The natural course of PFIC syndromes and the effect of diversion techniques, have so far not been characterized in a rigorous manner within a larger population of patients. In fact, the clinical or biochemical parameters which most directly define and/or predict the success of reduced enterohepatic circulation (either by surgical diversion or medically) are still unclear.
The present project aims to:
- Define the natural course of disease in patients with genetically defined FIC1 deficiency (PFIC1), BSEP deficiency (PFIC2), MDR3 deficiency (PFIC3) and other subtypes of the PFIC disease family (including e.g. Myo5B deficiency, TJP2 deficiency, a.o.), with respect to relevant biochemical and clinical parameters (and if available, histological). Included will be patients homozygous for a known, disease-causing mutation, patients compound homozygous for two disease-causing mutations or heterozygous for one disease-causing mutation in combination with the corresponding clinical phenotype .
- Define the change in the natural course of disease in response to biliary diversion surgery and or liver transplantation, based on short- and long(er)-term changes in biochemical (if available, histological) and clinical parameters, including outcome measures. Follow up after transplantation will be limited, follow up after surgical biliary diversion will be as long as possible.
- Assessment of biochemical variables as possible surrogate endpoints for clinical hard endpoints. If possible this allows for identification of low-risk to high-risk patients early during follow-up.
- If patient numbers permit, to establish genotype-phenotype relationships for the most common genetic mutations causing the indicated diseases.
Based on this project it is anticipated that the investigators are able:
- to characterize the variation in natural course of disease (whether or not genotype dependent) to allow clinicians to rationally select a target population for assessing the effect of medical intervention, rather than surgical biliary diversion);
- to identify and qualify one or more biomarkers that independently predict either improved or poor clinical outcomes of surgical biliary diversion;
- to investigate if the identified biomarker(s) can be used as surrogate end point(s) for assessing and predicting outcomes with novel interventional strategies.