PRO-C3 and ADAPT Algorithm Accurately Identify Patients With Advanced Fibrosis due to Alcohol-related Liver Disease

Bjørn S. Madsen; Maja Thiele; Sönke Detlefsen; Maria Kjærgaard; Linda S. Møller; Jonel Trebicka; Mette J. Nielsen; Natasja Stæhr Gudmann; Diana J. Leeming; Morten A. Karsdal; Aleksander Krag;


Aliment Pharmacol Ther. 2021;54(5):699-708. 

In This Article

Abstract and Introduction


Background: Alcohol is a main cause of preventable deaths and frequently leads to the development of alcohol-related liver disease. Due to the lack of diagnostics, patients are commonly diagnosed after developing clinical manifestations. Recently, the biomarker PRO-C3 was shown to accurately identify fibrosis due to non-alcoholic fatty liver disease.

Aim: To assess the diagnostic accuracy of PRO-C3, the ADAPT score and best-performing non-patented serological test to detect advanced alcohol-related liver fibrosis.

Methods: We enrolled 426 patients with alcohol overuse in a prospective biopsy-controlled study. We evaluated the accuracy of PRO-C3 and the PRO-C3-based algorithm ADAPT to detect advanced liver fibrosis.

Results: The accuracy of PRO-C3 was good with an AUROC of 0.85 (95% CI 0.79–0.90). The best-performing non-patented test was the Forns index with an AUROC of 0.83 (95% CI 0.78–0.89). The ADAPT algorithm performed better as compared to both the Forns index and PRO-C3 alone with an AUROC = 0.88 (95% CI 0.83–0.93).

Conclusion: PRO-C3 is a new marker with high accuracy to detect advanced alcohol-related liver fibrosis. The diagnostic accuracy of PRO-C3 can be further improved by using the ADAPT algorithm in which the test outperforms currently available non-patented serological fibrosis markers. The study is registered in the Odense Patient Data Exploratory Network (OPEN) under study identification numbers OP_040 ( and OP_239 (


Prgressive fibrosis due to alcohol-related (ALD) and non-alcoholic fatty liver disease (NAFLD) is the core process leading to the development of cirrhosis and increasingly drives the development of end-stage liver disease and liver-related death in the Western world.[1] Due to the epidemic burden of alcohol overuse, the majority of patients are handled in the primary care setting in which assessment of liver fibrosis is rarely performed.[2,3] As a result, ALD is frequently diagnosed in a disease stage with advanced fibrosis and after developing clinical manifestations.[4] Standard liver function tests (LFT) are already widely used to assess liver injury by general practitioners, but these tests do not reflect the severity of fibrosis.[5] Adding an accurate fibrosis biomarker on top of the LFTs complements current clinical practice and bears the potential to enter clinical practice, as this strategy does not require implementation of new technology in the primary care setting. Liver biopsies are due to their small size prone to sampling errors and there is considerable intra- and interobserver disagreement when assessing the severity of fibrosis.[6] Serological markers may prove to be a more objective measurement of the global content of fibrosis in the liver in the future.[7] However, a biomarker to detect liver fibrosis, prognosticate patients and evaluate efficacy of interventions remains an unmet need.[8]

Type III collagen, one of the major scar tissue-related collagens, is highly upregulated during hepatic fibrogenesis.[9] PRO-C3, a systemic marker of type III collagen formation and fibroblast activity, has shown promising utility to detect fibrosis stage, progression rate and treatment response in patients with chronic liver disease.[10–13] Recently, it was demonstrated that both PRO-C3 alone and when incorporated in an algorithm, known as the ADAPT score, had high diagnostic accuracy to detect NAFLD-related advanced liver fibrosis.[14] In the aforementioned study, PRO-C3 had an AUROC of 0.81 (95% CI 0.74–0.87) for the detection of advanced fibrosis. Integrating PRO-C3 with the widely available parameters age, diabetes and platelets into the ADAPT score further increased the AUROC to 0.86 (95% CI 0.79–0.91). The potential of PRO-C3 and ADAPT to detect alcohol-related liver fibrosis (ALF) has not previously been evaluated. Despite similarities between NAFLD and ALD, there are differences in the morphology and the abundance of specific collagen types in the extracellular matrix (ECM), which may impact the performance of a fibrosis biomarker.[15,16] In the current study, we thus sought to validate the previous finding from NAFLD in the setting of ALD. More specifically, we wanted to (a) explore the association between PRO-C3 and ALF, (b) evaluate the accuracy of PRO-C3, the ADAPT score and best-performing non-patented serological test to detect advanced ALF and (c) evaluate the diagnostic performance of PRO-C3 to detect advanced ALF, in different subpopulations.