With the increasing prevalence of liver disease worldwide, there is an urgent clinical need for reliable methods to diagnose and stage liver pathology. Liver biopsy, the current gold standard, is invasive and limited by sampling and observer dependent variability. In this study, we aimed to assess the diagnostic accuracy of a novel magnetic resonance protocol for liver tissue characterisation. We conducted a prospective study comparing our magnetic resonance technique against liver biopsy. The individual components of the scanning protocol were T1 mapping, proton spectroscopy and T2* mapping, which quantified liver fibrosis, steatosis and haemosiderosis, respectively. Unselected adult patients referred for liver biopsy as part of their routine care were recruited. Scans performed prior to liver biopsy were analysed by physicians blinded to the histology results. The associations between magnetic resonance and histology variables were assessed. Receiver-operating characteristic analyses were also carried out. Paired magnetic resonance and biopsy data were obtained in 79 patients. Magnetic resonance measures correlated strongly with histology (r(s)=0.68 p<0.0001 for fibrosis; r(s)=0.89 p<0.001 for steatosis; r(s)=-0.69 p<0.0001 for haemosiderosis). The area under the receiver operating characteristic curve was 0.94, 0.93, and 0.94 for the diagnosis of any degree of fibrosis, steatosis and haemosiderosis respectively. The novel scanning method described here provides high diagnostic accuracy for the assessment of liver fibrosis, steatosis and haemosiderosis and could potentially replace liver biopsy for many indications. This is the first demonstration of a non-invasive test to differentiate early stages of fibrosis from normal liver.

Background—: Noncontrast magnetic resonance T1 mapping reflects a composite of both intra- and extracellular signal. We hypothesized that noncontrast T1 mapping can characterize the myocardium beyond that achieved by the well-established late gadolinium enhancement (LGE) technique (which detects focal fibrosis) in both hypertrophic (HCM) and dilated (DCM) cardiomyopathy, by detecting both diffuse and focal fibrosis. Methods and Results—: Subjects underwent Cardiovascular Magnetic Resonance imaging at 3T (28 HCM, 18 DCM, and 12 normals). Matching short-axis slices were acquired for cine, T1 mapping, and LGE imaging (0.1 mmol/kg). Circumferential strain was measured in the midventricular slice, and ³¹ P magnetic resonance spectroscopy was acquired for the septum of the midventricular slice. Mean T1 relaxation time was increased in HCM and DCM (HCM 1209±28 ms, DCM 1225±42 ms, normal 1178±13 ms, P <0.05). There was a weak correlation between mean T1 and LGE ( r =0.32, P <0.001). T1 values were higher in segments with LGE than in those without (HCM with LGE 1228±41 ms versus no LGE 1192±79 ms, P <0.01; DCM with LGE 1254±73 ms versus no LGE 1217±52 ms, P <0.01). However, in both HCM and DCM, even in segments unaffected by LGE, T1 values were significantly higher than normal ( P <0.01). T1 values correlated with disease severity, being increased as wall thickness increased in HCM; conversely, in DCM, T1 values were highest in the thinnest myocardial segments. T1 values also correlated significantly with circumferential strain ( r =0.42, P <0.01). Interestingly, this correlation remained statistically significant even for the slices without LGE ( r =0.56, P =0.04). Finally, there was also a statistically significant negative correlation between T1 values and phosphocreatine/adenosine triphosphate ratios ( r =−0.59, P <0.0001). Conclusions—: In HCM and DCM, noncontrast T1 mapping detects underlying disease processes beyond those assessed by LGE in relatively low-risk individuals.

Quantitative T1-mapping is rapidly becoming a clinical tool in cardiovascular magnetic resonance (CMR) to objectively distinguish normal from diseased myocardium. The usefulness of any quantitative technique to identify disease lies in its ability to detect significant differences from an established range of normal values. We aimed to assess the variability of myocardial T1 relaxation times in the normal human population estimated with recently proposed Shortened Modified Look-Locker Inversion recovery (ShMOLLI) T1 mapping technique. A large cohort of healthy volunteers (n = 342, 50% females, age 11–69 years) from 3 clinical centres across two countries underwent CMR at 1.5T. Each examination provided a single average myocardial ShMOLLI T1 estimate using manually drawn myocardial contours on typically 3 short axis slices (average 3.4 ± 1.4), taking care not to include any blood pool in the myocardial contours. We established the normal reference range of myocardial and blood T1 values, and assessed the effect of potential confounding factors, including artefacts, partial volume, repeated measurements, age, gender, body size, hematocrit and heart rate. Native myocardial ShMOLLI T1 was 962 ± 25 ms. We identify the partial volume as primary source of potential error in the analysis of respective T1 maps and use 1 pixel erosion to represent “midwall myocardial” T1, resulting in a 0.9% decrease to 953 ± 23 ms. Midwall myocardial ShMOLLI T1 was reproducible with an intra-individual, intra- and inter-scanner variability of ≤2%. The principle biological parameter influencing myocardial ShMOLLI T1 was the female gender, with female T1 longer by 24 ms up to the age of 45 years, after which there was no significant difference from males. After correction for age and gender dependencies, heart rate was the only other physiologic factor with a small effect on myocardial ShMOLLI T1 (6ms/10bpm). Left and right ventricular blood ShMOLLI T1 correlated strongly with each other and also with myocardial T1 with the slope of 0.1 that is justifiable by the resting partition of blood volume in myocardial tissue. Overall, the effect of all variables on myocardial ShMOLLI T1 was within 2% of relative changes from the average. Native T1-mapping using ShMOLLI generates reproducible and consistent results in normal individuals within 2% of relative changes from the average, well below the effects of most acute forms of myocardial disease. The main potential confounder is the partial volume effect arising from over-inclusion of neighbouring tissue at the manual stages of image analysis. In the study of cardiac conditions such as diffuse fibrosis or small focal changes, the use of “myocardial midwall” T1, age and gender matching, and compensation for heart rate differences may all help to improve the method sensitivity in detecting subtle changes. As the accuracy of current T1 measurement methods remains to be established, this study does not claim to report an accurate measure of T1, but that ShMOLLI is a stable and reproducible method for T1-mapping.

NGM282, an engineered fibroblast growth factor 19 analogue, rapidly and significantly reduced liver fat content in a multicenter, randomized, double‐blind, placebo‐controlled study in patients with biopsy‐confirmed nonalcoholic steatohepatitis (NASH). However, it is unclear whether these changes would be accompanied by histological improvement. In this open‐label study, we assessed the histological efficacy of NGM282 in patients with biopsy‐confirmed nonalcoholic steatohepatitis. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1 mg, n = 24; 3 mg, n = 19) once daily for 12 weeks were evaluated blinded to time point, subject, and clinical information. At week 12, NGM282 significantly reduced nonalcoholic fatty liver disease activity score (NAS; −1.9; 95% confidence interval, −2.6 to −1.2; P < 0.001 in the 1 mg group; −2.2, −3.1 to −1.3; P < 0.001 in the 3 mg group) and fibrosis (−0.5; −0.9 to 0; P = 0.035 in the 3 mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1 mg or 3 mg, respectively, improved NAS by 2 or more points without fibrosis worsening. Of the patients receiving NGM282 1 mg or 3 mg, 25% and 42%, respectively, improved liver fibrosis by one stage or more without worsening of steatohepatitis. Treatment with NGM282 led to relative reductions in liver fat content (−58% and −67% in the 1 mg and 3 mg groups, respectively), corrected T1 (cT1; −8% and −9%), alanine aminotransferase (ALT) (−67% and −60%), aspartate aminotransferase (−57% and −52%), and fibrogenesis biomarkers neoepitope‐specific N‐terminal propeptide of type III collagen (Pro‐C3; −22% and −33%) and enhanced liver fibrosis score (ELF; −3% and −6%) at week 12. Greater reductions in Pro‐C3, ELF, and cT1, but not in liver fat content, 7alpha‐hydroxy‐4‐cholesten‐3‐one, or ALT, were observed in histological responders than in nonresponders. Conclusion: In this open‐label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.

Multiparametric magnetic resonance (MR) imaging has been demonstrated to quantify hepatic fibrosis, iron, and steatosis. The aim of this study was to determine if MR can be used to predict negative clinical outcomes in liver disease patients. Patients with chronic liver disease (n=112) were recruited for MR imaging and data on the development of liver related clinical events were collected by medical records review. The median follow-up was 27months. MR data were analysed blinded for the Liver Inflammation and Fibrosis score (LIF; <1, 1-1.99, 2-2.99, and ⩾3 representing normal, mild, moderate, and severe liver disease, respectively), T2∗ for liver iron content and proportion of liver fat. Baseline liver biopsy was performed in 102 patients. Liver disease aetiologies included non-alcoholic fatty liver disease (35%) and chronic viral hepatitis (30%). Histologically, fibrosis was mild in 54 (48%), moderate in 17 (15%), and severe in 31 (28%) patients. Overall mortality was 5%. Ten patients (11%) developed at least one liver related clinical event. The negative predictive value of LIF<2 was 100%. Two patients with LIF 2-2.99 and eight with LIF⩾3 had a clinical event. Patients with LIF⩾3 had a higher cumulative risk for developing clinical events, compared to those with LIF<1 (p=0.02) and LIF 1-1.99 (p=0.03). Cox regression analysis including all 3 variables (fat, iron, LIF) resulted in an enhanced LIF predictive value. Non-invasive standardised multiparametric MR technology may be used to predict clinical outcomes in patients with chronic liver disease.

Type 2 diabetes (T2D) and obesity are associated with nonalcoholic fatty liver disease, cardiomyopathy, and cardiovascular mortality. Both show stronger links between ectopic and visceral fat deposition, and an increased cardiometabolic risk compared with subcutaneous fat. This study investigated whether lean patients (Ln) with T2D exhibit increased ectopic and visceral fat deposition and whether these are linked to cardiac and hepatic changes. Twenty-seven obese patients (Ob) with T2D, 15 Ln-T2D, and 12 normal-weight control subjects were studied. Subjects underwent cardiac computed tomography, cardiac magnetic resonance imaging (MRI), proton and phosphorus MR spectroscopy, and multiparametric liver MR, including hepatic proton MRS, T1- and T2*-mapping yielding "iron-corrected T1" [cT1]. Diabetes, with or without obesity, was associated with increased myocardial triglyceride content (p = 0.01), increased hepatic triglyceride content (p = 0.04), and impaired myocardial energetics (p = 0.04). Although cardiac structural changes, steatosis, and energetics were similar between the T2D groups, epicardial fat (p = 0.04), hepatic triglyceride (p = 0.01), and insulin resistance (p = 0.03) were higher in Ob-T2D. Epicardial fat, hepatic triglyceride, and insulin resistance correlated negatively with systolic strain and diastolic strain rates, which were only significantly impaired in Ob-T2D (p < 0.001 and p = 0.006, respectively). Fibroinflammatory liver disease (elevated cT1) was only evident in Ob-T2D patients. cT1 correlated with hepatic and epicardial fat (p < 0.001 and p = 0.01, respectively). Irrespective of body mass index, diabetes is related to significant abnormalities in cardiac structure, energetics, and cardiac and hepatic steatosis. Obese patients with T2D show a greater propensity for ectopic and visceral fat deposition.