Ricki Bettencourt

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)

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

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. (Hepatology 2015;61:1239–1250)

Lipoprotein-Associated Phospholipase A2 Is an Independent Predictor of Incident Coronary Heart Disease in an Apparently Healthy Older Population: The Rancho Bernardo Study

OBJECTIVES Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels predict incident coronary heart disease (CHD) in adults without known CHD, independent of heart disease risk factors. We examined whether the independent association was apparent in older adults. BACKGROUND Serum levels of Lp-PLA2, an enzyme that hydrolyzes oxidized phospholipids to yield potentially proatherogenic particles, have been associated with CHD and may help predict cardiovascular risk. METHODS Participants were 1,077 community-dwelling men and women, median age 72 years, who had no known CHD at baseline (1984 to 1987) when blood samples and risk factor data were collected. Participants were followed for CHD events for a mean of 16 years, through 2002. Cox proportional hazards regression models were used to examine the association of serum Lp-PLA2 with incident CHD (myocardial infarction, angina, or coronary revascularization). RESULTS The Lp-PLA2 levels positively correlated with age (r = 0.09), body mass index (r = 0.11), low-density lipoprotein (r = 0.37), triglycerides (r = 0.25), and C-reactive protein (r = 0.10), and negatively correlated with high-density lipoprotein (r = -0.27) (all p < 0.05). During follow-up, 228 participants had incident CHD events. Lipoprotein-associated phospholipase A2 levels in the second, third, and fourth quartiles predicted an increased risk of CHD compared with the lowest quartile (hazard ratios 1.66, 1.80, and 1.89, respectively; p < 0.05 for each). This association persisted after adjusting for C-reactive protein and other CHD risk factors. CONCLUSIONS Elevated Lp-PLA2 levels predict CHD events in apparently healthy older adults, independent of CHD risk factors.

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.

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.

Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE

Current guidelines do not recommend screening for non‐alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis.

Sexual Activity and Satisfaction in Healthy Community-dwelling Older Women

BACKGROUND Female sexual dysfunction is a focus of medical research, but few studies describe the prevalence and covariates of recent sexual activity and satisfaction in older community-dwelling women. METHODS A total of 1303 older women from the Rancho Bernardo Study were mailed a questionnaire on general health, recent sexual activity, sexual satisfaction, and the Female Sexual Function Index. RESULTS A total of 806 of 921 respondents (87.5%) aged 40 years or more answered questions about recent sexual activity. Their median age was 67 years; mean years since menopause was 25; most were upper-middle class; 57% had attended at least 1 year of college; and 90% reported good to excellent health. Half (49.8%) reported sexual activity within the past month with or without a partner, the majority of whom reported arousal (64.5%), lubrication (69%), and orgasm (67.1%) at least most of the time, although one third reported low, very low, or no sexual desire. Although frequency of arousal, lubrication, and orgasm decreased with age, the youngest (<55 years) and oldest (>80 years) women reported a higher frequency of orgasm satisfaction. Emotional closeness during sex was associated with more frequent arousal, lubrication, and orgasm; estrogen therapy was not. Overall, two thirds of sexually active women were moderately or very satisfied with their sex life, as were almost half of sexually inactive women. CONCLUSION Half these women were sexually active, with arousal, lubrication, and orgasm maintained into old age, despite low libido in one third. Sexual satisfaction increased with age and did not require sexual activity.

Effects of Dehydroepiandrosterone Supplementation on Cognitive Function and Quality of Life: The DHEA and Well‐Ness (DAWN) Trial

OBJECTIVES: To examine the effects of dehydroepiandrosterone (DHEA) supplementation on cognitive function and quality of life in healthy older adults.

Synergistic association between alcohol intake and body mass index with serum alanine and aspartate aminotransferase levels in older adults: the Rancho Bernardo Study

Background The association between body‐mass‐index (BMI), alcohol consumption and their joint effect in increasing the risk of elevated serum alanine (ALT) and aspartate (AST) is unclear in older community‐dwelling adults.

Association Between Quantity of Liver Fat and Cardiovascular Risk in Patients With Nonalcoholic Fatty Liver Disease Independent of Nonalcoholic Steatohepatitis

BACKGROUND & AIMS The association between quantity of liver fat and the presence of metabolic syndrome needs to be assessed systematically. We aimed to determine the association between the quantity of liver fat and the presence of the metabolic syndrome in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), independent of nonalcoholic steatohepatitis (NASH). METHODS We recruited 146 patients with well-characterized biopsy-proven NAFLD and 50 individuals without NAFLD (controls) to participate in a case-control study at the NAFLD Translational Research Unit at the University of California San Diego. Liver fat was quantified in patients with NAFLD and controls using an advanced magnetic resonance imaging-based biomarker, the proton-density-fat-fraction (MRI-PDFF). Patients with NAFLD were divided into groups based on whether they were above or below the median MRI-PDFF value (15.4% in patients with NAFLD); the MRI-PDFF value for controls was less than 5%. The primary outcome was the presence of the metabolic syndrome using Adult Treatment Panel III criteria without and with adjustment for the presence of NASH. RESULTS Compared with NAFLD patients with MRI-PDFF values below the median, and compared with controls, NAFLD patients with MRI-PDFF values above the median were more likely to have abdominal obesity (P < .0001), lower levels of high-density cholesterol (P < .0001), higher levels of triglycerides (P < .0001), and higher fasting glucose levels (P < .001). Compared with NAFLD patients with MRI-PDFF values below the median, NAFLD patients with MRI-PDFF above the median were more likely to have the metabolic syndrome (60.3% vs. 44.4%; P < .04), independent of biopsy-detected NASH. CONCLUSIONS Increased liver fat content in patients with NAFLD is associated with increased rates of the metabolic syndrome, independent of NASH. There appears to be an association between the quantity of liver fat and the risk for cardiovascular disease in patients with NAFLD.