Gavin Hamilton

Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study

Background: Hepatic steatosis is associated with obesity and type II diabetes. Proton magnetic resonance spectroscopy (1H MRS) is a non-invasive method for measurement of tissue fat content, including intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL). Patients and methods: We used 1H MRS and whole body magnetic resonance imaging (MRI) to assess the relationship between IHCL accumulation, total body adipose tissue (AT) content/distribution, and IMCL content in 11 subjects with biopsy proven hepatic steatosis and 23 normal volunteers. Results: IHCL signals were detectable in all subjects but were significantly greater in hepatic steatosis (geometric mean (GM) 11.5 (interquartile range (IQR) 7.0–39.0)) than in normal volunteers (GM 2.7 (IQR 0.7–9.3); p = 0.02). In the study group as a whole, IHCL levels were significantly greater in overweight compared with lean subjects (body mass index (BMI) >25 kg/m2 (n = 23): GM 7.7 (IQR 4.0–28.6) v BMI <25 kg/m2 (n = 11): GM 1.3 (IQR 0.3–3.6; p = 0.004)). There was a significant association between IHCL content and indices of overall obesity (expressed as a percentage of body weight) for total body fat (p = 0.001), total subcutaneous AT (p = 0.007), and central obesity (subcutaneous abdominal AT (p = 0.001) and intra-abdominal AT (p = 0.001)), after allowing for sex and age. No correlation between IHCL content and IMCL was observed. A significant correlation was observed between serum alanine aminotransferase and liver fat content (r = 0.57, p = 0.006). Conclusions: Our results suggest that hepatic steatosis appears to be closely related to body adiposity, especially central obesity. MRS may be a useful method for monitoring IHCL in future interventional studies.

In vivo characterization of the liver fat 1H MR spectrum

A theoretical triglyceride model was developed for in vivo human liver fat 1H MRS characterization, using the number of double bonds (CHCH), number of methylene‐interrupted double bonds (CHCHCH2CHCH) and average fatty acid chain length. Five 3 T, single‐voxel, stimulated echo acquisition mode spectra (STEAM) were acquired consecutively at progressively longer TEs in a fat–water emulsion phantom and in 121 human subjects with known or suspected nonalcoholic fatty liver disease. T2‐corrected peak areas were calculated. Phantom data were used to validate the model. Human data were used in the model to determine the complete liver fat spectrum. In the fat–water emulsion phantom, the spectrum predicted by the model (based on known fatty acid chain distribution) agreed closely with spectroscopic measurement. In human subjects, areas of CH2 peaks at 2.1 and 1.3 ppm were linearly correlated (slope, 0.172; r = 0.991), as were the 0.9 ppm CH3 and 1.3 ppm CH2 peaks (slope, 0.125; r = 0.989). The 2.75 ppm CH2 peak represented 0.6% of the total fat signal in high‐liver‐fat subjects. These values predict that 8.6% of the total fat signal overlies the water peak. The triglyceride model can characterize human liver fat spectra. This allows more accurate determination of liver fat fraction from MRI and MRS. Copyright

Quantification of Hepatic Steatosis with T1-independent, T2*-corrected MR Imaging with Spectral Modeling of Fat: Blinded Comparison with MR Spectroscopy

PURPOSE To prospectively compare an investigational version of a complex-based chemical shift-based fat fraction magnetic resonance (MR) imaging method with MR spectroscopy for the quantification of hepatic steatosis. MATERIALS AND METHODS This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained before all studies. Fifty-five patients (31 women, 24 men; age range, 24-71 years) were prospectively imaged at 1.5 T with quantitative MR imaging and single-voxel MR spectroscopy, each within a single breath hold. The effects of T2 correction, spectral modeling of fat, and magnitude fitting for eddy current correction on fat quantification with MR imaging were investigated by reconstructing fat fraction images from the same source data with different combinations of error correction. Single-voxel T2-corrected MR spectroscopy was used to measure fat fraction and served as the reference standard. All MR spectroscopy data were postprocessed at a separate institution by an MR physicist who was blinded to MR imaging results. Fat fractions measured with MR imaging and MR spectroscopy were compared statistically to determine the correlation (r(2)), and the slope and intercept as measures of agreement between MR imaging and MR spectroscopy fat fraction measurements, to determine whether MR imaging can help quantify fat, and examine the importance of T2 correction, spectral modeling of fat, and eddy current correction. Two-sided t tests (significance level, P = .05) were used to determine whether estimated slopes and intercepts were significantly different from 1.0 and 0.0, respectively. Sensitivity and specificity for the classification of clinically significant steatosis were evaluated. RESULTS Overall, there was excellent correlation between MR imaging and MR spectroscopy for all reconstruction combinations. However, agreement was only achieved when T2 correction, spectral modeling of fat, and magnitude fitting for eddy current correction were used (r(2) = 0.99; slope ± standard deviation = 1.00 ± 0.01, P = .77; intercept ± standard deviation = 0.2% ± 0.1, P = .19). CONCLUSION T1-independent chemical shift-based water-fat separation MR imaging methods can accurately quantify fat over the entire liver, by using MR spectroscopy as the reference standard, when T2 correction, spectral modeling of fat, and eddy current correction methods are used.

Altered adiposity after extremely preterm birth

The quantity and distribution of adipose tissue are markers of morbidity risk. The third trimester of human development is a period of rapid adipose tissue deposition. Preterm infants may be at risk of altered adiposity. We measured anthropometric indices and quantified total, subcutaneous, and intraabdominal adipose tissue volumes using whole-body magnetic resonance adipose tissue imaging in 38 infants born at <32 wk gestational age, when they reached term, and 29 term-born infants. The preterm infants at term were significantly lighter and shorter than the term-born infants, but there was no significant difference in head circumference SD score or total adiposity. The preterm infants had a highly significant decrease in subcutaneous adipose tissue and significantly increased intraabdominal adipose tissue. Accelerated postnatal weight gain was accompanied by increased total and subcutaneous adiposity. Illness severity was the principal determinant of increased intraabdominal adiposity. Our data provide evidence of causal pathways linking accelerated postnatal growth with increased total and subcutaneous adiposity, and illness severity with altered adipose tissue partitioning. We suggest that these observations may in part explain the associations between small size at birth and later disease. Preterm infants may be at risk in later life of metabolic complications through increased and aberrant adiposity.

Nonalcoholic Fatty Liver Disease: Diagnostic and Fat-Grading Accuracy of Low-Flip-Angle Multiecho Gradient-Recalled-Echo MR Imaging at 1.5 T

PURPOSE To assess the accuracy of four fat quantification methods at low-flip-angle multiecho gradient-recalled-echo (GRE) magnetic resonance (MR) imaging in nonalcoholic fatty liver disease (NAFLD) by using MR spectroscopy as the reference standard. MATERIALS AND METHODS In this institutional review board-approved, HIPAA-compliant prospective study, 110 subjects (29 with biopsy-confirmed NAFLD, 50 overweight and at risk for NAFLD, and 31 healthy volunteers) (mean age, 32.6 years +/- 15.6 [standard deviation]; range, 8-66 years) gave informed consent and underwent MR spectroscopy and GRE MR imaging of the liver. Spectroscopy involved a long repetition time (to suppress T1 effects) and multiple echo times (to estimate T2 effects); the reference fat fraction (FF) was calculated from T2-corrected fat and water spectral peak areas. Imaging involved a low flip angle (to suppress T1 effects) and multiple echo times (to estimate T2* effects); imaging FF was calculated by using four analysis methods of progressive complexity: dual echo, triple echo, multiecho, and multiinterference. All methods except dual echo corrected for T2* effects. The multiinterference method corrected for multiple spectral interference effects of fat. For each method, the accuracy for diagnosis of fatty liver, as defined with a spectroscopic threshold, was assessed by estimating sensitivity and specificity; fat-grading accuracy was assessed by comparing imaging and spectroscopic FF values by using linear regression. RESULTS Dual-echo, triple-echo, multiecho, and multiinterference methods had a sensitivity of 0.817, 0.967, 0.950, and 0.983 and a specificity of 1.000, 0.880, 1.000, and 0.880, respectively. On the basis of regression slope and intercept, the multiinterference (slope, 0.98; intercept, 0.91%) method had high fat-grading accuracy without statistically significant error (P > .05). Dual-echo (slope, 0.98; intercept, -2.90%), triple-echo (slope, 0.94; intercept, 1.42%), and multiecho (slope, 0.85; intercept, -0.15%) methods had statistically significant error (P < .05). CONCLUSION Relaxation- and interference-corrected fat quantification at low-flip-angle multiecho GRE MR imaging provides high diagnostic and fat-grading accuracy in NAFLD.

Fatty Liver Disease: MR Imaging Techniques for the Detection and Quantification of Liver Steatosis

Fatty liver disease is the most common cause of chronic liver disease in the United States. Noninvasive detection and quantification of fat is becoming more and more important clinically, due in large part to the growing prevalence of nonalcoholic fatty liver disease. Steatosis, the accumulation of fat-containing vacuoles within hepatocytes, is a key histologic feature of fatty liver disease. Liver biopsy, the current standard of reference for the assessment of steatosis, is invasive, has sampling errors, and is not appropriate in some settings. Several magnetic resonance (MR) imaging-based techniques--including chemical shift imaging, frequency-selective imaging, and MR spectroscopy--are currently in clinical use for the detection and quantification of fat-water admixtures, with each technique having important advantages, disadvantages, and limitations. These techniques permit the breakdown of the net MR signal into fat and water signal components, allowing the quantification of fat in liver tissue, and are increasingly being used in the diagnosis, treatment, and follow-up of fatty liver disease.

Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials

The magnetic resonance imaging–estimated proton density fat fraction (MRI‐PDFF) is a novel imaging‐based biomarker that allows fat mapping of the entire liver, whereas the magnetic resonance spectroscopy–measured proton density fat fraction (MRS‐PDFF) provides a biochemical measure of liver fat in small regions of interest. Cross‐sectional studies have shown that MRI‐PDFF correlates with MRS‐PDFF. The aim of this study was to show the utility of MRI‐PDFF in assessing quantitative changes in liver fat through a three‐way comparison of MRI‐PDFF and MRS‐PDFF with the liver histology–determined steatosis grade at two time points in patients with nonalcoholic fatty liver disease (NAFLD). Fifty patients with biopsy‐proven NAFLD who participated in a randomized trial underwent a paired evaluation with liver biopsy, MRI‐PDFF, and MRS‐PDFF at the baseline and 24 weeks. The mean age and body mass index were 47.8 ± 11.7 years and 30.7 ± 6.5 kg/m2, respectively. MRI‐PDFF showed a robust correlation with MRS‐PDFF both at week 0 and at week 24 (r = 0.98, P < 0.0001 for both). Cross‐sectionally, MRI‐PDFF and MRS‐PDFF increased with increases in the histology‐determined steatosis grade both at week 0 and at week 24 (P < 0.05 for all). Longitudinally, patients who had a decrease (≥1%) or increase (≥1%) in MRI‐PDFF (confirmed by MRS‐PDFF) showed a parallel decrease or increase in their body weight and serum alanine aminotransferase and aspartate aminotransferase levels at week 24 (P < 0.05). This small increase or decrease in liver fat could not be quantified with histology. Conclusion: In this longitudinal study, MRI‐PDFF correlated well with MRS‐PDFF and was more sensitive than the histology‐determined steatosis grade in quantifying increases or decreases in the liver fat content. Therefore, it could be used to quantify changes in liver fat in future clinical trials. (Hepatology 2013; 58:1930–1940)

Nonalcoholic Fatty Liver Disease: MR Imaging of Liver Proton Density Fat Fraction to Assess Hepatic Steatosis

PURPOSE To evaluate the diagnostic performance of magnetic resonance (MR) imaging-estimated proton density fat fraction (PDFF) for assessing hepatic steatosis in nonalcoholic fatty liver disease (NAFLD) by using centrally scored histopathologic validation as the reference standard. MATERIALS AND METHODS This prospectively designed, cross-sectional, internal review board-approved, HIPAA-compliant study was conducted in 77 patients who had NAFLD and liver biopsy. MR imaging-PDFF was estimated from magnitude-based low flip angle multiecho gradient-recalled echo images after T2* correction and multifrequency fat modeling. Histopathologic scoring was obtained by consensus of the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network Pathology Committee. Spearman correlation, additivity and variance stabilization for regression for exploring the effect of a number of potential confounders, and receiver operating characteristic analyses were performed. RESULTS Liver MR imaging-PDFF was systematically higher, with higher histologic steatosis grade (P < .001), and was significantly correlated with histologic steatosis grade (ρ = 0.69, P < .001). The correlation was not confounded by age, sex, lobular inflammation, hepatocellular ballooning, NASH diagnosis, fibrosis, or magnetic field strength (P = .65). Area under the receiver operating characteristic curves was 0.989 (95% confidence interval: 0.968, 1.000) for distinguishing patients with steatosis grade 0 (n = 5) from those with grade 1 or higher (n = 72), 0.825 (95% confidence interval: 0.734, 0.915) to distinguish those with grade 1 or lower (n = 31) from those with grade 2 or higher (n = 46), and 0.893 (95% confidence interval: 0.809, 0.977) to distinguish those with grade 2 or lower (n = 58) from those with grade 3 (n = 19). CONCLUSION MR imaging-PDFF showed promise for assessment of hepatic steatosis grade in patients with NAFLD. For validation, further studies with larger sample sizes are needed.

Estimation of Hepatic Proton-Density Fat Fraction by Using MR Imaging at 3.0 T

PURPOSE To compare the accuracy of several magnetic resonance (MR) imaging-based methods for hepatic proton-density fat fraction (FF) estimation at 3.0 T, with spectroscopy as the reference technique. MATERIALS AND METHODS This prospective study was institutional review board approved and HIPAA compliant. Informed consent was obtained. One hundred sixty-three subjects (39 with known hepatic steatosis, 110 with steatosis risk factors, 14 without risk factors) underwent proton MR spectroscopy and non-T1-weighted gradient-echo MR imaging of the liver. At spectroscopy, the reference FF was determined from frequency-selective measurements of fat and water proton densities. At imaging, FF was calculated by using two-, three-, or six-echo methods, with single-frequency and multifrequency fat signal modeling. The three- and six-echo methods corrected for T2*; the two-echo methods did not. For each imaging method, the fat estimation accuracy was assessed by using linear regression between the imaging FF and spectroscopic FF. Binary classification accuracy of imaging was assessed at four reference spectroscopic thresholds (0.04, 0.06, 0.08, and 0.10 FF). RESULTS Regression intercept of two-, three-, and six-echo methods were -0.0211, 0.0087, and -0.0062 (P <.001 for all three) without multifrequency modeling and -0.0237 (P <.001), 0.0022, and -0.0007 with multifrequency modeling, respectively. Regression slope of two-, three-, and six-echo methods were 0.8522, 0.8528, and 0.7544 (P <.001 for all three) without multifrequency modeling and 0.9994, 0.9775, and 0.9821 with multifrequency modeling, respectively. Significant deviation of intercept and slope from 0 and 1, respectively, indicated systematic error. Classification accuracy was 82.2%-90.1%, 93.9%-96.3%, and 83.4%-89.6% for two-, three-, and six-echo methods without multifrequency modeling and 88.3%-92.0%, 95.1%-96.3%, and 94.5%-96.3% with multifrequency modeling, respectively, depending on the FF threshold. T2*-corrected (three- and six-echo) multifrequency imaging methods had the overall highest FF estimation and classification accuracy. Among methods without multifrequency modeling, the T2-corrected three-echo method had the highest accuracy. CONCLUSION Non-T1-weighted MR imaging with T2 correction and multifrequency modeling helps accurately estimate hepatic proton-density FF at 3.0 T.

Risk of Injury Associated With Body Checking Among Youth Ice Hockey Players

CONTEXT Ice hockey has one of the highest sport participation and injury rates in youth in Canada. Body checking is the predominant mechanism of injury in leagues in which it is permitted. OBJECTIVE To determine if risk of injury and concussion differ for Pee Wee (ages 11-12 years) ice hockey players in a league in which body checking is permitted (Alberta, Canada) vs a league in which body checking is not permitted (Quebec, Canada). DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study conducted in Alberta and Quebec during the 2007-2008 Pee Wee ice hockey season. Participants (N = 2154) were players from teams in the top 60% of divisions of play. MAIN OUTCOME MEASURES Incidence rate ratios adjusted for cluster based on Poisson regression for game- and practice-related injury and concussion. RESULTS Seventy-four Pee Wee teams from Alberta (n = 1108 players) and 76 Pee Wee teams from Quebec (n = 1046 players) completed the study. In total, there were 241 injuries (78 concussions) reported in Alberta (85 077 exposure-hours) and 91 injuries (23 concussions) reported in Quebec (82 099 exposure-hours). For game-related injuries, the Alberta vs Quebec incidence rate ratio was 3.26 (95% confidence interval [CI], 2.31-4.60 [n = 209 and n = 70 for Alberta and Quebec, respectively]) for all injuries, 3.88 (95% CI, 1.91-7.89 [n = 73 and n = 20]) for concussion, 3.30 (95% CI, 1.77-6.17 [n = 51 and n = 16]) for severe injury (time loss, >7 days), and 3.61 (95% CI, 1.16-11.23 [n=14 and n=4]) for severe concussion (time loss, >10 days). The estimated absolute risk reduction (injuries per 1000 player-hours) that would be achieved if body checking were not permitted in Alberta was 2.84 (95% CI, 2.18-3.49) for all game-related injuries, 0.72 (95% CI, 0.40-1.04) for severe injuries, 1.08 (95% CI, 0.70-1.46) for concussion, and 0.20 (95% CI, 0.04-0.37) for severe concussion. There was no difference between provinces for practice-related injuries. CONCLUSION Among 11- to 12-year-old ice hockey players, playing in a league in which body checking is permitted compared with playing in a league in which body checking is not permitted was associated with a 3-fold increased risk of all game-related injuries and the categories of concussion, severe injury, and severe concussion.