1. Liver III Lecture
(& Gallbladder too..)
Rob Edwards
November 16, 2011

2. Reading Assignment
Particular emphasis should be placed on the following topics:
Primary Biliary Cirrhosis vs. Primary Sclerosing Cholangitis (pp )
Hepatic Venous Outflow Obstruction (p. 873)
Nodular Hyperplasias, Benign and Malignant Neoplasms (pp )
Cholelithiasis (Gallstones) & Cholecystitis (pp )
Carcinoma of the Gallbladder (pp.888)

3. Outline Obstructive biliary disease Circulatory Disorders
Liver Masses and Neoplasms
Biliary Tract
Gallstones
Cholangitis
Cholangiocarcinoma

5. 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

6. 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:

7. 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

8. 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

9. 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

10. 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

11.
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12. Common Final Pathway: Biliary Cirrhosis

13. Review - Normal Lobule Flow

14. Circulatory Disorders (P. 870)

15. 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

16. 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

17. 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

19. 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

20. 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!

21. 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

22. 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

23. Benign Neoplasms- II Liver Cell Adenomas Clinical Significance:
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!

24. Malignant Neoplasms Primary Carcinomas
HCC (derived from hepatocytes) – 80-90%
Cholangiocarcinoma (derived from BD epithelium)
10-20%

25. Hepatocellular Carcinoma - I
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.

26. 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

27. 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 a-fetoprotein in 50-75%
Lots of false-positives (cirrhosis, liver necrosis)
Imaging most valuable for small (resectable) lesions

28. 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

29. Hepatocellular Carcinoma - V

30. 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

31. Fibrolamellar Carcinoma - VII

32. Hepatocellular Carcinoma - VIII
Most Common Malignancy in the Liver in US?
Metastatic Carcinoma
Most often from colon

33. 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

34. 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

35. Normal Biliary Tract
Liver makes 1 L bile/day, concentrated and stored in GB
GB: Undulating simple columnar epithelium, no submucosa.

36. 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

37. 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.

38. 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

39. Gallstones Cholesterol Stones Pigmented stones Smaller
Multiple, large
Radiolucent if >90% cholesterol
Pigmented stones
Smaller
Black if sterile
Brown if 2o cholangitis
Most radioopaque

40. 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

41. Cholecystitis Acute: Chronic: 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

42. Chronic Cholecystitis

43. 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

44. 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.

45. Gallbladder Carcinoma
Uncommon
7th decade, F>M
Rarely resectable at Dx, poor prognosis
Sx: Indistiguishable from cholelithiasis
Infiltrates deep thru wall, into adj. liver.

46. 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: confluence of L+R intrahepatic bile ducts