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

Shen, Jiayun; Chan, Henry Lik‐Yuen; Wong, Grace Lai–Hung; Choi, Paul Cheung–Lung; Chim, Angel Mei‐Ling; Yeung, David W. K.; Yu, Jun; Chu, Winnie C.W.; Wong, Vincent Wai‐Sun

doi:10.1111/apt.12091

Cited by 64 publications

(52 citation statements)

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“…Among 69 patients classified as NASH in our study, 32 (46%) had NAS over 5 points. 2 While we agree with Miller and Dillon that the inclusion of less florid cases in the NASH group might lead to lower apparent diagnostic accuracy of the cytokeratin-18-based cell death biomarkers, the meaning of NAS deserves clarification. According to current guidelines, NASH is a histological diagnosis based on global features of hepatic steatosis, inflammation and hepatocyte ballooning.…”

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confidence: 77%

Commentary: assessment of non‐alcoholic fatty liver disease using serum total cell death and apoptosis markers – authors’ reply

Shen

Wong

2012

Aliment Pharmacol Ther

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We thank Miller and Dillon for their comments.1 Their first point was on the definition of non-alcoholic steatohepatitis (NASH) and whether some NASH patients might have non-alcoholic fatty liver disease activity score (NAS) below 5 points. Among 69 patients classified as NASH in our study, 32 (46%) had NAS over 5 points. 2While we agree with Miller and Dillon that the inclusion of less florid cases in the NASH group might lead to lower apparent diagnostic accuracy of the cytokeratin-18-based cell death biomarkers, the meaning of NAS deserves clarification. According to current guidelines, NASH is a histological diagnosis based on global features of hepatic steatosis, inflammation and hepatocyte ballooning. 3 In contrast, NAS is the unweighted sum of the scores of these 3 histological parameters. NAS was originally developed by the NASH Clinical Research Network (CRN) to assess treatment response in NASH trials. 4 However, since its introduction, many hepatologists have mistaken its meaning and used a cut-off of 5 points to diagnose NASH. A number of subsequent studies suggest that this approach is inappropriate. When pathologists from the NASH CRN reviewed the histology and clinical data of 976 adult NAFLD patients, only 75% of patients with definite NASH had NAS above 5, and at least 29% of patients with NAS below 5 had NASH. 5 In an independent study of 386 adult patients, NAS was again shown to have only moderate correlation with the diagnosis of NASH.6, 7Finally, we agree that one of the important roles of new biomarkers of NASH is to monitor disease activity over time because serial liver biopsies are unrealistic outside research setting. 8,9 Further studies should be conducted to evaluate the performance of biomarkers against serial biopsies. This will eventually reduce the need for liver biopsy and improve patient care. ACKNOWLEDGEMENTThe authors' declarations of personal and financial interests are unchanged from those in the original article.

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confidence: 77%

Commentary: assessment of non‐alcoholic fatty liver disease using serum total cell death and apoptosis markers – authors’ reply

Shen

Wong

2012

Aliment Pharmacol Ther

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“…Although the multicenter validation study published by Feldstein et al showed higher AUROC for prediction of NASH (0.83), most of recent studies demonstrated lower values ranging from 0.53 to 0.63 for NASH and 0.53 to 0.68 for fibrosis prediction(24) , (23) , (27). One possible explanation for this contradictory results is the different percentages of subjects with NASH among studies- 49% of our cohort had NASH, compared to just 19% of the previous validation cohort.…”

Section: Discussionmentioning

confidence: 95%

Poor Inter-test Reliability Between CK18 Kits as a Biomarker of NASH

et al. 2015

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Background and aims Non-alcoholic fatty liver disease (NAFLD) affects 15–40% of the general population, 10–20% of those patients have a more severe form of the disease known as non-alcoholic steatohepatitis (NASH). Cytokeratin-18 (CK18), released during apoptosis and one of the most studied biomarker in NASH, can be measured by a number of commercially available kits. We compared serum measurements of the CK18-M30 from 2 different kits using the same cohort to evaluate the reliability between 2 test kits. Methods We measured serum levels of CK18-M30 from 185 patients with biopsy-proven NAFLD from a single-center from 2009 to 2015, using 2 different ELISA kits, Test1 (T1) and Test2 (T2). Advanced fibrosis was defined as fibrosis stages 3–4 and NASH defined by NAS score≥5. Results Mean age was 50.2 years (SD 12.6), 61.1% male and 87% white; 49.6% had NASH and 32.2% advanced fibrosis. There was no significant correlation between measurements from the two kits (p=0.86, r=0.01). While T2 predicted NASH and advanced fibrosis, T1 did not. The area under ROC curve (AUROC) for the prediction of NASH was 0.631 for T2 vs. 0.500 for T1. Conclusions Measurements from two different CK18 M30 test kits did not correlate with each other. One kit showed statistically significantly higher levels of CK18-M30 in patients with advanced fibrosis and NASH while the other kit did not. With the increasing use of CK18 as a biomarker in NASH, it is important to standardize the different kits as it could greatly bias the results.

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“…However, it is important to note that this population consisted of a relatively small percentage of subjects with borderline NASH (19%) [7]. Subsequently, Shen et al reported that M30 had an AUROC of 0.66 for detecting NASH in a study population which consisted of a larger percentage of subjects with borderline NASH (49.7%) [12]. In our study population which consisted of a similar proportion of subjects with borderline NASH (52.7%), we similarly demonstrated that plasma M30 was less useful for distinguishing NAFLD subjects with NASH from those without NASH with an AUROC of 0.59.…”

Section: Discussionmentioning

confidence: 98%

Limited Utility of Plasma M30 in Discriminating Non-Alcoholic Steatohepatitis from Steatosis – A Comparison with Routine Biochemical Markers

et al. 2014

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IntroductionThe utility of Cytokeratin-18 fragment, namely CK18Asp396 (M30), for the diagnosis of non-alcoholic steatohepatitis (NASH) is currently uncertain. We aimed to provide further data in this area among multi-ethnic Asian subjects with NAFLD.Materials and MethodsThe accuracy of M30 for detecting NASH was compared with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (GGT) levels in consecutive adult subjects with biopsy-proven non-alcoholic fatty liver disease (NAFLD).ResultsData for 93 NAFLD subjects (mean age 51.0±11.1 years old and 51.6% males) and 20 healthy controls (mean age 50.2±16.4 years old and 33.3% males) were analyzed. There were 39 NASH subjects (41.9%) and 54 non-NASH subjects (58.1%) among the NAFLD subjects. Plasma M30 (349 U/L vs. 162 U/L), and serum ALT (70 IU/L vs. 26 IU/L), AST (41 IU/L vs. 20 IU/L) and GGT (75 IU/L vs. 33 IU/L) were significantly higher in NAFLD subjects than in healthy controls. Serum ALT (86 IU/L vs. 61 IU/L), AST (58 IU/L vs. 34 IU/L) and GGT (97 IU/L vs. 56 IU/L) were significantly higher in NASH subjects compared to non-NASH subjects, but no significant difference was observed with plasma M30 (435 U/L vs. 331 U/L). The accuracy of plasma M30, and serum ALT, AST and GGT was good for predicting NAFLD (AUROC 0.91, 0.95, 0.87 and 0.85, respectively) but less so for NASH (AUROC 0.59, 0.64, 0.75 and 0.68, respectively). Serum ALT and AST, but not plasma M30 showed a significant trend with increasing grades of ballooning and lobular inflammation.ConclusionThe utility of M30 in the detection of NASH in clinical practice appears limited, in comparison to routine biochemical markers.

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

Abstract: SUMMARY BackgroundThe diagnosis of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and fibrosis relies on liver biopsy. Non-invasive assessments are urgently needed.

Cited by 64 publications

References 40 publications

Commentary: assessment of non‐alcoholic fatty liver disease using serum total cell death and apoptosis markers – authors’ reply

Commentary: assessment of non‐alcoholic fatty liver disease using serum total cell death and apoptosis markers – authors’ reply

Poor Inter-test Reliability Between CK18 Kits as a Biomarker of NASH

Limited Utility of Plasma M30 in Discriminating Non-Alcoholic Steatohepatitis from Steatosis – A Comparison with Routine Biochemical Markers

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