Kenneth Cusi1, Zhi Chang2, Steve Harrison3, Romina Lomonaco2, Fernando Bril2, Beverly Orsak2, Carolina Ortiz-Lopez2, Joan Hecht4, Ariel E Feldstein5, Amy Webb6, Christopher Louden7, Martin Goros7, Fermin Tio8. 1. Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States; Division of Diabetes, The University of Texas Health Science Center at San Antonio (UTHSCSA), United States; Audie L. Murphy Veterans Administration Medical Center (VAMC), San Antonio, TX, United States; Malcom Randall VAMC, Gainesville, FL, United States. Electronic address: kenneth.Cusi@medicine.ufl.edu. 2. Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States. 3. Brooke Army Medical Center, San Antonio, TX, United States. 4. Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States; Audie L. Murphy Veterans Administration Medical Center (VAMC), San Antonio, TX, United States. 5. Malcom Randall VAMC, Gainesville, FL, United States; Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Professor of Pediatrics, University of California San Diego, United States. 6. Division of Hepatology, The University of Texas Health Science Center at San Antonio (UTHSCSA), United States; Audie L. Murphy Veterans Administration Medical Center (VAMC), San Antonio, TX, United States. 7. Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio (UTHSCSA), United States. 8. Department of Pathology, The University of Texas Health Science Center at San Antonio (UTHSCSA), United States; Audie L. Murphy Veterans Administration Medical Center (VAMC), San Antonio, TX, United States.
Abstract
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.
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.
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