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Definition
Bile accumulation in the liver. Could be mechanical or functional.
Clinical Features
• May be acute or chronic
• Acute:
o usually:
complete
due to either:
total functional exocrine secretory failure of hepatocytes
e.g.:
drug-induced cholestasis
complete obstruction of extrahepatic bile ducts e.g.:
impacted gallstone
• Chronic:
o indicates longer duration cholestatic condition (weeks, months, years)
o may be:
complete e.g.:
chronic total extrahepatic bile duct obstruction by
carcinoma of pancreas or
variably incomplete e.g.:
primary biliary cirrhosis
primary sclerosing cholangitis).
o if incomplete may remain anicteric for long periods
Pathogenesis
• Arrest or marked reduction in bile secretion and bile flow due to:
o functional secretory disturbances of hepatic parenchymal cells1
o obstruction at any level in excretory pathways of bile, from canaliculi to
papilla of Vater2
Intrahepatic Cholestasis
• Cause:
o primary focus inside liver:
diseases of:
parenchymal cells
intrahepatic bile ducts
sometimes both parenchymal cells and intrahepatic bile
ducts1
Extrahepatic Cholestasis
• Cause:
o bile excretory block in larger ducts:
outside liver along extrahepatic bile ducts e.g.:
gallstones
bile duct tumors
bile duct strictures
in larger hilar intrahepatic ducts
• Involves both:
o intrahepatic segments of biliary tree
o extrahepatic segments of biliary tree
• Examples:
o extrahepatic bile duct atresia in neonates
o primary sclerosing cholangitis in adults and children
• Block in bile secretion:
o may be:
complete:
total arrest of bile secretion
retention of:
bile salts
bilirubin
functional or obstructive
incomplete
usually incomplete or partial obstruction of:
intrahepatic bile ducts:
mostly due to destructive diseases of
intrahepatic bile ducts (vanishing bile duct
diseases) such as:
primary biliary cirrhosis
primary sclerosing cholangitis
extrahepatic bile ducts:
incomplete obstruction (narrowing or
strictures) of segments of larger bile ducts
retention of:
bile salts (but not bilirubin)
Histopathology
Acute Complete Cholestasis
• Changes in:
o lobular parenchyma
o portal tracts
• Bilirubin accumulation in liver lobule (Fig. 1
):
Parenchymal Changes
• Include:
o cholate stasis
o cholestatic liver cell rosettes
o feathery degeneration
o xanthomatous cells
o bile infarcts
Cholate Stasis
o pale
o coarsely granular:
contain granules of lysosomal copper, complexed with copper-
binding protein (metallothionein):
stainable with:
rhodanine (copper) (Fig. 3
o with time:
contain Mallory bodies
o very late stages:
may be bilirubin inclusions
appear empty
be filled with eosinophilic or bilirubin-stained material in
variable degrees of inspissation
Feathery Degeneration
Extramedullary Hematopoiesis
• Comprise:
o ductular reaction
o ductular reabsorption
o periductular fibrosis
o biliary fibrosis
o final stage of biliary cirrhosis
Ductular Reaction
)7
Periductular Fibrosis
• Earliest stages:
o may be revealed by immunostaining for cytokeratin 7:
reveals a phenotypic switch to a biliary type of intermediate
filament cytoskeleton in periportal hepatocytes (Fig. 7
• With time:
o cytokeratin 7 expression extends with decreasing gradient from limiting
plate toward center of the lobule over a distance of several cells16
)16–18
Diagnosis
• If incomplete and anicteric:
o no microscopically visible accumulation of bilirubin in liver tissue
sections
o underscores usefulness of distinguishing between:
bilirubin stasis
cholate stasis
either separately or in combination may constitute picture
of histologic cholestasis19
• Basic differences between chronic complete and incomplete cholestasis are:
o absence of bilirubin stasis in incomplete category
o occasionally more pronounced expression of lesions in complete variety
• Chronic states of cholestasis sometimes lack obvious ductular reaction e.g. may
be absent in:
o Alagille's syndrome
o some cases of:
primary sclerosing cholangitis
chronic liver allograft rejection
Differential Diagnosis
Select up to 2 differential diagnoses to compare with Cholestasis
Bilirubin Stasis
• Dark brown to black deposits (in hepatocytes, canaliculi, Kupffer cells, and
ductules) in erythropoietic protoporphyria:
o easily identified by polarized light:
protoporphyrin deposits have a red to yellow birefringence with a
Maltese cross configuration in coarser (ductular) deposits (Figs 9
and 10
)20
Extramedullary Hematopoiesis
Biliary Fibrosis
Staging/grading
Staging In Chronic Cholestatic Liver Diseases
References
1 Trauner M, Meier PJ, Boyer JL. Molecular regulation of hepatocellular transport
systems in cholestasis. J Hepatol. 1999;31:165–178.
2 Desmet VJ. Cholestasis: extrahepatic obstruction and secondary biliary cirrhosis.
MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portmann BC editor. Pathology of
the liver. ed. 3. Edinburgh: Churchill Livingstone; 1994.
3 Desmet VJ, Roskams T. Histological features. In: Bircher J, Benhamou JP, McIntyre N,
Rizzetto M, Rodes J editor. Oxford Textbook of clinical hepatology, ed. 2. vol. 1:Oxford:
Oxford University Press; 1999.
4 Desmet VJ. Current problems in diagnosis of biliary disease and cholestasis. Semin
Liver Dis. 1986;6:233–245.
5 Nagore N, Howe S, Scheuer PJ. The three-dimensional liver. In: Popper H, Schaffner F
editor. Progress in liver diseases. vol. IX:Philadelphia: W.B. Saunders; 1990.
7 Desmet V, Roskams T, Van Eyken P. Ductular reaction in the liver. Path Res Pract.
1995;191:513–524.
8 James J, Lygidakis NJ, Van Eyken P, Tanka AKF, Bosch KS, Ramaekers FCS, et al.
Application of keratin immunocytochemistry and Sirius red staining in evaluating
intrahepatic changes with acute extrahepatic cholestasis due to hepatic duct carcinoma.
Hepatogastroenterology. 1989;36:151–155.
9 Slott PA, Liu MH, Tavoloni N. Origin, pattern and mechanism of bile duct proliferation
following biliary obstruction in the rat. Gastroenterology. 1990;99:466–477.
11 Desmet VJ, Roskams T, Van Eyken P. Pathology of the biliary tree in cholestasis:
ductular reaction. Manns MP, et al. editor. Cholestatic liver diseases. Lancaster: Kluwer
Academic Publishers; 1998.
17 Van Eyken P, Desmet VJ. Cytokeratins and the liver. Liver. 1993;13:113–122.
19 Desmet VJ. Chronic cholestasis. Hoofnagle JH, Goodman Z editor. Liver biopsy.
Interpretation for the 1990's. Thorofare: Slack Incorporated; 1991.