Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis: an international registry study.

Huai Zhang; Rafael S Rios; Jerome Boursier; Rodolphe Anty; Wah-kheong Chan; Jacob George; Yusuf Yilmaz; Vincent Wai-sun Wong; Jiangao Fan; Jean-françois Dufour; George Papatheodoridis; Li Chen; Jörn M Schattenberg; Junping Shi; Liang XU; Grace Lai-hung Wong; Naomi F Lange; Margarita Papatheodoridi; Yuqiang MI; Yujie Zhou; Christopher D Byrne; Giovanni Targher; Gong Feng; Minghua Zheng

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Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis: an international registry study.

Author: Huai ZHANG ¹ ; Rafael S RIOS ² ; Jerome BOURSIER ³ ; Rodolphe ANTY ⁴ ; Wah-Kheong CHAN ⁵ ; Jacob GEORGE ⁶ ; Yusuf YILMAZ ⁷ ; Vincent Wai-Sun WONG ⁸ ; Jiangao FAN ⁹ ; Jean-François DUFOUR ¹⁰ ; George PAPATHEODORIDIS ¹¹ ; Li CHEN ¹² ; Jörn M SCHATTENBERG ¹³ ; Junping SHI ¹⁴ ; Liang XU ¹⁵ ; Grace Lai-Hung WONG ⁸ ; Naomi F LANGE ¹⁰ ; Margarita PAPATHEODORIDI ¹¹ ; Yuqiang MI ¹⁵ ; Yujie ZHOU ² ; Christopher D BYRNE ¹⁶ ; Giovanni TARGHER ¹⁷ ; Gong FENG ¹⁸ ; Minghua ZHENG ²
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1. Department of Biostatistics and Medical Record, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
2. Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
3. Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France.
4. Université Côte d'Azur, CHU, INSERM, U1065, C3M, 06204 Nice, France.
5. Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
6. Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.
7. Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey.
8. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China.
9. Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200000, China.
10. University Clinic for Visceral Surgery and Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
11. Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital, of Athens "Laiko", Athens, Greece.
12. Department of Gastroenterology, Ruijin Hospital, Shanghai 200000, China.
13. Metabolic Liver Research Program I, Department of Medicine, University Medical Center Mainz, Mainz, Germany.
14. The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, China.
15. Tianjin Second People's Hospital, Tianjin 300000, China.
16. Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK.
17. Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
18. Xi'an Medical University, Xi'an, Shaanxi 710000, China.
Publication Type:Journal Article
MeSH: Humans; Non-alcoholic Fatty Liver Disease/diagnosis*; Keratin-18; Biomarkers; Biopsy; Hepatocytes/pathology*; Apoptosis; Liver/pathology*
From: Chinese Medical Journal 2023;136(3):341-350
CountryChina
Language:English
Abstract: BACKGROUND:Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.
METHODS:Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL).
RESULTS:A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P < 0.001, P = 0.026 and P = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal.
CONCLUSION:This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.