Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis.

BACKGROUND: The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis. METHODS: This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE). RESULTS: The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8-126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1-146.1, P = 0.0438). CONCLUSION: Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients. UCSD IRB: 140084. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.

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.

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-PDFF's 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.

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.

Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study.

BACKGROUND & AIMS: Little is known about the heritability of hepatic fibrosis, and the heritability of hepatic steatosis has not been assessed systematically in adults. We investigated the heritability of hepatic fibrosis and steatosis in a community-dwelling twin cohort. METHODS: We performed a cross-sectional analysis of a cohort of well-characterized twins residing in Southern California including 60 pairs of twins (42 monozygotic and 18 dizygotic; average age, 45.7 ± 22.1 y; average body mass index, 26.4 ± 5.7 kg/m(2)). We collected data on medical history, physical examinations, fasting laboratory test results, and liver health; all participants underwent an advanced magnetic resonance imaging (MRI) examination of the liver from January 2012 through January 2015. Hepatic steatosis was quantified noninvasively by MRI and determined based on the proton-density fat fraction (MRI-PDFF); liver fibrosis was measured based on stiffness measured by magnetic resonance elastography. RESULTS: Twenty-six of the 120 subjects (21.7%) had nonalcoholic fatty liver disease (defined as MRI-PDFF ≥ 5% after exclusion of other causes of hepatic steatosis). The presence of hepatic steatosis correlated between monozygotic twins (r(2) = 0.70; P < .0001) but not between dizygotic twins (r(2) = 0.36; P = .2). The level of liver fibrosis also correlated between monozygotic twins (r(2) = 0.48; P < .002) but not between dizygotic twins (r(2) = 0.12; P = .7). In multivariable models adjusted for age, sex, and ethnicity, the heritability of hepatic steatosis (based on MRI-PDFF) was 0.52 (95% confidence interval, 0.31-0.73; P < 1.1 × 10(-11)) and the heritability of hepatic fibrosis (based on liver stiffness) was 0.5 (95% confidence interval, 0.28-0.72; P <6.1 × 10(-11)). CONCLUSIONS: A study of twins provides evidence that hepatic steatosis and hepatic fibrosis are heritable traits.

Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).

UNLABELLED: Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). CONCLUSIONS: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH.