Diagnostic Exercise From The Davis-Thompson Foundation*

Case #: 77 Month: February Year: 2017

Answer Sheet

Contributor: Catherine A. Picut, VMD, JD, DACVP, DABT, FIATP, Senior Staff Pathologist, Charles River- Pathology Associates, Durham, N.C.

Clinical History: This Sprague Dawley Rat (Cr1:CD(SD)) was 17 weeks old at the end of a 28-day study. This particular rat was from the adjuvant-control group and did not receive the test article. There were no clinical signs and the animal survived until scheduled sacrifice.

Morphologic diagnosis: Cystic tubular dilatation with fibrosis, severe, disseminated, kidney

Other organ likely affected: Liver (see additional microscopic images below, Figures 5-6)

Figure 5. Liver, H&E, 1.85x (left) and 10x (right) objective magnification. Note multiple saccular distention of bile ducts and the portal and bridging fibrosis associated with dilated bile ductules and

ducts.

Figure 6. Liver, H&E, 40x objective magnification. Note periportal fibrosis with multiple dilated bile ducts, each lined by plump cuboidal epithelium.

Cause: Genetic mutation

Etiologic diagnosis: Congenital polycystic kidney disease and Congenital intrahepatic biliary dilatation

with fibrosis

Name of this condition: Caroli’s Disease

Typical gross findings: Enlargement and multiple cysts in the kidney and liver

Typical microscopic findings: Cystic distention of renal tubules and bile ducts with associated

peritubular and periductular fibrosis, respectively.

Discussion: Congenital polycystic kidney disease with intrahepatic biliary dilatation and fibrosis is an

autosomal recessive condition in man known as Caroli’s disease or Caroli’s syndrome. This multi-organ

developmental disease has been described in the rat (Sanzen et al. 2001; Katsuyama et al. 2000; Bettino

et al. 2003), mouse (Moser et al. 2005), dog (Gorlinger et al. 2003) and goat (Hananch and Faizee 2014).

The malformation in the liver is due to impaired remodeling of the fetal ductal plate (the precursor of

the intrahepatic biliary system) and is commonly associated with portal fibrosis. The underlying lesion in

the liver is a ductal plate malformation, and bile ducts are more numerous than usual. A similar

deranged epithelial-mesenchymal tissue induction occurs in the kidney leading to malformation and

cystic distention of renal tubules. The pathogenesis of this multi-organ syndrome is likely related to

fibrocystin, which is a large protein encoded by the polycystic kidney and hepatic disease 1 (PKHD1) gene

(Menezes and Onuchic, 2006).

In rats, enlargement and cysts of the liver and kidney are grossly observed at 3 weeks of age with

increase in severity and progression of the lesion (i.e., larger cysts and fibrosis) up to 4 months of age.

The renal cysts begin at the corticomedullary junction and expand into the cortex, generally sparing the

renal papillae and glomeruli. The cysts in the liver are confined to the liver, but distention of the

extrahepatic bile duct is possible. Elevation of serum chemistry parameters is variable. In this particular

case presentation, the liver and kidney weights of the affected rat were higher than those weights of

other control rats, and mild elevation of BUN was the only clinical pathology finding. Inflammation may

co-exist in the periportal regions and in the affected kidneys, but the inflammation is secondary.

Occasional intratubular granular casts were present in the kidney of this case.

In human cases of Caroli’s syndrome, dilated bile ducts are prone to development of

cholangitis/cholangiohepatitis, intraductal lithiasis, cirrhosis, portal hypertension, and

cholangiocarcinoma, and the polycystic kidneys may be accompanied by chronic renal disease and

rickets (Shenoy 2014).

Caroli’s disease or syndrome (involving liver and kidney) should be differentiated from cystic congenital

malformations limited to the liver, the latter being reported in the cat (Zandvliet et al. 2005), calf

(Yoshikawa et al. 2002), foal (Haechler et al 2000) and non-human primate (Wallace et al. 2009).

References:

Bettini G, Mandrioli L., Morini M, 2003. Bile duct dysplasia and congenital hepatic fibrosis associated with polycystic kidney (Caroli Syndrome) in a rat. Vet Pathol 40L693-694, 2003. Gorlinger S, Rothuizen J, Bunch S, van den Ingh TSGAM 2003. Congenital dilatation of the bile ducts in Caroli’s disease in young dogs. J Vet Intern Med 17:28-32. Haechler S, Van den Ingh TS, Rogivue C, Ehrensperger F, Welle M. 2000. Congenital hepatic fibrosis and cystic bile duct formation in Swiss Freiberger horses. Vet Pathol 37:669-671. Hananch W, Faizee N.2014. Caroli’s syndrome in a Shami goat. Res Opin Animal Vet Sci 4(7):382-384. Katsuyama M, Masuyama T, Komura I, Hibino T, Takahashi H, 2000. Characterization of a novel polycystic kidney rat model with accompanying polycystic liver. Exp Animal 49:51-55. Menezes LF, Onuchic LF 2006. Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease. Brazilian J of Medical and Biological Research 39:1537-1548. Moser M, Matthiesen S, Kirfel J, Schorle H, Borgmeann C, Senderek J, Rudnik-Schoeneborn ZK, Buettner R. 2005. A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney diasease (ARPKD). Hepatology 41:1113-1121. Sanzen T, Harada K, Yasoshima M, Kawamura Y, Ishibashi M, Nakanuma Y. 2001. Polycystic Kidney Rat is a Novel Animal Model of Caroli’s Disease Associated with Congenital Hepatic Fibrosis. Am J Pathol 158(5): 1605-1612. Shenoy P, Zki S, Shanbag P, Bhongade S. 2014. Caroli’s Syndrome with Autosomal Recessive polycystic Kidney Disease. Saudi J Kidney Dis Transp 25(4): 840-843. Wallace S, Blanchard T, Rabin LM, Dick E, Allann J, Hubbard G. 2009. Ductal Plate Malformation in a Nonhuman Primate. Vet Pathol 46:84-87.

Yoshikawa H, Fukuda T, Oyamada T, Yoshikawa T. 2002. Congenital hepatic fibrosis in a newborn calf. Vet Pathol 39L143-145. Zandvliet, MM, Szatmari, V, van den Ingh, T and Tothuizen, J. 2005. Acquired portosystemic shunting in 32 cats secondary to congenital hepatic fibrosis. J Vet Int Med 19:765-767.

*The Diagnostic Exercises are an initiative of the Latin Comparative Pathology Group (LCPG),

the Latin American subdivision of The Davis-Thompson Foundation. These exercises are

contributed by members and non-members from any country of residence. Consider submitting

an exercise! A final document containing this material with answers and a brief discussion will be

posted on the CL Davis website (http://www.cldavis.org/diagnostic_exercises.html).

Editor-in-chief: Vinicius Carreira

Associate Editor for this Diagnostic Exercise: Ingeborg Langohr