International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 33-41 http://medscipublisher.com/index.php/ijmms 34 kidney cyst formation and is frequently associated with liver cysts. These cysts, forming part of Polycystic Liver Disease (PLD), arise due to mutations in the PKD1 and PKD2 genes. PKD1 encodes polycystin-1, while PKD2 encodes polycystin-2, which function as a complex to regulate calcium signaling in biliary epithelial cells. Mutations in these genes disrupt ciliary function, leading to abnormal fluid secretion and cell proliferation in the bile ducts (Kataoka et al., 2021). Liver cysts in ADPKD are often asymptomatic but can cause complications such as hepatomegaly and biliary obstruction. Studies have shown that the severity of liver involvement correlates with specific mutation types. For example, truncating mutations in PKD1 are associated with larger cyst burdens compared to non-truncating mutations (Lee-Law et al., 2019). Gender differences also play a role, with estrogen being a major contributor to cyst proliferation, explaining why women often experience more severe liver manifestations (Chen et al., 2022). Emerging therapies targeting cAMP signaling pathways, such as the use of adenylyl cyclase inhibitors, show promise in reducing cyst growth and associated symptoms (Spirli et al., 2017). These treatments aim to slow disease progression, providing new hope for patients with severe ADPKD-associated PLD. 2.2 Isolated polycystic liver disease (PCLD) genes Isolated Polycystic Liver Disease (PCLD) is genetically distinct from ADPKD and involves mutations in genes like PRKCSH, SEC63, and LRP5, which are essential for protein folding and trafficking in the endoplasmic reticulum. Unlike ADPKD, PCLD typically manifests with liver cysts only and lacks significant renal involvement. Mutations in GANAB and ALG8 have also been implicated, contributing to defective glycosylation and maturation of polycystin-1 (Besse et al., 2017). A key mechanism in PCLD is the “second-hit hypothesis”, where somatic mutations in cystic tissue exacerbate cystogenesis. Loss of heterozygosity in affected cells leads to uncontrolled proliferation and fluid secretion, driving cyst growth (Wills et al., 2016). Interestingly, the prevalence and severity of PCLD vary across populations, with lower mutation frequencies in Asian populations compared to European cohorts (Masyuk et al., 2017; Wang et al., 2020). Research on PCLD has identified molecular pathways involving the Wnt signaling cascade and ciliary dysfunction, providing targets for pharmacological interventions. Experimental treatments include ER stress modulators and small-molecule inhibitors to suppress cyst progression (Ellis et al., 2022). 2.3 Emerging genetic insights Recent advancements in genomics have broadened our understanding of the genetic underpinnings of liver cysts. Whole-exome sequencing has uncovered new mutations in genes such as PKHD1 and ALG9, further linking defective glycoprotein biogenesis with cystogenesis (Masyuk et al., 2018; Barten et al., 2020). Novel models of hepatic cystogenesis, such as those involving zebrafish, have highlighted the role of ER stress and mTOR signaling pathways in disease progression (Ellis et al., 2022). These studies have emphasized the importance of cellular homeostasis in biliary cells, where disruptions in cytoskeletal organization and bile duct morphogenesis initiate cyst formation. Furthermore, insights into hormonal influences and the expression of proteins like aquaporin-1 in cystic cholangiocytes have revealed potential therapeutic targets for modulating fluid secretion into cysts (Li et al., 2015). These discoveries pave the way for precision medicine approaches, tailored to genetic and phenotypic variations in liver cyst disorders. 3 Clinical Significance of Liver Cysts 3.1 Symptomatology and disease progression Liver cysts encompass a spectrum of presentations, ranging from asymptomatic lesions to those causing severe morbidity. Simple liver cysts are often incidental findings during imaging studies and remain asymptomatic in most cases. However, in Polycystic Liver Disease (PLD), which often accompanies Autosomal Dominant Polycystic Kidney Disease (ADPKD), symptoms arise from the progressive enlargement of cysts, leading to hepatomegaly, abdominal distension, and discomfort (Giuliani et al., 2015).
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