In severe alcoholic hepatitis, serum cytokeratin-18 fragments are diagnostic, prognostic and theragnostic biomarkers

Atkinson, Stephen R.; Grove, Jane I.; Liebig, Stephanie; Astbury, Stuart; Vergis, Nikhil; Goldin, Robert; Quaglia, Alberto; Bantel, Heike; Neil Guha, Indra; Thursz, Mark R.; Newcombe, Paul; Strnad, Pavel; Aithal, Guruprasad P.

Abstract

INTRODUCTION:

Up to 40% of patients with severe alcoholic hepatitis (AH) die within 6 months of presentation, making prompt diagnosis and appropriate treatment essential. We determined the associations between serum keratin-18 (K18) and histological features, prognosis, and differential response to prednisolone in patients with severe AH.

METHODS:

Total (K18-M65) and caspase-cleaved K18 (K18-M30) were quantified in pretreatment sera from 824 patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (87 with suitable histological samples) and disease controls.

RESULTS:

K18 fragments were markedly elevated in severe AH and strongly predicted steatohepatitis (alcoholic steatohepatitis) on biopsy (area under receiver operating characteristics: 0.787 and 0.807). Application of published thresholds to predict alcoholic steatohepatitis would have rendered biopsy unnecessary in 84% of all AH cases. K18-M30 and M65 were associated with 90-day mortality, independent of age and Model for End-stage Liver Disease score in untreated patients. The association for K18-M65 was independent of both age and Model for End-stage Liver Disease in prednisolone-treated patients. Modelling of the effect of prednisolone on 90-day mortality as a function of pretreatment serum K18 levels indicated benefit in those with high serum levels of K18-M30. At low pretreatment serum K18 levels, prednisolone was potentially harmful. A threshold of K18-M30 5 kIU/L predicted therapeutic benefit from prednisolone above this level (odds ratio: 0.433, 95% confidence interval: 0.19–0.95, P = 0.0398), but not below (odds ratio: 1.271, 95% confidence interval: 0.88–1.84, P = 0.199). Restricting prednisolone usage to the former group would have reduced exposure by 87%.

DISCUSSION:

In a large cohort of patients with severe AH, serum K18 strongly correlated with histological severity, independently associated with 90-day mortality, and predicted response to prednisolone therapy. Quantification of serum K18 levels could assist in clinical decision-making.

Citation

Atkinson, S. R., Grove, J. I., Liebig, S., Astbury, S., Vergis, N., Goldin, R., Quaglia, A., Bantel, H., Neil Guha, I., Thursz, M. R., Newcombe, P., Strnad, P., & Aithal, G. P. (2020). In severe alcoholic hepatitis, serum cytokeratin-18 fragments are diagnostic, prognostic and theragnostic biomarkers. American Journal of Gastroenterology, 115(11), 1857-1868. https://doi.org/10.14309/ajg.0000000000000912

• Journal Article Type: Article
• Acceptance Date: Jun 19, 2020
• Online Publication Date: Oct 1, 2020
• Publication Date: 2020-11
• Deposit Date: Jun 21, 2020
• Publicly Available Date: Oct 2, 2021
• Journal: American Journal of Gastroenterology
• Print ISSN: 0002-9270
• Electronic ISSN: 1572-0241
• Publisher: Lippincott, Williams & Wilkins
• Peer Reviewed: Peer Reviewed
• Volume: 115
• Issue: 11
• Pages: 1857-1868
• DOI: https://doi.org/10.14309/ajg.0000000000000912
• Public URL: https://nottingham-repository.worktribe.com/output/4692935
• Publisher URL: https://journals.lww.com/ajg/Fulltext/2020/11000/In_Severe_Alcoholic_Hepatitis,_Serum_Keratin_18.21.aspx