Author(s): Rebecca W. Van Dyke, M.D., 2012

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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 activityrelease 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 bileflow

Structuresinvolved insecretion andpassage 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 bilirubinincreased serum alkaline phosphatase

Clinical cholestasis: jaundicedark urine/clay-colored fecespruritus

Pathological cholestasis: bile plugs in dilated canaliculiincreased bile pigment in hepatocytesbile lakes/bile infarctsbiliary 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:SepsisEstrogens

2. Intrahepatic cholestasis due to diseases that alter intrahepatic bile ducts:

Primary biliary cirrhosisInfiltration of liver with tumor/granulomas

3. Intrahepatic cholestasis due to any severe liver disease:Viral hepatitis

4. Extrahepatic bile duct obstruction:Tumor, gallstones, duct stricturesPrimary 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: EstrogensEndotoxin/tumor necrosis factor

Intrahepatic Cholestasis: Retained bile pigments/bilirubin in hepatocytes

Retained bile

ATP

ADPBile acids

ATPA

DP

Bilirubin conjugates Glutathione S-conjugates other organic anions

Bile Canaliculus

Hepatocyte Sinusoidal Blood

Na+

Bile Acid

Transporters Inhibited by Estrogens

Intrahepatic Cholestasis

Intrahepatic cholestasis due to diseases thatcompress 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 acidsand other substances)

Xanthomas/xanthalasmas (cholesterol deposits in skin)

Jaundice

Skin lesions onthe back fromscratching dueto pruritus inPrimary BiliaryCirrhosis

PBC: xanthalasmas

PBC: xanthomas

Infiltrative/Granulomatous Diseases

Often present with cholestasis:elevated alkaline phosphatasewith or without jaundice

Increased alk phos due to compression of smallintrahepatic bile ducts by expandinggranulomas

Examples: tuberculosissarcoidosis

Hepatic Granulomas/Sarcoidosis

Hepatic Sarcoidosis: granulomas and giant cells

Extrahepatic Biliary Obstruction

Intrahepatic

Perihilar

Distalextrahepatic

Duodenum

AmpullaOf Vater

Commonbile duct

Gallbladder

Commonhepatic duct

LiverExtra-HepaticBileDucts

Obstruction ofthe bile ductsat any pointoutside theliver can cause cholestasis by blocking bile flow.

Adapted from Gordon Flynn, Wikimedia Commons

ERCP (normal)Endoscopic Retrograde CholangioPancreatography

Intrahepatic

Perihilar

Distalextrahepatic

Duodenum

AmpullaOf Vater

Commonbile duct

Gallbladder

Commonhepatic duct

Liver

Does obstructionof the cystic ductor gallbladdercause jaundice?

Adapted from Gordon Flynn, Wikimedia Commons

Subsets of Extrahepatic Biliary Obstruction

Intrinsic Obstruction Extrinsic Obstruction

Gallstones Tumor:Biliary Strictures pancreatic postsurgical cholangiocarcinomaPrimary sclerosing cholangitis periampullary lymphomaWorms/parasites or metastatic tumorBlood clot/hemobilia 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 bacterialinfection of stagnant bile.

Cirrhosis

Sclerosing Cholangitis:“onion-skinning fibrosis” around bile ducts

very thickenedbile duct walldecreases luminaldiameter

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 tubularstructures that runparallel to the portalveins (white arrows).

Portal veins are whitedue to IV contrast.liver parenchyma islight gray due to IVcontrast.

Dilated bile ducts and gallbladder

Gallbladder

Dilated bile ducts

Mass in head ofthe 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 IUBili = 17.5 mg/dlAST = 68 IUALT = 38 IU

More permanent metal mesh stent placed

A plastic stent bridgesthe stenosis

Bile ductobstructionfrom chronicpancreatitis

Biliary Obstruction:

Multiple stonesin biliary tree

Large ducts nearhilum massivelydilated

Small peripheralducts also enlargedand visible

Bile Duct Dilation due to Obstruction

An unusualcause of biliary obstruction

Radio-opaque dye injected through T-tubefills common bile ductand intrahepatic bileducts.

Dark linear structures are ascariasislocated 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 Informationfor 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