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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 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 Phos1050 IU/l(nl ) Bilirubin mg/dl (nl ) AST/ALT IU/l(nl 25-60) Albumin3.7 gm/dl(nl ) Prothrombin time11 seconds(nl 8-12) Cholesterol420 mg/dl(nl ) 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

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

ERCP (normal) Endoscopic Retrograde CholangioPancreatography

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

Subsets of Extrahepatic Biliary Obstruction Intrinsic ObstructionExtrinsic Obstruction GallstonesTumor: Biliary Strictures pancreatic postsurgical cholangiocarcinoma Primary sclerosing cholangitis periampullary lymphoma Worms/parasites or metastatic tumor Blood clot/hemobiliaAcute/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 Phos875 IU/l(nl ) Bilirubin mg/dl(nl ) AST/ALT IU/l(nl 25-60) Albumin3.5 gm/dl(nl ) Prothrombin time11 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

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

Bile duct obstruction from chronic pancreatitis

Biliary Obstruction: Multiple stones in biliary tree

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

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: Slide 32 & 34: Adapted from Gordon Flynn, Wikimedia Commons, CC:BY- SA,