Liver III Lecture(& Gallbladder too..)

Rob EdwardsNovember 16, 2011

Rob EdwardsNovember 16, 2011

Reading Assignment• Particular emphasis should be placed on the following topics:•• Primary Biliary Cirrhosis vs. Primary Sclerosing Cholangitis

(pp. 867-869)

• Hepatic Venous Outflow Obstruction (p. 873)•• Nodular Hyperplasias, Benign and Malignant Neoplasms (pp.

875-880)•• Cholelithiasis (Gallstones) & Cholecystitis (pp. 882-886)•• Carcinoma of the Gallbladder (pp.888)

Outline

• Obstructive biliary disease • Circulatory Disorders• Liver Masses and Neoplasms• Biliary Tract

– Gallstones– Cholangitis– Cholangiocarcinoma

Imaging the Bile Ducts:

ERCP• Scope thru Stomach

to 1st segment of Duodenum

• Cannulate CBD via major papilla (duct of Wirsung)

• Shoot contrast, light up CBD, intrahepatic R&L bile ducts, branches by fluoroscopy

Obstructive Biliary Disease• May be extrahepatic

– 2o Biliary Cirrhosis (chronic obstruction of the extrahepatic bile ducts)

• Or intrahepatic– 1o Biliary Cirrhosis– 1o Sclerosing Cholangitis– 2o to other liver dz- drug toxicity,

viral hepatitis

• All can lead to development of cirrhosis:

Secondary Biliary Cirrhosis

• Prolonged extrahepatic obstruction– Most often due to cholelithiasis, malignancy,

post-op strictures

-In kids: biliary atresia, CF, choledochal cysts

• Early: reversible cholestasis, inflammation• Late: Periportal fibrosis/scarring

– Complications: 2o enteric bacterial infection = ascending cholangitis

Primary Biliary Cirrhosis• PF: Autoimmune• Chronic progressive

cholestasis• 40’s-50’s 6:1 F>M• Insidious onset; pruritis, skin

pigmentation, jaundice (late) Granulomatous Inflammatory destruction of intrahepatic bile ducts, periductal autoreactive T-cells

• Many years’ progression to cirrhosis, portal HTN, varices, encephalopathy

Primary Biliary Cirrhosis• Lab:

Hyperbilirubinemia late, implies liver dysfunction

• Hypercholesterolemia = xanthelasmas

• 90% have Antimitochondrial antibodies (anti-PDC E2, leaks from damaged hepatocytes

• Other AI sx: Sicca, RA

Primary Sclerosing Cholangitis• 3rd-5th decade, 2:1 M:F• Segmental inflammation

and fibrosis of intra- and extrahepatic BD’s with intervening dilatations

• PF: Unknown, cytokine-mediated vs. ischemia?

• AI: 75% have anti-SM Ab

• 70% w/ PSC have UC• Micro: Onion-skin fibrosis,

obliteration of duct. Severe cholestasis

• Long term: Inc. Risk of cholangiocarcinoma

http://www.hopkins-gi.org/pages/latin/templates/index.cfm?pg=disease3&organ=6&disease=20&lang_id=1&pagetype=13&pagenum=179

Common Final Pathway: Biliary Cirrhosis

Review - Normal Lobule Flow

Circulatory Disorders (P. 870)

Circulatory Disorders- Inflow• Impaired Arterial Inflow:

– Infarcts rare, but intrahepatic artery occlusion by embolism, tumor compression, vasculitis = Infarct

• Portal Vein Obstruction:– Sx: Abd pain, portal HTN,

varices– Rare, – 50% idiopathic. 2o to

intrabdominal sepsis, hypercoagulable states, trauma

Circulatory Disorders- Intrahepatic• Impaired INTRAhepatic

flow:– Cirrhosis– Sludging in Sickle Cell Dz

• 2o to systemic circulatory compromise:– Right CHF = passive

centrilobular congestion– (NUTMEG LIVER)– Left heart failure: hypoxia,

centrilobular necrosis

Circulatory Disorders-Outflow

• Budd-Chiari Synrdome = Hepatic Vein Thrombosis– Must block multiple main

veins– Assoc w/ hypercoagulable

states (ATIII deficiency, Factor V Leiden, etc)

– Assoc with pregnancy, OCP’s; 10% idiopathic

Liver Masses – Hyperplasias & Neoplasms

• Schema:– Nodular Hyperplasias (NOT neoplastic)

• Focal Nodular Hyperplasia• Nodular Regenerative Hyperplasia

– Benign Neoplasms• Cavernous Hemangioma• Liver cell adenoma

– Malignant Neoplasms• Mets• Hepatocellular Carcinoma• Angiosarcoma

Focal Nodular Hyperplasia

– Congenital vascular abnormality?

– May be symptomatic (if large) or‘incidentalomas’

– Spontaneous, F>M (8:1) 3rd-5th decade. 75% Asx.

– Solitary circumscribed Pale Yellowish mass w/ central scar

– ‘Spoke and Wheel’ pattern on angiography-hyperperfused.

– Thick plates of hepatocytes ONLY!

Nodular Hyperplasias-II• Nodular Regenerative

Hyperplasia:– 2o to portal HTN,

associated w/ altered intrahepatic blood flow:

• Renal Tx, BMT (Veno-occlusive disease)

• Vasculitides

– Involves entire liver – Multiple spherical

nodules, NO fibrosis

Benign Neoplasms- I• Cavernous

Hemangioma• Most common benign

stromal liver neoplasm (1-20% in autopsy studies)

• 1-2 cm subcapsular mass, may be symptomatic if larger (record = ~30cm….)

• DON’T LET A PATHOLOGIST BIOPSY THEM!

• DDX: Mets

Benign Neoplasms- II• Liver Cell Adenomas

– Seen in women using OCP’s. Regress w/ discontinuation.

– May be up to 30 cm!

• Clinical Significance:– ~10% risk of HCC– Subcapsular adenomas

rupture during pregnancy (~20% mortality)

– MICRO: Disorganized hepatocyte cords, very vascular. NO portal tracts within mass!

Malignant Neoplasms

• Primary Carcinomas– HCC (derived from hepatocytes) – 80-90%– Cholangiocarcinoma (derived from BD epithelium)

• 10-20%

Hepatocellular Carcinoma - I

• Hepatocellular Carcinoma– Relatively rare in US (1-2% of cancers, ~14,000

cases, ~14,000 deaths/yr)– 5% of ALL cancer worldwide (75% of cases in

Asia; 0.5-1M deaths/yr worldwide)

• “Two Diseases”:– 85% cases occur in areas endemic for chronic

HBV infection, half have cirrhosis, occurs in 20’s-40’s

– In US – Complicates other liver dz, 90% have cirrhosis, rare before age 60.

Hepatocellular Carcinoma - II

• Pathogenesis:– Three major etiologies:

• Viral Infection (HBV, HCV)• Chronic Alcoholism• Food (Aflatoxins (A. flavus) in grains/peanuts)• Areca nuts (remove from candy dish in waiting room…)

• Path-o-Fizz:– Repeated cell death/regeneration– Mutations in GF genes, LOH in TS genes– Genomic instability with integrated HBV genome

Hepatocellular Carcinoma - III

• Clinical Features of HCC:– Often obscured by comorbid sx of cirrhosis/hepatitis– Upper abdominal pain/fullness, malaise, WT loss– Variable degrees of jaundice, fever, variceal

bleeding

• Lab: Elevated serum -fetoprotein in 50-75%– Lots of false-positives (cirrhosis, liver necrosis)

• Imaging most valuable for small (resectable) lesions

Hepatocellular Carcinoma - IV• Gross: Unifocal or multifocal,

diffusely infiltrative.• Pale, greenish if making bile• Tend to invade major vessels

(IVC up to right atrium!)• Intrahepatic metastasis• Late mets to lung• Death from cachexia,bleeds

• Micro:– Wide degree of differentiation– Cords with >3 cells’ thick– Glandular formations– Poorly diff/anaplastic

Hepatocellular Carcinoma - V

Hepatocellular Carcinoma - VI

• Variant: Fibrolamellar Carcinoma– Seen in younger patients (20-40, M=F)– No association with HBV or Cirrhosis– Better Prognosis (often resectable)– Gross: Solitary, Hard nodule with fibrous

bands, central scar. Characteristic on CT, MR– Micro: Well differentiated cells & dense

collagen bundles

Fibrolamellar Carcinoma - VII

Hepatocellular Carcinoma - VIII

• Most Common Malignancy in the Liver in US?– Metastatic Carcinoma

• Most often from colon

Hepatoblastoma

• Most common liver neoplasm of young childhood

• 2 types:– Epithelial – small polygonal fetal cells

recapitulating liver development– Mixed epithelial-mesenchymal – foci of

primitive mesnchyme/osteoid/cartilage/skeletal muscle

• Death by 1 year if unresectable

Angiosarcoma• Malignant neoplasm of

endothelial cells• Rare • Most common in H&N,

legs. Liver most common visceral site.

• Arises in exposure to vinyl chloride, arsenic, thorotrast (not used anymore!)

• Several decades lag time

• Recur locally

• High grade neoplasms, poor survival

Normal Biliary Tract

• Liver makes 1 L bile/day, concentrated and stored in GB

• GB: Undulating simple columnar epithelium, no submucosa.

Biliary Atresia

• 1/3 of neonatal cholestasis, 1:10,000 live births• = COMPLETE obstruction of extrahepatic biliary

tree in first 3 months of life• Induces rapid (~6 weeks) 2o biliary cirrhosis,

causes 50% of pedi liver transplant.• Fetal form (20%): Congenital, other anomalies• Perinatal form (80%): Normal, but destroyed

postnatally. (toxic insult or Reovirus/rotavirus?)• Rx: Surgical- Kasai procedure

Choledochal Cysts• Congenital dilation of the

CBD• F:M 4:1• Present <10 yo w/ jaundice

or biliary colic• Dilation may be segmental,

or form diverticuli• Predispose to stone

formation, stricture, pancreatitis

• Risk of cholangiocarcinoma in elderly pts.

Cholelithiasis

• Affects 10-20% of Adults wherever calories are not a limiting factor

• ~50 tons of gallstones currently roaming the U.S. as we speak.

• 80% are cholesterol, rest are bilirubin salts• Most are asymptomatic• Risk: Native Americans (>75%), age, ♀• PF: cholesterol supersaturation, GB

hypomotility, crystal nucleation, accretion

Gallstones

• Cholesterol Stones– Multiple, large– Radiolucent if >90%

cholesterol

• Pigmented stones• Smaller• Black if sterile• Brown if 2o cholangitis• Most radioopaque

Cholelithiasis/Cholecystitis

• May be Asx for decades, 1-3% per year become symptomatic– Biliary pain: Colicky (spasmodic due to

contractions), also from cholecystitis

• Complications:• Empyema• Perforation• Cholangitis• Gallstone Pancreatitis

Cholecystitis

• Acute: – 2o to stone obstructing the cystic duct– Rarely seen in post-op pts, trauma, burns, MOF– GB enlarged, Inflammation, serosal fibrin/exudate

• Chronic:– Arises following repeated bouts of acute disease– Smooth serosa, thickened/fibrotic wall– Rokitansky-Aschoff sinuses

Chronic Cholecystitis

Choledocholithiasis • Choledocholithiasis =

Stones in the bile ducts– In US, almost all from

GB– In Asia, pigmented

stones form de novo in ducts, 2o to infection

– May be Asx or cause obstruction, pancreatitis, cholangitis, hepatic abscess, 2o biliary cirrhosis

Cholangitis

• = Bacterial Infection of the Bile Ducts– Can follow any obstruction (stones, tumors,

stents, pancreatitis, strictures)– Iatrogenic: Post-ERCP, T-tube placement– Usually Gram-negative aerobes– May be complicated by sepsis, significant

mortality.

Gallbladder Carcinoma• Uncommon• 7th decade, F>M• Rarely resectable at Dx,

poor prognosis• Sx: Indistiguishable

from cholelithiasis• Infiltrates deep thru

wall, into adj. liver.

Cholangiocarcinoma• DEF: Malignancy of the biliary tree• Risks: PSC, congenital biliary cystic dz, chronic liver fluke

infection• Arise in non-cirrhotic liver, nodular or arborizing• Micro: Adenocarcinoma,well to mod-diff, prominent

desmoplasia• 50% Mets to lung, bone, brain• Advanced at Dx, bad prognosis• Klatskin tumor: CA @ confluence of L+R intrahepatic bile ducts