Carolyn Hernandez

Magnetic resonance elastography vs. transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease

BACKGROUND & AIMS Magnetic resonance imaging (MRI) techniques and ultrasound-based transient elastography (TE) can be used in noninvasive diagnosis of fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We performed a prospective study to compare the performance of magnetic resonance elastography (MRE) vs TE for diagnosis of fibrosis, and MRI-based proton density fat fraction (MRI-PDFF) analysis vs TE-based controlled attenuation parameter (CAP) for diagnosis of steatosis in patients undergoing biopsy to assess NAFLD. METHODS We performed a cross-sectional study of 104 consecutive adults (56.7% female) who underwent MRE, TE, and liver biopsy analysis (using the histologic scoring system for NAFLD from the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System) from October 2011 through May 2016 at a tertiary medical center. All patients received a standard clinical evaluation, including collection of history, anthropometric examination, and biochemical tests. The primary outcomes were fibrosis and steatosis. Secondary outcomes included dichotomized stages of fibrosis and nonalcoholic steatohepatitis vs no nonalcoholic steatohepatitis. Receiver operating characteristic curve analyses were used to compare performances of MRE vs TE in diagnosis of fibrosis (stages 1-4 vs 0) and MRI-PDFF vs CAP for diagnosis of steatosis (grades 1-3 vs 0) with respect to findings from biopsy analysis. RESULTS MRE detected any fibrosis (stage 1 or more) with an area under the receiver operating characteristic curve (AUROC) of 0.82 (95% confidence interval [CI], 0.74-0.91), which was significantly higher than that of TE (AUROC, 0.67; 95% CI, 0.56-0.78). MRI-PDFF detected any steatosis with an AUROC of 0.99 (95% CI, 0.98-1.00), which was significantly higher than that of CAP (AUROC, 0.85; 95% CI, 0.75-0.96). MRE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.89 (95% CI, 0.83-0.96), 0.87 (95% CI, 0.78-0.96), and 0.87 (95% CI, 0.71-1.00); TE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.86 (95% CI, 0.77-0.95), 0.80 (95% CI, 0.67-0.93), and 0.69 (95% CI, 0.45-0.94). MRI-PDFF identified steatosis of grades 2 or 3 with AUROC values of 0.90 (95% CI, 0.82-0.97) and 0.92 (95% CI, 0.84-0.99); CAP identified steatosis of grades 2 or 3 with AUROC values of 0.70 (95% CI, 0.58-0.82) and 0.73 (95% CI, 0.58-0.89). CONCLUSIONS In a prospective, cross-sectional study of more than 100 patients, we found MRE to be more accurate than TE in identification of liver fibrosis (stage 1 or more), using biopsy analysis as the standard. MRI-PDFF is more accurate than CAP in detecting all grades of steatosis in patients with NAFLD.

Magnetic resonance elastography is superior to acoustic radiation force impulse for the Diagnosis of fibrosis in patients with biopsy‐proven nonalcoholic fatty liver disease: A prospective study

Magnetic resonance elastography (MRE), an advanced magnetic resonance–based imaging technique, and acoustic radiation force impulse (ARFI), an ultrasound‐based imaging technique, are accurate for diagnosing nonalcoholic fatty liver disease (NAFLD) fibrosis. However, no head‐to‐head comparisons between MRE and ARFI for diagnosing NAFLD fibrosis have been performed. We compared MRE versus ARFI head‐to‐head for diagnosing fibrosis in well‐characterized patients with biopsy‐proven NAFLD. This cross‐sectional analysis of a prospective cohort involved 125 patients (54.4% female) who underwent MRE, ARFI, and contemporaneous liver biopsies scored using the Nonalcoholic Steatohepatitis Clinical Research Network histological scoring system. The performances of MRE versus ARFI for diagnosing fibrosis were evaluated using area under the receiver operating characteristic curves (AUROCs). The mean (± standard deviation) age and body mass index were 48.9 (±15.4) years and 31.8 (±7.0) kg/m2, respectively. For diagnosing any fibrosis (≥ stage 1), the MRE AUROC was 0.799 (95% confidence interval [CI] 0.723‐0.875), significantly (P = 0.012) higher than the ARFI AUROC of 0.664 (95% CI 0.568‐0.760). In stratified analysis by presence or absence of obesity, MRE was superior to ARFI for diagnosing any fibrosis in obese patients (P < 0.001) but not in nonobese patients (P = 0.722). The MRE AUROCs for diagnosing ≥stages 2, 3, and 4 fibrosis were 0.885 (95% CI 0.816‐0.953), 0.934 (95% CI 0.863‐1.000), and 0.882 (95% CI 0.729‐1.000); and the ARFI AUROCs were 0.848 (95% CI 0.776‐0.921), 0.896 (95% CI 0.824‐0.968), and 0.862 (95% CI 0.721‐1.000). MRE had higher AUROCs than ARFI for discriminating dichotomized fibrosis stages at all dichotomization cutoff points, but the AUROC differences decreased as the cutoff points (fibrosis stages) increased. Conclusion: MRE is more accurate than ARFI for diagnosing any fibrosis in NAFLD patients, especially those who are obese. (Hepatology 2016;63:453–461)

Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial

BACKGROUND & AIMS Uncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase and liver histology in non-alcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin vs. the efficacy of a placebo in reducing liver fat measured by MRI-derived proton density-fat fraction (MRI-PDFF). METHODS This randomized, double-blind, allocation-concealed, placebo-controlled trial included 50 NAFLD patients with prediabetes or early diabetes randomized to sitagliptin orally 100mg/day or placebo for 24weeks. Primary outcome was liver fat change measured by MRI-PDFF in colocalized regions of interest within each of nine liver segments. Additional advanced assessments included MR spectroscopy (MRS) for internal validation of MRI-PDFFs accuracy, and magnetic resonance elastography (MRE) and FIBROSpect® II to assess liver fibrosis. RESULTS Sitagliptin was not significantly better than placebo in reducing liver fat measured by MRI-PDFF (mean difference between sitagliptin and placebo arms: -1.3%, p=0.4). Compared to baseline, there were no significant differences in end-of-treatment MRI-PDFF for sitagliptin (18.1% to 16.9%, p=0.27) or placebo (16.6% to 14.0%, p=0.07). The groups had no significant differences for changes in alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein, homeostatic model assessment insulin resistance, and MRE-derived liver stiffness. In both groups at baseline and post-treatment, MRI-PDFF and MRS showed robust correlation coefficients ranging from r(2)=0.96 to r(2)=0.99 (p<0.0001), demonstrating the strong internal validity of the findings. FIBROSpect® II showed no changes in the sitagliptin group but was significantly increased in the placebo group (p=0.03). CONCLUSIONS Sitagliptin was safe but not better than placebo in reducing liver fat in prediabetic or diabetic patients with NAFLD. LAY SUMMARY In a randomized, double-blind, placebo-controlled study, the anti-diabetic drug sitagliptin was no more effective than placebo for improving liver fat and liver fibrosis in patients with non-alcoholic fatty liver disease. This study demonstrates that non-invasive magnetic resonance imaging techniques, including magnetic resonance imaging-proton density-fat fraction and magnetic resonance elastography, can be used to assess treatment response in non-alcoholic fatty liver disease clinical trials.

MRE is superior to ARFI for the diagnosis of fibrosis in patients with biopsy‐proven NAFLD: A prospective study

Magnetic resonance elastography (MRE), an advanced magnetic resonance–based imaging technique, and acoustic radiation force impulse (ARFI), an ultrasound‐based imaging technique, are accurate for diagnosing nonalcoholic fatty liver disease (NAFLD) fibrosis. However, no head‐to‐head comparisons between MRE and ARFI for diagnosing NAFLD fibrosis have been performed. We compared MRE versus ARFI head‐to‐head for diagnosing fibrosis in well‐characterized patients with biopsy‐proven NAFLD. This cross‐sectional analysis of a prospective cohort involved 125 patients (54.4% female) who underwent MRE, ARFI, and contemporaneous liver biopsies scored using the Nonalcoholic Steatohepatitis Clinical Research Network histological scoring system. The performances of MRE versus ARFI for diagnosing fibrosis were evaluated using area under the receiver operating characteristic curves (AUROCs). The mean (± standard deviation) age and body mass index were 48.9 (±15.4) years and 31.8 (±7.0) kg/m2, respectively. For diagnosing any fibrosis (≥ stage 1), the MRE AUROC was 0.799 (95% confidence interval [CI] 0.723‐0.875), significantly (P = 0.012) higher than the ARFI AUROC of 0.664 (95% CI 0.568‐0.760). In stratified analysis by presence or absence of obesity, MRE was superior to ARFI for diagnosing any fibrosis in obese patients (P < 0.001) but not in nonobese patients (P = 0.722). The MRE AUROCs for diagnosing ≥stages 2, 3, and 4 fibrosis were 0.885 (95% CI 0.816‐0.953), 0.934 (95% CI 0.863‐1.000), and 0.882 (95% CI 0.729‐1.000); and the ARFI AUROCs were 0.848 (95% CI 0.776‐0.921), 0.896 (95% CI 0.824‐0.968), and 0.862 (95% CI 0.721‐1.000). MRE had higher AUROCs than ARFI for discriminating dichotomized fibrosis stages at all dichotomization cutoff points, but the AUROC differences decreased as the cutoff points (fibrosis stages) increased. Conclusion: MRE is more accurate than ARFI for diagnosing any fibrosis in NAFLD patients, especially those who are obese. (Hepatology 2016;63:453–461)

Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non‐invasive diagnosis of advanced fibrosis in biopsy‐proven non‐alcoholic fatty liver disease: a prospective study

Two‐dimensional magnetic resonance elastography (2D‐MRE) is an advanced magnetic resonance method with high diagnostic accuracy for predicting advanced fibrosis in non‐alcoholic fatty liver disease (NAFLD) patients. However, no prospective, head‐to‐head comparisons between 2D‐MRE and clinical prediction rules (CPRs) have been performed in patients with biopsy‐proven NAFLD.

Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis

Background: Magnetic resonance imaging-estimated proton-density-fat-fraction (MRI-PDFF) has been shown to be a noninvasive, accurate and reproducible imaging-based biomarker for assessing steatosis and treatment response in nonalcoholic steatohepatitis (NASH) clinical trials. However, there are no data on the magnitude of MRI-PDFF reduction corresponding to histologic response in the setting of a NASH clinical trial. The aim of this study was to quantitatively compare the magnitude of MRI-PDFF reduction between histologic responders versus histologic nonresponders in NASH patients. Methods: This study is a secondary analysis of the MOZART trial, which included 50 patients with biopsy-proven NASH randomized to ezetimibe 10 mg/day orally or placebo for 24 weeks. The primary aim was to perform a head-to-head comparative analysis of histologic responders [defined as a ⩾2-point reduction in the nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) without worsening fibrosis] versus nonresponders, and the corresponding quantitative change in liver fat content measured via MRI-PDFF. Results: Of the 35 patients who underwent paired liver biopsy and MRI-PDFF assessment at the beginning and end of treatment, 10 demonstrated a histologic response. Compared with histologic nonresponders, histologic responders had a statistically significant reduction in MRI-PDFF of −4.1% ± 4.9 versus −0.6 ± 4.1 (p < 0.04) with a mean relative percent change of −29.3% ± 33.0 versus +2.0% ± 24.0 (p < 0.004), respectively. Conclusions: Utilizing paired MRI-PDFF and liver histology data, we demonstrate that a relative reduction of 29% in liver fat on MRI-PDFF is associated with a histologic response in NASH. After external validation by independent research groups, these results can be incorporated into designing future NASH clinical trials, especially those utilizing change in hepatic fat quantified by MRI-PDFF, as a treatment endpoint.

Optimal threshold of controlled attenuation parameter with MRI‐PDFF as the gold standard for the detection of hepatic steatosis

The optimal threshold of controlled attenuation parameter (CAP) for the detection of hepatic steatosis using both M and XL probe is unknown in nonalcoholic fatty liver disease (NAFLD). Magnetic resonance imaging proton density fat fraction (MRI‐PDFF) is an accurate and precise method of detecting the presence of hepatic steatosis that is superior to CAP. Thus, the aim of this study was to evaluate the diagnostic accuracy and optimal threshold of CAP for the detection of hepatic steatosis as defined by MRI‐PDFF ≥ 5%. This prospective cross‐sectional study included 119 adults (59% women) with and without NAFLD who underwent MRI‐PDFF and CAP using either M or XL probe when indicated within a 6‐month period at the NAFLD Research Center, University of California, San Diego. The mean ( ± standard deviation) age and body mass index were 52.4 (±15.2) years and 29.9 (±5.5) kg/m2, respectively. The prevalence of NAFLD (MRI‐PDFF ≥ 5%) and MRI‐PDFF ≥ 10% was 70.6% and 47.1%, respectively. The area under the receiver operating characteristic (AUROC) of CAP for the detection of MRI‐PDFF ≥ 5% was 0.80 (95% confidence interval [CI], 0.70‐0.90) at the cut‐point of 288 dB/m and of MRI‐PDFF ≥ 10% was 0.87 (95% CI, 0.80‐0.94) at the cut‐point of 306 dB/m. When stratified by the interquartile range (IQR) of CAP, we observed that an IQR below the median (30 dB/m) had a robust AUROC compared with an IQR above the median (0.92 [95% CI, 0.85‐1.00] versus 0.70 [95% CI, 0.56‐0.85]; P = 0.0117), and these differences were statistically and clinically significant. Conclusion: The cut‐point of CAP for presence of hepatic steatosis (MRI‐PDFF ≥ 5%) was 288 dB/m. The diagnostic accuracy of CAP for the detection of hepatic steatosis is more reliable when the IQR of CAP is <30 dB/m. These data have implications for the clinical use of CAP in the assessment of NAFLD. (Hepatology 2018;67:1348‐1359)

Cardiovascular risk assessment in the treatment of nonalcoholic steatohepatitis: a secondary analysis of the MOZART trial

Background: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular risk and mortality. No US Food and Drug Administration (FDA) approved therapies for NASH are available; clinical trials to date have not yet systematically assessed for changes in cardiovascular risk. This study examines the prospective utility of cardiovascular risk assessments, the Framingham risk score (FRS) and coronary artery calcium (CAC) score, as endpoints in a NASH randomized clinical trial, and assesses whether histologic improvements lead to lower cardiovascular risk. Methods: Secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial (MOZART) in which 50 biopsy-proven NASH patients received oral ezetimibe 10 mg daily (n = 25) versus placebo (n = 25). Biochemical profiling, FRS, CAC scores, liver biopsies were obtained at baseline and endpoint. Results: Ezetimibe improved FRS whereas placebo did not (4.4 ± 6.2 to 2.9 ± 4.8, p = 0.038; 3.0 ± 4.4 to 2.9 ± 4.2, p = 0.794). CAC scores did not change with ezetimibe or placebo (180.4 ± 577.2 to 194.1 ± 623.9, p = 0.293; 151.4 ± 448.9 to 183.3 ± 555.7, p = 0.256). Ezetimibe improved FRS and CAC scores in more patients than placebo (48% versus 23%, p = 0.079, and 21% versus 0%, p = 0.090, respectively), though not significantly. No differences were noted in cardiovascular risk scores among histologic responders versus nonresponders. Conclusions: Ezetimibe improved FRS whereas placebo did not. FRS and CAC scores improved in a greater proportion of patients with ezetimibe; this trend did not reach significance. These findings indicate the utility and feasibility of monitoring cardiovascular risk in a NASH trial. The utility of CAC scores may be higher in trials of longer duration (⩾52 weeks) and with older patients (age ⩾45). ClinicalTrials.gov registration: NCT01766713.

Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy.

Novel association between serum pentraxin-2 levels and advanced fibrosis in well-characterised patients with non-alcoholic fatty liver disease

Pentraxin‐2 (PTX‐2), a serum protein, inhibits inflammation and fibrosis, and recombinant PTX‐2 is being tested as an anti‐fibrotic agent.