Liver & intrahepatic bile ducts

• Ductal plate is a layer of hepatoblasts (multipotent liver progenitor cells) that envelops portal vein branches and accompanies them as they spread through liver (beginning at hilum) during embryonic development (Anat Rec (Hoboken) 2008;291:628)
  • From ~12 weeks of gestation onward, ductal plate remodels and forms intrahepatic biliary tree
• Ductal plate malformation
  • Aberrant remodeling or lack of remodeling of ductal plate
  • Defects in biliary precursor cell differentiation, maturation of primitive bile ducts and abnormal bile duct enlargement (Nat Rev Gastroenterol Hepatol 2014;11:750)
  • Can lead to persistence of primitive duct structures
• Abnormal dilation of intrahepatic ducts leading to biliary cystic formation in polycystic liver disease (Orphanet J Rare Dis 2014;9:69)
  • Abnormalities in signaling function of cholangiocyte cilia (Annu Rev Pathol 2022;17:251)
  • Enhanced cholangiocyte proliferation and fluid secretion (Nat Rev Gastroenterol Hepatol 2014;11:750)
  • Cysts become detached from biliary tree as disease progresses
  • May arise from cystic dilation of biliary ducts in biliary hamartomas (von Meyenburg complexes)

• Cystic dilation of intrahepatic biliary tree related to ductal plate malformation (see Pathophysiology section)
• In adults, most frequently associated with autosomal dominant polycystic kidney disease (ADPKD)
  • ~80 - 85% due to mutations in PKD1 gene (encoding polycystin 1, PC1) (Adv Anat Pathol 2005;12:126, Adv Chronic Kidney Dis 2010;17:118)
  • ~15% due to mutations in PKD2 gene (encodes polycystin 2, PC2) (Annu Rev Pathol 2022;17:251)
  • Remaining small percentage of cases due to mutations in GANAB, LRP5, DNAJB11, ALG9 (Eur J Med Genet 2021;64:104160)
  • PC1 and PC2 form a heterodimeric plasma membrane channel with roles in regulation of tubular morphology, cell proliferation, migration and differentiation (Nat Cell Biol 2005;7:1202, J Med Genet 2003;40:311)
• Isolated polycystic liver disease (PCLD) / autosomal dominant polycystic liver disease (ADPLD)
  • Occurs independently from renal cystic disease (Clin Genet 1986;30:29)
  • Mutations in PRKCSH gene encoding hepatocystin (Hepatology 2004;39:924, Nat Genet 2003;33:345, Am J Hum Genet 2003;72:691)
  • Mutations in SEC63 gene encoding Sec63p (Nat Genet 2004;36:575)
  • Mutation in LRP5 gene encoding LRP5 transmembrane protein (Proc Natl Acad Sci U S A 2014;111:5343)
• Other rare syndromes can also be associated with polycystic liver disease
  • Nephronophthisis (Am J Med Genet C Semin Med Genet 2009;151C:296)
  • Congenital disorders of glycosylation (J Pediatr Gastroenterol Nutr 2021;73:444)

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Contributed by Alexander Kikuchi, M.D., Ph.D.

Contributed by Alexander Kikuchi, M.D., Ph.D. and Debra L. Zynger, M.D.

A 35 year old woman is found to have numerous liver cysts on imaging and the above is seen on partial hepatectomy. This finding is most likely seen in which disease process?

1. Autosomal dominant polycystic kidney disease
2. Cholangiocarcinoma
3. Congenital hepatic fibrosis
4. Endometriosis
5. Mucinous cystic neoplasm

A. Autosomal dominant polycystic kidney disease. The finding in the image shows multiple benign simple cysts of varying sizes, each with bland biliary epithelial lining. The finding is consistent with polycystic liver disease. Polycystic liver disease in adults can rarely occur in isolation but is most frequently associated with autosomal dominant polycystic kidney disease, driven by mutations in PKD1 and PKD2. Answer B is incorrect because cholangiocarcinoma is typically composed of small, irregular, infiltrative biliary glands with associated desmoplastic stroma. Large duct cholangiocarcinomas can be composed of some larger glands histologically resembling cysts but these are typically associated with mucin production and demonstrate greater degree of cytomorphologic atypia and architectural complexity than the enlarged simple cysts in this image. Answer C is incorrect because congenital hepatic fibrosis is a form of ductal plate malformation affecting predominantly children and adolescents and is characterized by irregular ductal structures and prominent periportal fibrosis rather than frank biliary cyst formation. Answer D is incorrect because endometriosis is characterized by glands lined by pseudostratified, columnar proliferative type endometrium and underlying spindled, ovarian type stroma. Answer E is incorrect because mucinous cystic neoplasm (MCN) is characterized by areas of ovarian type stroma in the cyst wall underlying the cystic epithelial lining. Additionally, the radiologic description of numerous cysts is uncharacteristic of MCN, which typically manifests as a solitary cyst (although this can be multiloculated).

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Reference: Polycystic liver disease