LAUSR

Dear Editor, In their study on regenerative liver nodules in Alagille syndrome, Rapp et al. [1] state that the pathogenesis of these nodules is unclear and might be related to geographical variability of the phenotyic expression of the JAG1 mutation. However, as we [2] and Rougemont et al. [3] previously showed, neither genetic mosaicism nor a variability in gene dosage effect can explain the presence of these nodules in the liver of Alagille patients. Both in patients [2] and animal models [4], there is ample evidence that normal embryonic and fetal bile duct development followed by defective postnatal bile duct branching and elongation lead to a healthy zone in the central liver with intact bile ducts surrounded by ductopenic and cholestatic liver and the development of central regenerative nodules. The histopathological images provided by Rapp et al. [1] are in line with this mechanism. While the pathogenesis of central regenerative liver nodules as such is clear, there was until recently no data on the frequency of such nodules in patients with Alagille syndrome. There are seven case reports or reports of very small series (five referred to byRapp et al. [1], our case report [2] and since the acceptance of the manuscript of Rapp et al. [1] another case report was published [5]), but the occurrence rate cannot be deduced from such studies. Therefore, Rapp et al. [1] have to be commended for using imaging techniques. Strikingly, both their study [1] as well as the recent study by Alhammad et al. [6], which is the only other study looking at the frequency of these nodules, reported that nodules were detected in 30% of patients (6/20 patients in the former study and 12/39 patients in the latter). Why the liver nodules are detected by imaging in only 1/3 of patients is unexplained and raises new questions regarding their origin and the pathogenesis of liver disease in Alagille syndrome in general. Do the patients without nodules represent a subtype of Alagille syndrome with a different and anomalous course of embryonic and fetal bile duct development or do they have nodules early in life that shrink for unknown reasons and thus remain undetected on imaging later in the course of the disease? A size decrease seems less likely since the healthy central nodule has a growth advantage compared to the diseased liver part. Interestingly, the median age of the 39 patients studied by Alhammad et al. [6] was 8 years, while the mean age of the group of 12 patients with liver nodules was 10 years. Further imaging studies performed during different time points in the course of the life of patients with Alagille syndrome might yield answers to the remaining questions regarding the pathogenesis and evolution of central liver nodules in these patients.