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


In this study, we measured PRO-C3 in a large cohort of patients suffering from the full spectrum of ALF. Our main findings were: (a) PRO-C3 was significantly associated with the degree of ALF, also after adjustment for a variety of parameters. (b) The diagnostic accuracy of PRO-C3 as a stand-alone marker to detect advanced ALF was good, but did not differ significantly when compared to the Forns index. (c) A high level of GGT was associated with increased risk of being wrongly classified as having advanced ALF and reduced the diagnostic accuracy of PRO-C3. (d) Combining PRO-C3 with available clinical parameters into the ADAPT score increased diagnostic accuracy to an excellent level in the total cohort and outperformed all non-patented serological fibrosis markers including the Forns index.

Our results validate the recent study based on NAFLD patients, that PRO-C3 and the ADAPT algorithm can be used to detect advanced liver fibrosis. In the previous study, the AUROC for identification of advanced liver fibrosis by PRO-C3 was 0.81 (95% CI 0.74–0.87) and increased to 0.86 (95% CI 0.79–0.91) by the ADAPT algorithm. Due to the epidemic in fatty liver disease from alcohol and obesity, there is, from a management point of view, a lack of biomarkers to rule out advanced fibrotic liver disease in a population with low disease prevalence. Interestingly, a PRO-C3 concentration below the threshold of 15.6 ng/ml almost abolished the risk of having advanced ALF and could potentially be used as a first diagnostic tool to rule out disease in the primary care setting.

We identified GGT as an independent risk factor for being falsely classified as having advanced ALF and GGT should be taken into account when interpreting PRO-C3. A high concentration of GGT likewise increased the risk of false-positive results when elastography was used to assess the degree of liver fibrosis.[21] The mechanism by which GGT affects diagnostic accuracy of PRO-C3 and elastography is not completely understood. A change in GGT probably reflects subtle alcohol-induced rearrangements in the hepatic parenchyma, leading to an increase in stiffness and/or release of ECM proteins into the blood stream, without a concurrent effect on the fibrosis stage.

Some limitation of the study should be mentioned. The optimal cut-off values for detecting advanced fibrosis were based on the NAFLD setting. Disease aetiology may impact ECM remodelling processes which could potentially impact the optimal cut-off values for PRO-C3.[22] However, fibrosis in the setting of NAFLD and ALD shares commonalities, as both diseases at an early stage lead to deposition of ECM in a perisinusoidal and pericellular (chicken wire) pattern.[23] Harmful alcohol consumption may coexist with and then impair the outcome of other prevalent chronic liver diseases including NAFLD.[24] Biomarkers and algorithms should have the robustness to identify liver fibrosis in patients with mixed clinical phenotypes, if they should translate into clinical practice. Difference in disease spectrum impacts the diagnostic accuracy of a test and complicates comparison between different cohorts.[25]

In conclusion, our results validate PRO-C3 as biomarker with high diagnostic accuracy to detect liver fibrosis. The diagnostic accuracy can be further increased by incorporating clinical and biochemical parameters into the ADAPT algorithm, which outperforms currently available non-patented serological fibrosis assessment markers.