Letters to the Editor
Alhammad et al (1) described central hyperplastic liver nodules in Alagille syndrome patients and Rougemont et al (2) proposed that vascular anomalies lead to the development of central liver nodules with intact bile ducts, while bile duct integrity is affected in the peripheral liver.
Based on our findings in the explant liver of an Alagille syndrome patient, we proposed that defects in postnatal bile duct branching and elongation lead to bile duct paucity in the peripheral liver, while normal bile ducts are present in the central portion (3). Our hypothesis was supported in an animal model (4).
Although bile duct paucity causes cholate statis in the liver periphery, intact bile ducts in the central portion prevent the accumulation of hepatotoxic bile salts (3). This leads to compensatory hyperplasia of the central liver, yielding the picture of a hyperplastic regenerative nodule. This hyperplasia will be associated with changes in the vasculature, so we propose that the vascular anomalies are secondary to the biliary anomalies and not vice versa.
We speculate that the growth advantage in the central liver can lead to the development of hepatocellular carcinoma. It has been shown in transgenic mouse models that hepatocellular carcinoma arises from liver nodules resistant totoxic products in these models (5,6). Wetli et al (7) described hepatocellular carcinoma next to a central regenerating nodule. Because our suggestion is currently speculative, we propose that extra attention should be paid to the relative location of hepatocellular carcinomas and regenerative liver nodules in Alagille syndrome.
1. Alhammad A, Kamath BM, Chami R, et al. Solitary hepatic nodule adjacent to the right portal vein: a common finding of Alagille syndrome? J Pediatr Gastroenterol Nutr
2. Rougemont AL, McLin VA. Central liver nodules in Alagille syndrome and biliary atresia after Kasai portoenterostomy. J Pediatr Gastroenterol Nutr
3. Libbrecht L, Spinner NB, Moore EC, et al. Peripheral bile duct paucity and cholestasis in the liver of a patient with Alagille syndrome: further evidence supporting a lack of postnatal bile duct branching and elongation. Am J Surg Pathol
4. Sparks EE, Huppert KA, Brown MA, et al. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology
5. Sandgren EP, Palmiter RD, Heckel JL, et al. DNA rearrangement causes hepatocarcinogenesis in albumin-plasminogen activator transgenic mice. Proc Natl Acad Sci U S A
6. Demers SI, Russo P, Lettre F, et al. Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia. Hum Pathol
7. Wetli S, Gralla ES, Schibli S, et al. Hepatocellular carcinoma and regenerating nodule in a 3-year-old child with Alagille syndrome. Pediatr Radiol