Polycystic liver disease: New insights into disease pathogenesis

Polycystic kidney (PCK) rats exhibit a multiorgan cyst pathology similar to human autosomal recessive polycystic kidney disease, and are proposed as an animal model of Caroli's disease with congenital hepatic fibrosis (CHF). This study investigated the expression and function of selected components of the mitogen activated protein kinase (MAPK) pathway in cultured intrahepatic biliary epithelial cells (BECs) of PCK rats. Compared to the proliferative activity of cultured BECs of control rats, those of the PCK rats were hyperresponsive to epidermal growth factor (EGF). The increase in BEC proliferation was accompanied by overexpression of MAPK/extracellular signal-regulated protein kinase (ERK) kinase 5 (MEK5), and subsequent phosphorylation of ERK5 in vitro. The increased proliferative activity was significantly inhibited by the transfection of short interfering RNA against MEK5 mRNA. An EGF receptor tyrosine kinase inhibitor, gefitinib ("Iressa", ZD1839), also significantly inhibited the abnormal growth of cultured BECs of PCK rats. By contrast, treatment with PD98059 and U0126, inhibitors for MEK1/2, was less effective. These results suggest that the activation of the MEK5-ERK5 cascade plays a pivotal role in the biliary dysgenesis of PCK rats, and also provide insights into the pathogenesis of Caroli's disease with CHF. As the MEK5-ERK5 interaction is highly specific, it may represent a potential target of therapy.

We studied the sonographic findings and the changes in renal function seen on long-term follow-up of children who had the initial diagnosis of autosomal recessive polycystic kidney disease made in the neonatal period. The case records and sonograms of 14 children with biopsy evidence of autosomal recessive polycystic kidney disease were evaluated. Nine children who survived the neonatal period were followed up for a mean of 13 years (range, 5-19 years) after diagnosis and form the basis of this study. Serial changes in renal size, echogenicity, and function were assessed sonographically. The imaging findings were compared with those described in published reports. The sonographic findings showed that five of the nine children had a decrease in renal size, and three had stable renal size over a minimum follow-up period of 5 years. Only one of the nine survivors showed progressive increase in renal size. All had increased cortical echogenicity and large kidneys. Three patients showed a subjective change in renal echogenicity over time. A change in the echogenic pattern to one that resembles autosomal dominant polycystic kidney disease was noted with no evidence of increase in size of the kidneys. None of the surviving children had renal stones or massively enlarged kidneys. The renal function of seven of the nine survivors has remained stable with creatinine clearance nearly normal (> 60 ml/min/1.73 m2), and there was no correlation between renal size and renal function. In patients with autosomal recessive polycystic kidney disease who survive the neonatal period, kidney size as seen on sonograms does not continue to increase despite the patients' linear growth and maintained normal renal function. Rather, a decrease in kidney size and change in echogenicity occurs, producing a pattern that is similar to that seen on sonograms of patients with autosomal dominant polycystic kidney disease but without the marked increase in kidney size that occurs in that entity. This changing cystic pattern on follow-up sonograms may be the reason that previous descriptions of the sonographic findings in cases of autosomal recessive polycystic kidney disease have varied and why a decrease in size may not herald deteriorating renal function.