Article

Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease.

Department of Clinical Medicine, University of Rome Sapienza, via R. Rossellini 51, 00137 Rome, Italy. domenico.alvaro@uniroma1
American Journal Of Pathology (Impact Factor: 4.6). 02/2008; 172(2):321-32. DOI: 10.2353/ajpath.2008.070293
Source: PubMed

ABSTRACT We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [(3)H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1- to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-fold more enriched in the hepatic cyst fluid than in serum. Serum-deprived liver cyst-derived epithelial cells proliferated when exposed to 17beta-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17beta-estradiol, and IGF1. Our findings could explain the role of estrogens in accelerating the progression of ADPKD and may suggest a potential benefit of therapeutic strategies based on estrogen antagonism.

0 Followers
 · 
109 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications. Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ. Renal failure due to polycystic kidneys and non-renal extra-hepatic features are common in ADPKD in contrast to VMC and PCLD. In general, liver function remains prolonged preserved in PLD. Ultrasonography is the first instrument to assess liver phenotype. Indeed, PCLD and ADPKD diagnostic criteria rely on detection of hepatorenal cystogenesis, and secondly a positive family history compatible with an autosomal dominant inheritance pattern. Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics. Screening mutations of the genes causing PCLD (PRKCSH and SEC63) or ADPKD (PKD1 and PKD2) confirm the clinical diagnosis. Genetic studies showed that accumulation of somatic hits in cyst epithelium determine the rate-limiting step for cyst formation. Management of adult PLD is based on liver phenotype, severity of clinical features and quality of life. Conservative treatment is recommended for the majority of PLD patients. The primary aim is to halt cyst growth to allow abdominal decompression and ameliorate symptoms. Invasive procedures are required in a selective patient group with advanced PCLD, ADPKD or liver failure. Pharmacological therapy by somatostatin analogues lead to beneficial outcome of PLD in terms of symptom relief and liver volume reduction.
    Orphanet Journal of Rare Diseases 05/2014; 9(1):69. DOI:10.1186/1750-1172-9-69 · 3.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatic stem/progenitor cells (HPCs) are stem cells residing in the most peripheral branches of the biliary tree; these cells are able to differentiate towards mature hepatocyte or mature cholangiocyte; moreover in normal conditions, they are mostly quiescent cells. HPC activation has been involved in the progression of chronic parenchymal diseases (chronic viral hepatitis) and chronic biliary diseases (such as Primary Biliary Cirrhosis: PBC) and in the occurrence of intrahepatic cholangiocarcinoma. The HPCs participate in the repair of liver damage either through the replacement of dead cells or by driving fundamental repair processes, including fibrosis and angiogenesis. Little information exists regarding the expression of VEGF by HPC in the course of liver non-malignant pathologies. In this study, we evaluated: (I) the presence of HPCs in PBC and HCV-related Cirrhosis (HCV-C) samples, and (II) the expression of VEGFs and VEGF-Rs in PBC and HCV-C samples. Our results showed (I) PBC samples presented a more extensive expansion of HPC population in comparison with those of HCV-C samples; (II) PBC samples showed a more extensive angiogenesis if compared to HCV-C; and (III) PBC samples were characterized by an increased expression of VEGF-A and VEGF-C if compared to HCV-C and the number of HPCs expressing VEGFs was correlated with the extension of ductular reaction and angiogenesis. The role of VEGFs in the expansion of HPC niche could have important implication in the management of fibrogenic processes and carcinogenesis.
    04/2013; 2(2):68-77. DOI:10.3978/j.issn.2304-3881.2012.10.11
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases.

Full-text (2 Sources)

Download
59 Downloads
Available from
May 19, 2014