Introduction

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease affecting the biliary epithelium, leading to bile duct strictures and eventually cirrhosis. Liver fibrosis is a well-established predictor of disease outcome in PSC. The Enhanced Liver Fibrosis (ELF) test, which combines three direct serum markers—hyaluronic acid (HA), tissue inhibitor of metalloproteinases-1 (TIMP-1), and amino-terminal pro-peptide of type III pro-collagen (PIIINP)—has been shown to correlate with the Ishak staging of liver histology in PSC. Both the ELF score and its individual components demonstrate moderate diagnostic accuracy in distinguishing advanced fibrosis (AUROC 0.73–0.78) and cirrhosis (AUROC 0.73–0.81) [1].
However, liver fibrosis and cirrhosis in PSC develop as secondary consequences of bile duct strictures and therefore represent late-stage indicators of disease progression. We have previously shown that biliary levels of calprotectin and interleukin-8 (IL-8) can help identify patients at higher risk of developing bile duct strictures. Moreover, our findings indicated that commonly used liver function tests, particularly plasma alkaline phosphatase (P-ALP), lack both sensitivity and specificity for effectively monitoring PSC progression [2].

Aims & Methods

To study: 1) the association of ELF with ERC-score, 2) the predictive value of ELF for bile duct disease progressio assessed by ≥2 increase in ERC score or need for dilatation, 3) the role of ELF-test to predict the overall disease outcome.
We included patients from Helsinki PSC-registry with ELF determined at least once, and ≥2 ERC examinations. End of f/u was 31.12.23. ERC -score was determined as described earlier [3]. ELF ≥9.8 was used as a marker for advanced liver fibrosis.

Results

In total, we included 397 patients. Demographics, laboratory results, and outcomes stratified by ELF levels, are presented in the table. Increase of ERC-score did not differ between groups, but the score at baseline associated with ELF-test (p<0.001). Progression of PSC assessed by increase of ERC score≥2 or dilatation did not correlated with ELF-levels (p=0.11), but ln[P-hyaluronic acid] showed close association with progression of bile duct changes (p<0.001). The probability for LTx increased in a linear way with the increase of ELF-level. (<0.001).

Variables	ELF ≤9.8 N=310	ELF 9.8-11.2 N=62	ELF ≥11.3 N=25	p for linearity
Person years. [Median (IQR) of person years]	2181 [5.6(3.5,11.8)]	414 [5.6(3.5,11.8)]	82 [2.5(1.3,3.8)]	-
PSC duration, mean (SD), years	6.9(5.8)	8.8(6.0)	11.2(8.1)	<0.001
AOM, mean (SD)	1.39(0.46)	1.83(0.56)	2.49(0.67)	<0.001
P-ALP, U/l, median (IQR)	94(74,135)	168(107,250)	317(203,438)	<0.001
P-Bil, µmol/l, median (IQR)	11(8,17)	13(9,18)	29(17,48)	<0.001
Biliary calprotectin, mg/l, median (IQR)	1.3(0.2,15.8)	13.4(0.9,71.0)	22.4(9.1,133.0)	<0.001
Increase of ERC score ≥2, n(%)*	35(11)	9(15)	4(16)	0.35
Increase of ERC score≥2 or dilatation, n(%)*	142(46)	40(65)	20(80)	<0.001
CCA, HCC, GBCA, Death, LTx (Incidence (95% CI), [no])**	15(10 to 21), [32]	60(39 to 89), [25]	220(30 to 347), [18]	<0.001

* Adjusted linearity for age, sex, PSC duration, intra-and extrahepatic disease,and ERC-score at baseline
** per 1000 pyrs. Adjusted for age, sex, PSC duration, intra-and extrahepatic disease.
Abbreviations: AOM, Amsterdam-Oxford model; CCA, cholangiocarcinoma, GB-CA, gallbladder carcinoma; LTx, liver transplantation.

Conclusion

The ELF test correlates with the severity of bile duct disease and the risk of liver transplantation, but it is not suitable for assessing the progression of bile duct changes based on sequential ERC examinations. The role of hyaluronic acid as a surrogate marker of bile duct changes deserves further studies.

References

[1] Thorburn DT et al. Hepatology Communications 2024;8(7):e0467, [2] Färkkilä M et al. JHEP Rep. 2024 Jul 2;6(10):101161, [3] Boyd S, et al. Endoscopy. 2016;48:432-9.