Biliary calprotectin, lactoferrin and dimeric pyruvate kinase after liver transplantation are markers for biliary damage and predict graft survival

Background & Aims:

Biliary complications are an important cause of mortality and morbidity after liver transplantation. Endoscopic management is the mainstay for biliary strictures complicating LT. The localization and etiology of the stricture is important for subsequent patient management and prognosis. The prognosis of anastomotic strictures is largely beneficial and they resolve upon repeat endoscopic intervention. By contrast non-anastomotic strictures are often related to increased donor ischemia time and reperfusion injury while in many patients none of these risk factors can be identified. They carry a dismal prognosis with almost inevitable graft failure and need for re-transplantation. A reliable biliary marker for the assessment of irreversible versus reversible biliary damage would be of great value for patient triage and early consideration for re-transplantation.

Patients & Methods:

A cohort of 111 patients with liver graft complications after LT, who received ERC during 2006 – 2014 was analyzed. Bile fluid was collected during first ERC after LT. The cohort comprised 23 controls, 7 CMV infections, 8 biopsy proven acute rejections (ACR), 20 anastomotic strictures (AS), 15 non-anastomotic strictures (NAS) and 26 ischemic type biliary lesions (ITBL). Biliary calprotectin, lactoferrin and dimeric pyruvate kinase was measured by ELISA. Biliary markers were correlated with regard to the primary endpoint of re-transplantation free survival.

Results:

Median calprotectin level in bile was 1426 pg/ml (range: 26 – 203100 pg/ml). Calprotectin was significantly higher in bile of ITBL and NAS compared to control, bile leakage, CMV infection, AS or ACR patients (p < 0.001) independent of serum liver values at ERC. Median biliary lactoferrin concentration was 153 pg/ml (range: 0 – 2714pg/ml). Lactoferrin was significantly higher in ITBL patients compared to the NAS (p < 0.05), AS or controls (p < 0.001). Median M2PK concentration was 296 pg/ml (range: 0 – 654pg/ml). Median M2PK values in ITBL were significantly higher compared to NAS (p < 0.05), AS (p < 0.01) and controls (p < 0.001). Calprotectin had the best predictive value for ERC diagnosed ITBL with an AUC of 0.838 at an optimal cutoff of > 3940 pg/ml for ITBL with a sensitivity of 81% and a specificity of 76%. Median re-LT-free-survival in the highest calprotectin and lactoferrin tertial was significantly reduced (24.5 months vs. not reached, p < 0.01 and 16.0 months versus not reached, p < 0.01). In multivariate analysis including age, gender, cold ischemia time, ERC radiographic classification of the biliary damage only biliary calprotectin (p = 0.02) and serum gGT (p = 0.03) were independent risk factors for reduced re-TL free survival.

Conclusion:

Calprotectin and lactoferrin are bile markers for biliary damage and predict re-transplantation free survival. They can differentiate progressive biliary damage from reversible biliary damage or non-biliary liver value alterations after LT.