title: Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  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.
authors: 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.
authors: Kenneth
authors: K
authors: Cusi
authors: Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States.
authors: Zhi
authors: Z
authors: Chang
authors: Brooke Army Medical Center, San Antonio, TX, United States.
authors: Steve
authors: S
authors: Harrison
authors: Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States.
authors: Romina
authors: R
authors: Lomonaco
authors: Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States.
authors: Fernando
authors: F
authors: Bril
authors: Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States.
authors: Beverly
authors: B
authors: Orsak
authors: Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States.
authors: Carolina
authors: C
authors: Ortiz-Lopez
authors: 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.
authors: Joan
authors: J
authors: Hecht
authors: Malcom Randall VAMC, Gainesville, FL, United States; Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Professor of Pediatrics, University of California San Diego, United States.
authors: Ariel E
authors: AE
authors: Feldstein
authors: 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.
authors: Amy
authors: A
authors: Webb
authors: Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio (UTHSCSA), United States.
authors: Christopher
authors: C
authors: Louden
authors: Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio (UTHSCSA), United States.
authors: Martin
authors: M
authors: Goros
authors: 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.
authors: Fermin
authors: F
authors: Tio
mesh_terms: D015415:Biomarkers / Q000097:blood; D005234:Fatty Liver / Q000097:blood* / Q000175:diagnosis / Q000473:pathology; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D053538:Keratin-18 / Q000097:blood*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood* / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D011237:Predictive Value of Tests
chemical_list: D015415:Biomarkers; D053538:Keratin-18
keywords: Cytokeratin-18; Diabetes; Fatty liver; Insulin resistance; NAFLD; NASH