This document provides an overview of cholestatic liver diseases. It defines cholestasis as impaired bile flow and classifies cholestatic diseases as involving the hepatocyte, small intrahepatic bile ducts, or large/extrahepatic bile ducts. Specific examples of intrahepatic cholestasis discussed include those caused by decreased bile formation from sepsis or estrogens, and diseases like primary biliary cirrhosis that destroy bile ducts. Extrahepatic obstruction can result from gallstones, strictures, or tumors compressing the bile ducts. The document outlines approaches to diagnosing the cause of cholestasis through imaging and biopsy and discusses consequences like secondary liver damage if cholestasis is

1. Author(s): Rebecca W. Van Dyke, M.D., 2012
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3. M2 GI Sequence
Cholestatic Liver Diseases
Rebecca W. Van Dyke, MD
Winter 2012

4. Learning Objectives
• At the end of this lecture the student should be able to:
•
• 1. Define cholestatic and hepatocellular liver disease, provide examples of both
and be able to interpret panels of liver tests.
•
• 2. Define the difference between intrahepatic and extrahepatic cholestasis and
outline approaches to distinguishing them.
•
• 3. Define the pathophysiology of representative cholestatic diseases, including
drug-induced cholestasis, primary biliary cirrhosis, primary sclerosing
cholangitis and bile duct obstruction.
•
• 4. Outline an approach to the evaluation of the jaundiced patient.
•
• 5. Define acute and chronic hepatocellular liver disease and provide
representative examples.

5. Industry Relationship
Disclosures
Industry Supported Research and
Outside Relationships
• None

6. Common Types of Liver Disease
Hepatocellular: Injury to hepatocytes (necrosis/apoptosis)
Consequences:
decreased synthetic/metabolic activity
release of intracellular contents (AST/ALT)
Cholestasis: Impaired bile formation (hepatocytes)
Impaired bile flow (bile ducts/ductules)
Consequences:
build up in blood of substances normally
excreted in bile (bilirubin, bile acids)
synthesis/release of apical membrane
proteins (AP)

7. Cholestasis =
impaired bile
flow
Structures
involved in
secretion and
passage of
bile

8. Cholestatic Liver Disease
Classification of cholestatic diseases:
1. A functional impairment in bile formation at the level
of the hepatocyte.
2. A structural interference with normal bile secretion and
flow at the level of small intrahepatic bile ducts.
3. A structural interference with normal bile flow at the
level of large and extrahepatic bile ducts.

9. Cholestatic Liver Disease
Biochemical cholestasis: increased serum bilirubin
increased serum alkaline phosphatase
Clinical cholestasis: jaundice
dark urine/clay-colored feces
pruritus
Pathological cholestasis: bile plugs in dilated canaliculi
increased bile pigment in hepatocytes
bile lakes/bile infarcts
biliary infection (acute cholangitis)

10. Tests for Evaluating Cholestasis
• Screening tests that suggest cholestasis
– Color change in skin/sclerae/stool/urine
– Laboratory biochemical tests (Alk Phos, Bilirubin)
• Diagnostic tests to establish proof of disease
– Liver biopsy
– Indirect visualization of dilated bile ducts and/or masses
compressing bile ducts/stones (CT, U/S)
– Direct visualization of lumen of bile ducts allowing
identification of plumbing problems
• ERCP - endoscopic retrograde cholangiopancreatography
• MRCP - magnetic resonance cholangiopancreatography

11. Jaundice: Consequence of Cholestasis

12. Hypercarotenemia (hand on the right) –
the only other potential disease in the
differential diagnosis of yellow skin

13. Clinical Consequences of Severe
Cholestasis: 1. Clay-colored stools 2. Bilirubin in urine

14. Cholestasis: Specific Examples
1. Intrahepatic cholestasis due to decreased bile formation:
Sepsis
Estrogens
2. Intrahepatic cholestasis due to diseases that alter
intrahepatic bile ducts:
Primary biliary cirrhosis
Infiltration of liver with tumor/granulomas
3. Intrahepatic cholestasis due to any severe liver disease:
Viral hepatitis
4. Extrahepatic bile duct obstruction:
Tumor, gallstones, duct strictures
Primary sclerosing cholangitis

15. Cholestasis:
Specific Abnormalities in Bile Formation
Transporters involved in uptake and biliary secretion
of bilirubin and/or bile acids may be inhibited by
various agents, leading to cholestasis and jaundice.
Examples: Estrogens
Endotoxin/tumor necrosis factor

16. Intrahepatic Cholestasis: Retained bile
pigments/bilirubin in hepatocytes
Retained bile

17. Transporters Inhibited by Estrogens
Hepatocyte
Sinusoidal
Blood
N+
a
Bile
Canaliculus
Bile
Acid
ADP
Bile acids
ATP
Bilirubin conjugates
G lutathione S-conjugates
other organic anions
P
AD
P
AT

18. Intrahepatic Cholestasis
Intrahepatic cholestasis due to diseases that
compress and/or destroy intrahepatic bile ducts:
Primary Biliary Cirrhosis
Infiltration of liver with tumor/granulomas

19. Primary Biliary Cirrhosis
• Chronic, slowly evolving cholestatic
disorder
• Primarily affects middle-aged women
• Primary lesion:
– T cell mediated destruction of intrahepatic
bile ducts
– Slow progression to cirrhosis
• Relative sparing of hepatocytes with
relative preservation of liver function

20. Primary Biliary Cirrhosis (PBC)
Typical laboratory abnormalities:
Alk Phos 1050 IU/l (nl 50-110)
Bilirubin 1.0-2.0 mg/dl (nl 0.4-1.0)
AST/ALT 75-150 IU/l (nl 25-60)
Albumin 3.7 gm/dl (nl 3.5-4.5)
Prothrombin time 11 seconds (nl 8-12)
Cholesterol 420 mg/dl (nl 110-200)
Antimitochondrial antibody:positive in 95%
Liver copper: may be elevated due to chronic cholestasis

21. Early lesion of Primary Biliary Cirrhosis

22. Bile duct

23. Primary Biliary Cirrhosis (PBC)
Clinical Findings:
Jaundice
Pruritus (related to retention of bile acids
and other substances)
Xanthomas/xanthalasmas
(cholesterol deposits in skin)

24. Jaundice

25. Skin lesions on
the back from
scratching due
to pruritus in
Primary Biliary
Cirrhosis

26. PBC: xanthalasmas

27. PBC: xanthomas

28. Infiltrative/Granulomatous Diseases
Often present with cholestasis:
elevated alkaline phosphatase
with or without jaundice
Increased alk phos due to compression of small
intrahepatic bile ducts by expanding
granulomas
Examples: tuberculosis
sarcoidosis

29. Hepatic Granulomas/Sarcoidosis

30. Hepatic Sarcoidosis: granulomas and giant cells

31. Extrahepatic Biliary
Obstruction

32. Liver
Extra- Common
hepatic duct
Hepatic
Gallbladder
Bile Intrahepatic
Ducts Perihilar
Obstruction of Distal
the bile ducts extrahepatic
at any point
outside the Common
bile duct
liver can
cause Ampulla
Of Vater
cholestasis
Duodenum
by blocking
bile flow.
Adapted from Gordon Flynn, Wikimedia Commons

33. ERCP (normal)
Endoscopic Retrograde CholangioPancreatography

34. Common Liver
hepatic duct
Gallbladder
Does Intrahepatic
obstruction
of the cystic Perihilar
duct
or gallbladder Distal
cause jaundice? extrahepatic
Common
bile duct
Ampulla
Of Vater
Duodenum
Adapted from Gordon Flynn, Wikimedia Commons

35. Subsets of Extrahepatic Biliary Obstruction
Intrinsic Obstruction Extrinsic Obstruction
Gallstones Tumor:
Biliary Strictures pancreatic
postsurgical cholangiocarcinoma
Primary sclerosing cholangitis periampullary lymphoma
Worms/parasites or metastatic tumor
Blood clot/hemobilia Acute/chronic pancreatitis
(edema/fibrosis in head
of
pancreas)
Congenital disease:
biliary atresia
choledochal cyst

36. Primary Sclerosing Cholangitis
• Slowly evolving disease with fibrosis, stricturing and
inflammation around extrahepatic bile ducts.
– May also affect intrahepatic ducts
• Primarily affects middle-aged men
– Associated with ulcerative colitis.
• Complications include complete duct obstruction, jaundice, biliary
infection (cholangitis), pruritus.
• Relative preservation of hepatocytes.

37. Primary Sclerosing Cholangitis
Typical laboratory abnormalities:
Alk Phos 875 IU/l (nl 50-110)
Bilirubin 2.0-5.0 mg/dl (nl 0.4-1.0)
AST/ALT 75-150 IU/l (nl 25-60)
Albumin 3.5 gm/dl (nl 3.5-4.5)
Prothrombin time 11 seconds (nl 8-12)

38. Primary Sclerosing Cholangitis
Typical Clinical Findings:
Bile duct obstruction: best seen on direct imaging
Jaundice and dilated bile ducts if complete obstruction
of major duct occurs.
Bile plugs/bile lakes/bile infarcts on liver biopsy
Biliary infection (cholangitis) - acute bacterial
infection of stagnant bile.
Cirrhosis

39. Sclerosing Cholangitis:
“onion-skinning fibrosis” around bile ducts
very thickened
bile duct wall
decreases
luminal
diameter

41. Biliary obstruction
• When bile ducts are obstructed, what
happens to the bile?
• What happens to the bile duct upstream
of the obstruction?

43. Evidence of Bile Duct Obstruction:
Dilated ducts upstream of the obstruction
Bile-filled dilated bile
ducts are large dark
gray tubular
structures that run
parallel to the portal
veins (white arrows).
Portal veins are white
due to IV contrast.
liver parenchyma is
light gray due to IV
contrast.

44. Dilated bile ducts and gallbladder
Gallbladder
Dilated bile ducts
Mass in head of
the pancreas

45. Bile Duct Obstruction: Bile Plugs in Bile Ducts
Portal
vein
HA

46. More canalicular cholestasis

47. Acute Cholangitis: PMNs in Bile Duct
HA

48. Other Causes of Extra-hepatic
Biliary Obstruction

49. High grade cholangiocarcinoma
at the hilum

50. High grade bilateral obstruction
from metastatic rectal carcinoma

51. Biliary stricture due to cholangiocarcinoma
Alk phos = 669 IU
Bili = 17.5 mg/dl
AST = 68 IU
ALT = 38 IU

52. A plastic stent bridges More permanent metal
the stenosis mesh stent placed

53. Bile duct
obstruction
from chronic
pancreatitis

54. Biliary Obstruction:
Multiple stones
in biliary tree

55. Bile Duct Dilation due to Obstruction
Large ducts near Small peripheral
hilum massively ducts also enlarged
dilated and visible

56. An unusual
cause of biliary
obstruction
Radio-opaque dye
injected through T-tube
fills common bile duct
and intrahepatic bile
ducts.
Dark linear
structures are ascariasis
located in biliary system
(black arrows).

57. Ascaris emerging from common
bile duct as seen endoscopically

58. Consequences of Cholestasis
• Secondary liver damage
– Bile acid-induced hepatocyte injury
– Secondary biliary cirrhosis
• Failure of substances secreted in bile to
reach intestine
– Bile acid deficiency in gut
– Fat malabsorption/fat-soluble vitamin
malabsorption

59. SUMMARY:
EVALUATION OF CHOLESTASIS AND/OR JAUNDICE
1. Suspect cholestasis based on history, physical exam,
lab tests.
2. Look for clues to mechanical obstruction of ducts and/or
mass lesions (radiologic studies).
3. Visualize, diagnose and treat mechanical obstruction.
4. Consider intrahepatic cholestasis, obtain liver biopsy.
See algorithms in syllabus and in textbook

60. Additional Source Information
for more information see: http://open.umich.edu/wiki/CitationPolicy
Slide 32 & 34: Adapted from Gordon Flynn, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Digestive_system_with_liver.png, CC:BY-
SA, http://creativecommons.org/licenses/by-sa/2.5/deed.en