Author(s): Rebecca W. Van Dyke, M.D., 2012
License: Unless otherwise noted, this material is made available under the terms
of the Creative Commons Attribution – Share Alike 3.0 License:
http://creativecommons.org/licenses/by-sa/3.0/
We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,
share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this
material.
Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions,
corrections, or clarification regarding the use of content.
For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.
Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement
for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have
questions about your medical condition.
Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
Attribution Key
for more information see: http://open.umich.edu/wiki/AttributionPolicy
Use + Share + Adapt
{ Content the copyright holder, author, or law permits you to use, share and adapt. }
Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105)
Public Domain – Expired: Works that are no longer protected due to an expired copyright term.
Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain.
Creative Commons – Zero Waiver
Creative Commons – Attribution License
Creative Commons – Attribution Share Alike License
Creative Commons – Attribution Noncommercial License
Creative Commons – Attribution Noncommercial Share Alike License
GNU – Free Documentation License
Make Your Own Assessment
{ Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. }
Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in
your jurisdiction may differ
{ Content Open.Michigan has used under a Fair Use determination. }
Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in
your jurisdiction may differ
Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee
that your use of the content is Fair.
To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
M2 GI Sequence
Cholestatic Liver Diseases
Rebecca W. Van Dyke, MD
Winter 2012
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.
Industry Relationship
Disclosures
Industry Supported Research and
Outside Relationships
• None
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)
Cholestasis =
impaired bile
flow
Structures
involved in
secretion and
passage of
bile
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.
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)
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
Jaundice: Consequence of Cholestasis
Hypercarotenemia (hand on the right) –
the only other potential disease in the
differential diagnosis of yellow skin
Clinical Consequences of Severe
Cholestasis: 1. Clay-colored stools 2. Bilirubin in urine
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
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
Intrahepatic Cholestasis: Retained bile
pigments/bilirubin in hepatocytes
Retained bile
Intrahepatic Cholestasis
Intrahepatic cholestasis due to diseases that
compress and/or destroy intrahepatic bile ducts:
Primary Biliary Cirrhosis
Infiltration of liver with tumor/granulomas
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
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
Early lesion of Primary Biliary Cirrhosis
Bile duct
Primary Biliary Cirrhosis (PBC)
Clinical Findings:
Jaundice
Pruritus (related to retention of bile acids
and other substances)
Xanthomas/xanthalasmas
(cholesterol deposits in skin)
Jaundice
Skin lesions on
the back from
scratching due
to pruritus in
Primary Biliary
Cirrhosis
PBC: xanthalasmas
PBC: xanthomas
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
Hepatic Granulomas/Sarcoidosis
Hepatic Sarcoidosis: granulomas and giant cells
Extrahepatic Biliary
Obstruction
ExtraHepatic
Bile
Ducts
Obstruction of
the bile ducts
at any point
outside the
liver can
cause
cholestasis
by blocking
bile flow.
Common
hepatic duct
Liver
Gallbladder
Intrahepatic
Perihilar
Distal
extrahepatic
Common
bile duct
Ampulla
Of Vater
Duodenum
Adapted from Gordon Flynn, Wikimedia Commons
ERCP (normal)
Endoscopic Retrograde CholangioPancreatography
Common
hepatic duct
Liver
Gallbladder
Intrahepatic
Does
obstruction
of the cystic
duct
or gallbladder
cause jaundice?
Perihilar
Distal
extrahepatic
Common
bile duct
Ampulla
Of Vater
Duodenum
Adapted from Gordon Flynn, Wikimedia Commons
Subsets of Extrahepatic Biliary Obstruction
Intrinsic Obstruction
Extrinsic Obstruction
Gallstones
Biliary Strictures
postsurgical
Primary sclerosing cholangitis
Worms/parasites
Blood clot/hemobilia
Tumor:
pancreatic
cholangiocarcinoma
periampullary lymphoma
or metastatic tumor
Acute/chronic pancreatitis
(edema/fibrosis in head of
pancreas)
Congenital disease:
biliary atresia
choledochal cyst
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.
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)
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
Sclerosing Cholangitis:
“onion-skinning fibrosis” around bile ducts
very thickened
bile duct wall
decreases
luminal
diameter
Biliary obstruction
• When bile ducts are obstructed, what
happens to the bile?
• What happens to the bile duct upstream
of the obstruction?
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.
Dilated bile ducts and gallbladder
Gallbladder
Dilated bile ducts
Mass in head of
the pancreas
Bile Duct Obstruction:
Bile Plugs in Bile Ducts
Portal
vein
HA
More canalicular cholestasis
Acute Cholangitis: PMNs in Bile Duct
HA
Other Causes of Extra-hepatic
Biliary Obstruction
High grade cholangiocarcinoma
at the hilum
High grade bilateral obstruction
from metastatic rectal carcinoma
Biliary stricture due to cholangiocarcinoma
Alk phos = 669 IU
Bili =
17.5 mg/dl
AST =
68 IU
ALT =
38 IU
A plastic stent bridges
the stenosis
More permanent metal
mesh stent placed
Bile duct
obstruction
from chronic
pancreatitis
Biliary Obstruction:
Multiple stones
in biliary tree
Bile Duct Dilation due to Obstruction
Large ducts near
hilum massively
dilated
Small peripheral
ducts also enlarged
and visible
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).
Ascaris emerging from common
bile duct as seen endoscopically
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
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
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:BYSA, http://creativecommons.org/licenses/by-sa/2.5/deed.en