Environmental Contribution to Pathogenesis of Cyst Formation in Autosomal-Dominant Polycystic Liver Diseases

Abstract

Dear Sir: We read with interest the paper by Janssen et al,1 which elegantly demonstrates that, among patients with polycystic liver disease (PCLD) carrying a heterozygous germline mutation in the PRKCSH gene, somatic mutations (second hits) are highly and widely detectable in the liver cyst epithelia with the loss of heterozygosity being the mechanism underling cyst formation through decreased hepatocystin expression in 67% of the cases. The authors conclude that autosomal-dominant PCLD is recessive at the cellular level and a loss of functional PRKCSH is an important step in cystogenesis. 1 Regarding the liver involvement, the autosomaldominantly inherited polycystic diseases PCLD and autosomal-dominant polycystic kidney disease (ADPKD) could be considered clinically homogeneous entities characterized by a massive liver derangement with multiple cysts, the severity being greater in women than in men and correlating with the number of pregnancies and estrogen use. 2,3 These observations are consistent with a role of estrogens in the development of PCLDs and support the similarity in the mechanism of liver cyst formation between ADPKD and PCLD.2 The recent findings by Janssen et al, together with several clinical observations, promote the need to elucidate the role of environmental factors in the phenotypic manifestations of inherited autosomal dominant PCLDs. Second somatic mutations underlie the liver cyst formation both in PCLD and in ADPKD, with the loss of heterozygosity being more frequent in PCLD.1,4 Posttrascriptional modifications of polycystins (PC) or hepatocystin could play a pivotal role in development and evolution of the PCLDs. Recently, we demonstrated that in cholangiocytes, 17-estradiol triggers PCs proteolysis associated with a proliferative cell response. 5 Estrogens are able to regulate several cell proteolytic complexes. Epithelium lining the hepatic cysts of patients with ADPKD showed a higher expression of receptors for estrogen and insulin-like growth factor 1 with respect to normal cholangiocytes and a strong proliferative response to estrogen administration. 3 This evidence provides a scientific basis for clinical observations that in