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Bril F.,University of Florida | Bril F.,Malcom Randall Veterans Administration Medical Center | Maximos M.,Malcom Randall Veterans Administration Medical Center | Maximos M.,University of Florida | And 16 more authors.
Journal of Hepatology | Year: 2015

Background & Aims: The role of plasma vitamin D deficiency in the development of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) remains poorly understood. Previous studies have suggested a role for vitamin D deficiency in the pathogenesis of NAFLD/NASH, but they have been rather small, and/or NAFLD was diagnosed using only aminotransferases or liver ultrasound. This study aimed to assess the role of vitamin D deficiency in relationship to liver fat accumulation and severity of NASH. Methods: A total of 239 patients were recruited and state-of-theart techniques were used to measure insulin resistance (euglycemic insulin clamp with 3-3H-glucose), liver fat accumulation (magnetic resonance spectroscopy or 1H-MRS), total body fat (dual energy X-ray absorptiometry), and severity of liver disease (liver biopsy). Results: Patients were divided into 3 groups according to plasma 25-hydroxyvitamin D levels (normal: >30 ng/ml; insufficiency: 20-30 ng/ml; deficiency: <20 ng/ml). When well-matched for clinical parameters (BMI, total adiposity, or prevalence of prediabetes/ type 2 diabetes), no significant differences were observed among groups in terms of skeletal muscle, hepatic, or adipose tissue insulin sensitivity, the amount of liver fat by 1H-MRS, or the severity of histological inflammation, ballooning, or fibrosis. Patients were then divided according to liver histology into those with definite NASH and those without NASH. Although patients with NASH had higher insulin resistance, plasma vitamin D concentrations were similar between both groups. Conclusions: Our results suggest that plasma vitamin D levels are not associated with insulin resistance, the amount of liver fat accumulation, or the severity of NASH. © 2014 European Association for the Study of the Liver.

Bril F.,University of Florida | Lomonaco R.,University of Florida | Orsak B.,University of Florida | Ortiz-Lopez C.,University of Florida | And 7 more authors.
Hepatology | Year: 2014

Hyperinsulinemia is believed to play a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and associated cardiovascular risk. However, the relative contribution of insulin clearance to hyperinsulinemia and its relationship to liver histology have not been carefully evaluated before. To examine this, we enrolled 190 patients (32 without nonalcoholic fatty liver disease [NAFLD], 36 with simple steatosis [SS], and 122 with biopsy-proven NASH). Insulin secretion and hepatic insulin clearance were estimated by means of an oral glucose tolerance test, whereas peripheral insulin sensitivity and whole-body insulin clearance were measured during a euglycemic insulin clamp. A liver biopsy was performed to assess histology (grade/stage). Patients with NASH had similar hepatic insulin sensitivity, compared to patients with SS, but more severe adipose tissue insulin resistance and worse hyperinsulinemia. Patients with SS and NASH had a similar ∼30% reduction (P<0.01) in hepatic insulin clearance, when compared to patients without NAFLD. Reduced hepatic insulin clearance was not associated with severity of inflammation, ballooning, and fibrosis. In contrast, worse histological inflammation and ballooning (but not steatosis or fibrosis) were associated with a progressive reduction in whole-body insulin clearance (P<0.001 for trend). There was no significant difference in insulin secretion between patients with SS versus NASH. Conclusion: Decreased hepatic insulin clearance develops with a mild increase in liver fat (LFAT) accumulation. It appears to be largely driven by hepatic steatosis, whereas steatohepatitis is more closely associated with reduced whole-body insulin clearance. Hyperinsulinemia in NAFLD correlated strongly with impaired insulin clearance, but not with insulin secretion. Strategies that reduce LFAT and improve insulin clearance hold the potential to revert the unfavorable effects of hyperinsulinemia in these patients. © 2014 by the American Association for the Study of Liver Diseases.

Cusi K.,University of Florida | Cusi K.,University of Texas Health Science Center at San Antonio | Cusi K.,Audie rphy Veterans Administration Medical Center Vamc | Chang Z.,University of Florida | And 15 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Liver biopsy is the only reliable way of diagnosing and staging NASH but its invasive nature limits its use. Plasma caspase-generated cytokeratin-18 fragments (CK-18) have been proposed as a non-invasive alternative. We studied its clinical value in a large multiethnic NAFLD population and examined its relationship to clinical/metabolic/ histological parameters. Methods 424 middle-aged subjects in whom we measured adipose tissue, liver and muscle insulin resistance (IR), liver fat by MRS (n = 275) and histology (n = 318). Results Median CK-18 were elevated in patients with vs. without NAFLD by MRS (209 [IQR: 137-329] vs. 122 [IQR: 98-155] U/L) or with vs. without NASH (232 [IQR: 151-387] vs. 170 [IQR: 135-234] U/L, both p <0.001). Plasma CK-18 raised significantly with any increase in steatosis, inflammation and fibrosis, but there was a significant overlap across disease severity. The CK-18 AUROC to predict NAFLD, NASH or fibrosis were 0.77 (95% CI = 0.71-0.84), 0.65 (95% CI = 0.59-0.71) and 0.68 (95% CI = 0.61-0.75), respectively. The overall sensitivity/specificity for NAFLD, NASH and fibrosis were 63% (57-70%)/83% (69-92%), 58% (51-65%)/68% (59-76%) and 54% (44-63%)/85% (75-92%), respectively. CK-18 correlated most strongly with ALT (r = 0.57, p <0.0001) and adipose tissue IR (insulin-suppression of FFA: r = -0.43; p <0.001), less with steatosis, lobular inflammation and fibrosis (r = 0.28-0.34, all p <0.001), but not with ballooning, BMI, metabolic syndrome or T2DM. Conclusions Plasma CK-18 has a high specificity for NAFLD and fibrosis, but its limited sensitivity makes it inadequate as a screening test for staging NASH. Whether combined as a diagnostic panel with other biomarkers or clinical/laboratory tests may prove useful requires further study. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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