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. 2019 Jun 11;9(1):8450.
doi: 10.1038/s41598-019-44762-7.

Autotaxin activity predicts transplant-free survival in primary sclerosing cholangitis

Amandeep K Dhillon  1   2   3 , Andreas E Kremer  4 , Martin Kummen  1   2   3 , Kirsten M Boberg  1   2   5 , Ronald P Oude Elferink  6 , Tom H Karlsen  1   2   3   5 , Ulrich Beuers  6 , Mette Vesterhus  1   7   8 , Johannes R Hov  9   10   11   12
Affiliations

Autotaxin activity predicts transplant-free survival in primary sclerosing cholangitis

Amandeep K Dhillon et al. Sci Rep. .

Abstract

Autotaxin has been associated with liver disease severity and transplant-free survival. This study aimed to validate autotaxin as a biomarker in two cohorts of Norwegian large-duct PSC patients, one discovery panel (n = 165) and one validation panel (n = 87). Serum activity of autotaxin was measured in diluted sera by a fluorometric enzymatic assay. Patients reaching an end-point, liver transplantation or death, (discovery panel: n = 118 [71.5%]; validation panel: n = 35 [40.2%]), showed higher autotaxin activity compared with the other patients, P < 0.001 and P = 0.004, respectively. Kaplan-Meier survival analyses showed a strong association between increasing autotaxin activity and shorter liver transplant-free survival (discovery panel: P < 0.001, validation panel: P = 0.001). There was no relationship between autotaxin activity and the presence of inflammatory bowel disease or occurrence of hepatobiliary malignancy. In a multivariable analysis, high autotaxin activity was associated with an increased risk of liver transplantation or death (hazard ratio 2.03 (95% confidence interval 1.21-3.40), P < 0.01), independent from Mayo risk score, an in-house enhanced liver fibrosis score and interleukin-8 in serum. In conclusion, increased serum autotaxin activity is associated with reduced liver transplant-free survival independent from Mayo risk score and markers of inflammation and fibrosis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
High autotaxin levels are associated with poor prognosis. Autotaxin levels in PSC patients without/with end-point, in (a) the discovery panel and (b) validation panel. Autotaxin based liver transplant-free survival based on tertiles of autotaxin activity in (c) the discovery panel, and (d) the validation panel. Poorer prognosis in patients with high autotaxin activity levels (>7.5 nmol mL−1 min−1 as defined by Wunsch et al.), in (e) the discovery panel, P < 0.001, and (f) and validation panel, P < 0.001. ATX, autotaxin; PSC, primary sclerosing cholangitis. Data in (a) and (b) shown as median (min-max).
Figure 2
Figure 2
High autotaxin levels are associated with poor prognosis irrespective of liver synthesis function. (a) In the combined cohort, patients with impaired liver synthesis function (defined as INR ≥ 1.2 or Normotest < 70) showed higher autotaxin-levels compared to patients with normal liver synthesis function (INR < 1.2 or Normotest ≥ 70). (b) Survival curves for patients with normal and impaired liver synthesis function, separated by high/low autotaxin levels (>or ≤7.5 nmol mL−1 min−1 as defined by Wunsch et al.). ATX, autotaxin activity; INR, international normalized ratio. Data on INR and Normotest missing for n = 43 in the combined cohort. Data in (a) shown as median (max-min).
Figure 3
Figure 3
Relationship between autotaxin and markers of inflammation and fibrosis. (a) Scatterplot of autotaxin and the inflammation marker IL-8. (b) Scatterplot of autotaxin and an in-house ELF score. IL, interleukin; ELF, enhanced liver fibrosis.
Figure 4
Figure 4
Autotaxin and other established biomarkers in PSC. High autotaxin levels (>7.5 nmol mL−1 min−1 as defined by Wunsch et al.) are associated with poor survival in subgroups with both (a) low IL-8 values, and (b) high IL-8 values (divided by median). Similar, high autotaxin levels are associated with reduced liver transplant-free survival irrespective of (c) low ELF score or (d) high ELF-score (divided by median). ATX, autotaxin; ELF, enhanced liver fibrosis; IL, interleukin.
Figure 5
Figure 5
Comparison of autotaxin and other biomarkers in PSC. (a) Mayo risk score had a better ability to discriminate patients with and without liver transplantation or death during follow-up (AUC 0.81 vs. 0.66, P < 0.001), as had bilirubin (AUC 0.77 vs. 0.66, P < 0.001), while Mayo risk score and bilirubin were similar (P = 0.07). The same was apparent for the in-house ELF score (AUC 0.79, P < 0.001) but not IL-8 (AUC 0.71, P = 0.25) (panel b). AUC, area under the receiver operating characteristic curve; ELF, enhanced liver fibrosis; IL, interleukin; PSC, primary sclerosing cholangitis.
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