Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: A multicenter validation study

Feldstein, Ariel E.; Więckowska, Anna; López, Rocío; Liu, Yao-Chang; Zein, Nizar N.; McCullough, Arthur J.

doi:10.1002/hep.23050

Cited by 624 publications

(558 citation statements)

References 41 publications

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“…Methods such as ranked assessment (classifying as better, worse, or unchanged), or a truly quantitative measurement of the area of fibrosis by micromorphometry could be useful especially in early phase trials. Importantly, biomarkers for each cardinal feature of steatohepatitis [56][57][58][59][60][61][62] need to be developed and validated for longitudinal changes on therapy.…”

Section: Lessons For the Design Of Future Clinical Trialsmentioning

confidence: 99%

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

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Section: Lessons For the Design Of Future Clinical Trialsmentioning

confidence: 99%

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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“…[9][10][11][12][13][14][15][16] 21,22 Our previous study revealed that M30 has high overall accuracy in differentiating NAFLD from control subjects and moderate accuracy in differentiating NASH from simple steatosis. 20 Recent studies suggest that other cell death markers may also be useful in the prediction of NASH.…”

Section: Introductionmentioning

confidence: 99%

Assessment of non‐alcoholic fatty liver disease using serum total cell death and apoptosis markers

Shen

Chan

Wong

et al. 2012

Aliment Pharmacol Ther

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“…CK-18 is not an exclusively validated biomarker for AH but is a direct marker of hepatocyte apoptosis and, as such, probably should not be considered a diagnostic tool. (2) High levels of CK-18 has been most validated in patients with nonalcoholic steatohepatitis (versus simple steatosis) (3) and toxinassociated steatohepatitis. (4) Obese alcoholics with AH could have components of nonalcoholic steatohepatitis and AH working in tandem.…”

Section: To the Editormentioning

confidence: 99%

Plasma biomarkers to diagnose alcoholic hepatitis: Are we there yet?

Philips

Augustine

2017

Hepatology

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We read with interest the study by Bissonnette et al. (1) that was published recently in HEPATOLOGY. The authors attempted to fill the gap in noninvasive diagnosis of alcoholic hepatitis in a prospective study. They demonstrate that circulating fragments of cytokeratin-18 (CK-18), especially the M65 component, had good diagnostic performance for estimating the presence of alcoholic hepatitis (AH) among patients with clinical suspicion in a test and validation cohort. This was particularly true in patients without recent bacterial infection. They also concluded that analyzing CK-18 fragment levels could help avoid transjugular liver biopsy (TJLB) in two thirds of AH patients. CK-18 is not an exclusively validated biomarker for AH but is a direct marker of hepatocyte apoptosis and, as such, probably should not be considered a diagnostic tool. (2) High levels of CK-18 has been most validated in patients with nonalcoholic steatohepatitis (versus simple steatosis) (3) and toxinassociated steatohepatitis. (4) Obese alcoholics with AH could have components of nonalcoholic steatohepatitis and AH working in tandem. The current study does not shed light on this matter, hence the proposal of CK-18 fragments in noninvasive diagnosis of AH should remain a research tool. With an overall incidence of infections approaching approximately 50% in AH, the noninvasive utility of CK-18 becomes superficial. Discriminating primary liver insults (e.g., druginduced liver injury) among heavy drinkers versus AH still requires a liver biopsy for clarity. In the current study, the authors state that the proposed upper limit cutoffs for CK-18 M65 fragments had a low negative predictive value and that the diagnostic performance was much lower in the validation cohort in which the results were not reproducible using the proposed algorithm, and most patients underwent TJLB. Currently, TJLB is no longer a "cry for the moon," and most liver units have the expertise to implement it. On the contrary, performing advanced laboratory testing for CK-18 fragments requires more prowess with regard to research personnel, equipment, and costs and is less available at many centers. Diagnosing AH relies on astute history taking-including attention to drug history, careful biochemical interpretation, and histopathology-to be certain in cases where multiple insults or a mimic of AH is expected. CJ. Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer/polymer workers.

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Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: A multicenter validation study

Cited by 624 publications

References 41 publications

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

Assessment of non‐alcoholic fatty liver disease using serum total cell death and apoptosis markers

Plasma biomarkers to diagnose alcoholic hepatitis: Are we there yet?

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