Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies

Abstract

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP-other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations. (Hepatology Communications 2018;2:515-528).

Figures

Figure 1

Timeline of surgeries in patients receiving IE. Of 6 patients who underwent IE, 3 (patient numbers 3, 4, and 6, spread across gene and mutation categories) remained with IE for ≥4 years. Of the remaining 3, 2 (patient numbers 3 and 5) proceeded to PEBD or LTX within 6‐7 months and the third (patient number 1) had a short follow‐up time. A brief summary of outcomes for each patient follows, incorporating available information: For patient 1, partial improvement in pruritus was reported but follow‐up time was short. For patient 2, incomplete response to IE was reported and improvement was noted after PEBD was performed. sBAs were normal for a time after IE in patient 3, but this patient experienced complications (recurrent cholangitis, pancreatitis, pain, weight loss, requirement for total parenteral nutrition) as well as worsening cholestasis and jaundice and was ultimately referred for LTX. For patient 4, sBA normalized after IE and remained normal at the last available testing date, >3.5 years after IE; some pruritus was reported, and the patient was on ursodeoxycholate. Patient 5 was referred for LTX soon after IE. For patient 6 post‐IE, minimal pruritus was reported and sBA demonstrated a sustained improvement of >50% (although remaining elevated).

Figure 2

Probability of survival without a poor outcome after PEBD, by mutation group. Patients were followed from PEBD to the first poor outcome (progression to cirrhosis, listing for or receiving a liver transplant, or dying) or last follow‐up. Number at risk reflects the number of patients remaining at risk for a poor outcome at each time point.

Figure 3

Comparison of growth before and after LTX. As with http://onlinelibrary.wiley.com/doi/10.1002/hep4.1168/full, patients' growth was binned into three categories: ≥10th percentile, 3rd‐10th percentile, and <3rd percentile. The categories in the graphs are as follows: patient already ≥10th percentile prior to surgery and remained in that category post‐LTX; patient growth improved by one to two categories post‐LTX; patient growth remained in the same category after LTX; patient growth category worsened post‐LTX.