05). Conclusions: Consistent relations exist between pancreatic fibro-inflammation on MRI and endocrine function in individuals with MASLD. However, despite shared dysmetabolic drivers, our study suggests IPFD is a separate pathophysiological process from MASLD. Impact and implications: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and 68% of people with type 2 diabetes have MASLD. However, fat infiltration and inflammation in the pancreas are understudied in individuals with MASLD. In this cross-sectional MRI study, we found no relationship between fat accumulation in the pancreas and liver in a cohort of patients with MASLD. However, our results show that inflammatory and fibrotic processes in the pancreas may be interrelated to features of type 2 diabetes and to the severity of liver disease in patients with MASLD. Overall, the results suggest that pancreatic endocrine dysfunction in individuals with MASLD may be more related to glucotoxicity than to lipotoxicity. Clinical trial number: NTR7191 (Dutch Trial Register).

Sex Steroids Regulate Liver Fat Content and Body Fat Distribution in Both Men and Women: A Study in Transgender Persons.

CONTEXT: Liver fat content and visceral fat volume are associated with insulin resistance and cardiovascular disease and are higher in men than in women. OBJECTIVE: To determine the effect of estradiol and testosterone treatment on liver fat and visceral fat in transgender persons. DESIGN: Open-label intervention study (SHAMVA) with a 1-year follow-up. SETTING: Gender clinic in a hospital. PATIENTS: 8 trans women and 18 trans men receiving hormone treatment. INTERVENTIONS: Trans women received an antiandrogen and after 6 weeks estradiol was added. Trans men were randomized to receive triptorelin, testosterone, and anastrozole for 12 weeks or triptorelin and testosterone for 12 weeks, followed by only testosterone until week 52. MAIN OUTCOME MEASURES: Liver fat content, visceral and abdominal subcutaneous fat volume, measured by magnetic resonance spectrometry or imaging at baseline, 6, 8, 18, and 58 weeks in transwomen or at baseline; at 6 and 12 weeks in trans men with anastrozole; and at 52 weeks in trans men without anastrozole. RESULTS: In trans women, liver fat content decreased by 1.55% (-2.99 to -0.12) after 58 weeks, compared to week 6. Visceral fat did not change. In trans men with anastrozole, the liver fat content and visceral fat volume did not change. In trans men without anastrozole, after 52 weeks, liver fat content increased by 0.83% (0.14 to 1.52) and visceral fat volume increased by 34% (16 to 51). CONCLUSIONS: Sex hormones regulate liver fat content and visceral fat in men and women.

A natural history study of paediatric non-alcoholic fatty liver disease over 10 years.

Background & Aims: The long-term outcome of paediatric non-alcoholic fatty liver disease (NAFLD) has not been well established. Between 2008 and 2012, an unselected cohort of 133 children with severe obesity was screened for NAFLD. The aim of this study was to determine the 10-year natural history of NAFLD in this cohort. Methods: All 133 participants of the original study were approached. Proton magnetic resonance spectroscopy (1H-MRS) and the Enhanced Liver Fibrosis® (ELF) test were used to assess longitudinal changes in steatosis and fibrosis, respectively. Risk factors for disease progression were explored. Results: Fifty-one of the 133 participants (38%) from the original cohort were included. The mean follow-up time was 10.3 years (range 7-13 years), 65% were female and 92% had persistent obesity. The proportion of participants with steatosis remained unchanged (47%). Nine individuals developed steatosis and in nine individuals steatosis resolved. Predefined relevant individual changes in 1H-MRS were seen in 38% of the participants. The mean ELF test did not change significantly (8.70 ± 0.58 vs. 8.51 ± 0.71, p = 0.22). However, 16% had a relevant increase in ELF test and 6% of those with NAFLD developed advanced fibrosis at follow-up. Changes in steatosis correlated with changes in established metabolic risk factors, alanine aminotransferase, and bariatric surgery. A change in the ELF test was associated with a change in triglycerides. Conclusions: This 10-year follow-up study shows that one-third of the young adults who had childhood obesity develop steatosis and in one-third steatosis resolves. Six percent of those with NAFLD had developed advanced fibrosis at follow-up. These data underscore the importance of screening for NAFLD and monitoring for progression to advanced NAFLD in young people with obesity. Impact and implications: Childhood obesity accompanied by fat accumulation in the liver persists into young adulthood in the vast majority, and 6% develop serious liver injury. Worsening of metabolic disturbances increases the risk of liver injury.

Self-supervised neural network improves tri-exponential intravoxel incoherent motion model fitting compared to least-squares fitting in non-alcoholic fatty liver disease.

Recent literature suggests that tri-exponential models may provide additional information and fit liver intravoxel incoherent motion (IVIM) data more accurately than conventional bi-exponential models. However, voxel-wise fitting of IVIM results in noisy and unreliable parameter maps. For bi-exponential IVIM, neural networks (NN) were able to produce superior parameter maps than conventional least-squares (LSQ) generated images. Hence, to improve parameter map quality of tri-exponential IVIM, we developed an unsupervised physics-informed deep neural network (IVIM3-NET). We assessed its performance in simulations and in patients with non-alcoholic fatty liver disease (NAFLD) and compared outcomes with bi-exponential LSQ and NN fits and tri-exponential LSQ fits. Scanning was performed using a 3.0T free-breathing multi-slice diffusion-weighted single-shot echo-planar imaging sequence with 18 b-values. Images were analysed for visual quality, comparing the bi- and tri-exponential IVIM models for LSQ fits and NN fits using parameter-map signal-to-noise ratios (SNR) and adjusted R 2. IVIM parameters were compared to histological fibrosis, disease activity and steatosis grades. Parameter map quality improved with bi- and tri-exponential NN approaches, with a significant increase in average parameter-map SNR from 3.38 to 5.59 and 2.45 to 4.01 for bi- and tri-exponential LSQ and NN models respectively. In 33 out of 36 patients, the tri-exponential model exhibited higher adjusted R 2 values than the bi-exponential model. Correlating IVIM data to liver histology showed that the bi- and tri-exponential NN outperformed both LSQ models for the majority of IVIM parameters (10 out of 15 significant correlations). Overall, our results support the use of a tri-exponential IVIM model in NAFLD. We show that the IVIM3-NET can be used to improve image quality compared to a tri-exponential LSQ fit and provides promising correlations with histopathology similar to the bi-exponential neural network fit, while generating potentially complementary additional parameters.

Shear wave cardiovascular MR elastography using intrinsic cardiac motion for transducer-free non-invasive evaluation of myocardial shear wave velocity.

Changes in myocardial stiffness may represent a valuable biomarker for early tissue injury or adverse remodeling. In this study, we developed and validated a novel transducer-free magnetic resonance elastography (MRE) approach for quantifying myocardial biomechanics using aortic valve closure-induced shear waves. Using motion-sensitized two-dimensional pencil beams, septal shear waves were imaged at high temporal resolution. Shear wave speed was measured using time-of-flight of waves travelling between two pencil beams and corrected for geometrical biases. After validation in phantoms, results from twelve healthy volunteers and five cardiac patients (two left ventricular hypertrophy, two myocardial infarcts, and one without confirmed pathology) were obtained. Torsional shear wave speed in the phantom was 3.0 ± 0.1 m/s, corresponding with reference speeds of 2.8 ± 0.1 m/s. Geometrically-biased flexural shear wave speed was 1.9 ± 0.1 m/s, corresponding with simulation values of 2.0 m/s. Corrected septal shear wave speeds were significantly higher in patients than healthy volunteers [14.1 (11.0-15.8) m/s versus 3.6 (2.7-4.3) m/s, p = 0.001]. The interobserver 95%-limits-of-agreement in healthy volunteers were ± 1.3 m/s and interstudy 95%-limits-of-agreement - 0.7 to 1.2 m/s. In conclusion, myocardial shear wave speed can be measured using aortic valve closure-induced shear waves, with cardiac patients showing significantly higher shear wave speeds than healthy volunteers. This non-invasive measure may provide valuable insights into the pathophysiology of heart failure.

Donor Fecal Microbiota Transplantation Alters Gut Microbiota and Metabolites in Obese Individuals With Steatohepatitis.

The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of . Conclusion: Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis.

A novel magnetic resonance elastography transducer concept based on a rotational eccentric mass: preliminary experiences with the gravitational transducer.

BACKGROUND: Magnetic resonance elastography (MRE) is used to non-invasively estimate biomechanical tissue properties via the imaging of propagating mechanical shear waves. Several factors including mechanical transducer design, MRI sequence design and viscoelastic reconstruction influence data quality and hence the reliability of the derived biomechanical properties. PURPOSE: To design and characterize a novel mechanical MRE transducer concept based on a rotational eccentric mass, coined the gravitational transducer. MATERIALS AND METHODS: Table top measurements were performed using accelerometers to characterize the frequency response of the new transducer concept at different driving frequencies (f VIB) and different rotating masses. These were compared to a commercially available pneumatically driven MRE transducer. MR data were acquired on a 3T scanner using a fractionally encoded gradient echo MRE sequence in three healthy volunteers. Acceleration and displacement spectra were plotted in units of g and mm, respectively, and visually compared, emphasizing the ratio between the peaks at f VIB and its 2nd harmonic, a known cause of error in the reconstruction of biomechanical properties as is explored in more detail in numerical simulations here. No formal statistical testing was performed in this proof-of-principle paper. RESULTS: The new transducer concept shows-as expected from theory-a quadratic or linear increase of acceleration amplitude with increase in f VIB or mass, respectively. Furthermore, different versions of the transducer show markedly lower 2nd harmonic-to-f VIB ratios compared to the commercially available pneumatically driven transducer. Displacement was constant over a range of f VIB, in accordance with theory. Phantom and in vivo data show low nonlinearity and excellent data quality. CONCLUSION: The table top measurements are in concordance with the theory behind a transducer based on a rotational eccentric mass. The resulting constant displacement amplitude irrespective of f VIB and low 2nd harmonic-to-f VIB ratio result in low nonlinearity and high data fidelity in both phantom and in vivo examples.

Comparison of clinical MRI liver iron content measurements using signal intensity ratios, R 2 and R 2.

PURPOSE: To compare three types of MRI liver iron content (LIC) measurement performed in daily clinical routine in a single center over a 6-year period. METHODS: Patients undergoing LIC MRI-scans (1.5T) at our center between January 1, 2008 and December 31, 2013 were retrospectively included. LIC was measured routinely with signal intensity ratio (SIR) and MR-relaxometry (R 2 and R 2*) methods. Three observers placed regions-of-interest. The success rate was the number of correctly acquired scans over the total number of scans. Interobserver agreement was assessed with intraclass correlation coefficients (ICC) and Bland-Altman analysis, correlations between LICSIR, R 2, R 2*, and serum values with Spearman's rank correlation coefficient. Diagnostic accuracies of LICSIR, R 2 and serum transferrin, transferrin-saturation, and ferritin compared to increased R 2* (≥44 Hz) as indicator of iron overload were assessed using ROC-analysis. RESULTS: LIC MRI-scans were performed in 114 subjects. SIR, R 2, and R 2* data were successfully acquired in 102/114 (89%), 71/114 (62%), and 112/114 (98%) measurements, with the lowest success rate for R 2. The ICCs of SIR, R 2, and R 2* did not differ at 0.998, 0.997, and 0.999. R 2 and serum ferritin had the highest diagnostic accuracies to detect elevated R 2* as mark of iron overload. CONCLUSIONS: SIR and R 2* are preferable over R 2 in terms of success rates. R 2*'s shorter acquisition time and wide range of measurable LIC values favor R 2* over SIR for MRI-based LIC measurement.