CHAPTER 18

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LIVER AND BILIARY TRACT

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THE LIVER

GENERAL FEATURES OF HEPATIC DISEASE

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Patterns of Hepatic Injury:
• hepatocyte degeneration
• intracellular accumulations
• hepatocyte necrosis and apoptosis
• inflammation
• regeneration
• fibrosis
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HEPATIC FAILURE:
• occurs when 80-90% of function is lost; 80% mortality rate
• Causes include:
• Fulminant liver failure - massive acute detraction
• Acute liver failure - liver illness assoc with encephalopathy within 6 mo of initial dx
• caused by hepatic necrosis (drugs/toxins), viral hepatitis, AI
• Chronic liver failure - end point of relentless chronic hepatitis ending in cirrhosis
• Hepatic dysfunction w/o overt necrosis (eg. tetracycline toxicity)
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Complications of Hepatic Failure
o Hepatic encephalopathy
o Associated with elevated ammonia levels
o impaired neuronal functioning → brain edema → confusion to coma, rigidity, hyper-
reflexia, asterixis
o Multiple organ failure
o Coagulopathy
o Hepatorenal syndrome
o Sodium retention, reduced water excretion, decreased renal perfusion and CRF
o Requires transplant, very poor px
o Hepatopulmonary syndrome
o Triad of chronic liver disease, hypoxemia, intrapulmonary vascular dilations
o NO may be the mediator →intrapulmonary vascular dilation and functional shunting of
blood from pulmonary arteries to veins → ventilation-perfusion mismatch
o Requires transplant
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CIRRHOSIS
• most common causes: EtOH, viral hepatitis, NASH, then biliary disease and hemochromatosis less freq;
20% is cryptogenic
• death results from progressive liver failure, complications of portal HTN, HCC
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• Morphologic features:
• bridging fibrosis (PT to PT and PT to CV)
• Parenchymal nodules (hepatocyte regeneration while encased in fibrosis)
• disruption of hepatic parenchyma architecture
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PORTAL HYPERTENSION
• form combo of increased flow into portal circulation and/or increased resistance to portal flow.
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Causes:
• Prehepatic
• Obstructive thrombosis
• Narrowing of the portal vein
• Massive splenomegaly with increased splenic flow, which secondarily increases the portal flow
• Post hepatic
• CHF
• Constrictive pericarditis
• Hepatic vein outflow obstruction
• Intra-Hepatic
• Cirrhosis (most common)
• Schisto
• Fatty change
• Granulomatous dx
• NRH
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Consequences of Portal Hypertension (4 major)
• Ascites
• Porto-systemic shunts (esophageal varices (most significant), haemorrhoids, caput medusa)
• Splenomegaly
• Hepatic encephalopathy
• Additional clinical consequences: testicular atrophy, malnutrition, spider angiomas, cirrhosis
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OVERVIEW OF MICROSCOPIC FINDINGS IN HEPATITIS
General Features
• Broad range of histologic appearances with some features in common
◦ Portal inflammation
▪ Infiltrate consists primarily of lymphocytes, may have admixed plasma cells,
histiocytes, and granulocytes
▪ Lymphoid follicles common in hepatitis C
▪ Nonspecific cholangiolar proliferation may be present at periphery of portal tract
◦ Lobular inflammation/necrosis
▪ Necrosis may be mild and spotty or confluent and bridging
▪ May be accompanied by ballooning degeneration, reactive hepatocellular changes
◦ Piecemeal necrosis (interface activity)
▪ Defined as extension of inflammation into adjacent parenchyma with destruction of
individual hepatocytes at interface
▪ Results in ragged interface between portal tract and hepatic parenchyma
◦ Fibrosis
• Predominant pattern of inflammation in a given case may be portal, periportal, lobular, or a
combination
◦ Acute hepatitis usually diffusely involves lobule and is not confined to portal area
• Lesions may be sporadically distributed within liver, resulting in sampling bias
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Grading
 • Grade 1 (minimal activity): Mild portal inflammation with scant piecemeal necrosis and no lobular
necrosis
• Grade 2 (mild activity): Mild portal inflammation with piecemeal necrosis but scant lobular spotty
necrosis
• Grade 3 (moderate activity): Moderate portal inflammation, piecemeal necrosis, spotty lobular
necrosis
• Grade 4 (severe activity): Marked portal inflammation, brisk piecemeal necrosis, significant spotty
lobular necrosis, areas of confluent necrosis resulting in bridging necrosis
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Staging
• Stage 1 (portal fibrosis): Mild fibrous expansion of portal tracts
• Stage 2 (periportal fibrosis): Fine periportal strands of connective tissue with only rare portal-portal
septa
• Stage 3 (septal or bridging fibrosis): Connective tissue bridges that link portal tracts to other portal
tracts and to central veins
• Stage 4 (cirrhosis): Established bridging fibrosis with regenerative nodules
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Histologic Patterns and Clinical Associations
• Predominantly portal-based hepatitis
◦ Autoimmune hepatitis
◦ Chronic hepatitis C
◦ Nonspecific reactive hepatitis
• Predominantly periportal hepatitis
◦ Autoimmune hepatitis
◦ Chronic viral hepatitis
◦ Drug-associated hepatitis
◦ α-1-antitrypsin deficiency
◦ Wilson disease
◦ Nonspecific reactive hepatitis
• Predominantly lobular hepatitis
◦ Acute viral hepatitis
◦ Chronic or unresolved viral hepatitis
◦ Autoimmune hepatitis
◦ Drug-associated hepatitis
◦ Nonspecific reactive hepatitis
• Some etiologies may occasionally have prominent cholestatic features
◦ Acute or unresolved viral hepatitis
◦ Autoimmune hepatitis
◦ Drug-associated hepatitis
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Differential Diagnoses
• Chronic biliary disease
◦ Copper deposition
◦ Bile duct damage or loss
◦ Elevation of alkaline phosphatase out of proportion to transaminases
◦ Appropriate serologic studies &/or imaging studies may be helpful
• Large bile duct obstruction
◦ Elevated alkaline phosphatase, GGT, and bilirubin
◦ Usually lacks increased fibrosis
◦ Imaging studies helpful
• Lymphoma
◦ Infiltrates composed of atypical lymphocytes
 ◦ Immunohistochemistry, gene rearrangement studies may be required
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Reporting
• Chronic hepatitis must be graded and staged in pathology report
◦ "Chronic persistent" and "chronic active" hepatitis should no longer be used
• Comments regarding etiology, if possible


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JAUNDICE AND CHOLESTASIS
• NB: bilirubin and bile formation
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CLASSIFICATION OF JAUNDICE:
• Unconjugated
o Excess bilirubin production
o Hemolysis
o Resorption of blood from internal hemorrhage
o Reduced hepatic uptake
o Medications
o Impaired conjugation leading to decreased excretion
o Physiologic of newborn
o Breast milk jaundice
o Genetic enzyme deficiency
▪ Crigler-Najjar syndrome type 1 and 2
▪ Gilberts syndrome
o Diffuse hepatocellular disease
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• Conjugated
o Hereditary enzyme deficiency
o Dubin-Johnson syndrome
o Rotor syndrome
o Impaired flow
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CHOLESTASIS
• impaired bile formation and flow → accumulation of intrahepatic bile pigments → dilated bile canaliculi
and hepatocyte degeneration
• obstruction → distended proliferating bile ducts in PT’s with edema and periductular pmn’s
• prolonged obstruction → extensive hepatocyte injury with formation of bile lakes, PT fibrosis and
cirrhosis
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Classification of Cholestasis
o Extrahepatic
o Intraductal
▪ Tumors
▪ Stones
o Inflammatory
▪ PSC
o Infectious
▪ Worms, parasites, cholecystitis
o Congenital – biliary atresia
o Intrahepatic
o Congenital
▪ Progressive familial intrahepatic cholestasis (PFIC) - 3 forms
▪ Metabolic disorders
▪ BRIC
▪ Biliary atresia
o Acquired
▪ Viral
▪ ASH
▪ NASH
▪ Pregnancy
▪ Post-op
▪ Drugs
▪ Shock and septicemia
▪ TPN
▪ Vanishing bile duct syndromes (PSC, AIH, PBC)
▪ Rejection
▪ GVHD
▪ ERCP
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INFECTIOUS DISORDERS
VIRAL HEPATITIS
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Clinicopathologic Syndromes of Viral Hepatitis
• Acute As’c Infection with Recovery
• Acute Sx’c Infection with Recovery
• Chronic Hepatitis
• Carrier State
• HIV and Chronic Viral Hepatitis
 The Hepatits Viruses
Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E

Type of virus ssRNA partially dsDNA ssRNA circular defective ssRNA

ssRNA

Viral family Hepatovirus; related Hepadnavirus Flaviviridae Subviral particle in Calicivirus

to picornavirus Deltaviriade family

Route of Fecal-oral Parenteral, sexual Parenteral; Parenteral Fecal-oral

transmission (contaminated food contact, perinatal intranasal cocaine
or water) use is RF

Mean incubation 2-4 weeks 1-4 months 7-8 weeks Same as HBV 4-5 weeks
period

Frequency of Never 10% ~80% 5% (coninfection); Never

chronic liver ≤70% for
disease superinfection

Diagnosis Dectection of serum Detection of PCR for HCV RNA; Detection of IgM PCR for HEV
IgM Ab’s HBsAg or Ab to 3rd gen ELISA for and IgG Ab’s; HDV RNA; detection of
HBcAg Ab detection RNA serum; HSAg serum IgM and
in liver IgG Ab’s

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MORPHOLOGY OF ACUTE AND CHRONIC HEPATITIS
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ACUTE HEPATITIS:
• injured hepatocytes: apoptotic or ballooning degeneration
• in very severe hepatitis, confluent damage causes bridging necrosis b/w PT and CV
• possible cholestasis
• Kupffer cell hyperplaia, macrophage aggregates at sites of cell loss
• mononuclear inflammation at PT often with spillover (interface hepatitis)
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Histologic Patterns in Acute Hepatitis
Key features Causes
Classic viral pattern Diffuse hepatocyte injury and necrosis Hepatitis viruses, drugs
Mononucleosis pattern Lobular inflammation in a sinusoidal EBV, HCV, CMV, drugs
distribution
Herpetic pattern Random scattered foci of necrosis HSV, adenovirus, VZV, enterovirus

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Histologic Features
• Lobular disarray
◦ Diffuse, mixed lobular inflammatory cell infiltrates
▪ Predominantly mononuclear inflammatory cell infiltrates
◦ Hepatocyte necrosis
▪ Foci of parenchymal collapse evident on trichrome or reticulin stains
◦ Hepatocyte swelling
◦ Hepatocyte regeneration
◦ Kupffer cell hyperplasia
• May see mild portal and periportal inflammation, particularly in acute hepatitis A virus infection
◦ Portal inflammation usually less prominent than lobular inflammation and injury
 • Pigment-laden macrophages may be seen on periodic acid-Schiff stain
• Areas of confluent hepatocyte necrosis in severe cases
• Canalicular cholestasis present in some cases
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Cytologic Features
• Hepatocyte swelling
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Predominant Pattern/Injury Type
• Inflammatory
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Predominant Cell/Compartment Type
• Hepatic lobules
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CHRONIC HEPATITIS:
• histo changes range from mild to severe cirrhosis
• mild: inflammation limited to PT
• progressive disease: extension of chronic inflammation from PT with interface hepatitis ; linking
PT-PT and PT-CV - bringing necrosis
• continued loss of hepatocytes → fibrous septum formation; assoc hepatocyte regeneration results
in cirrhosis
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Histologic Features of Hep B Infection
• Acute hepatitis B
◦ Hepatocytic swelling
◦ Inflammatory cell infiltrates
▪ Mainly mononuclear, including lymphocytes, plasma cells, and Kupffer cells
◦ Spotty necrosis
◦ Many apoptotic bodies
◦ Confluent necrosis
◦ Bridging necrosis
◦ Collapse of hepatocytic cords
▪ Best demonstrated by reticulin stain
◦ Hepatocytic regeneration
! • Chronic hepatitis B
◦ Portal inflammation
▪ Mononuclear inflammatory cells infiltrates, composed predominantly of
lymphocytes admixed with Kupffer cells and plasma cells
▪ May expand portal tracts
◦ Interface hepatitis
▪ Mononuclear inflammatory cells and apoptotic hepatocytes beyond limiting plate
▪ Previously termed piecemeal necrosis
◦ Lobular hepatitis
▪ Aggregates of mononuclear inflammatory cells, apoptotic hepatocytes, hepatocytic
debris, &/or confluent necrosis
◦ Fibrosis
▪ Begins in portal regions, extends beyond limiting plate, and then forms bridging
septa between portal-portal and portal-central regions
▪ Cirrhosis is final stage
 ▪ Stage of fibrosis indicates disease progression and is important therapeutic and
prognostic indicator
◦ Ground-glass hepatocytes
▪ Finely granular cytoplasmic inclusion
▪ Pushes cellular contents and nucleus to side due to proliferation of smooth ER in
response to abundant HBsAg
▪ Can be highlighted by Shikata Orcein stain, Victoria Blue stain, and anti-HBs
immunohistochemical stain
▪ Indicate chronic hepatitis B infection
▪ Not specific for hepatitis B
◦ Sanded nuclei of hepatocytes
▪ Pale pink granular inclusions in hepatocytic nuclei containing HBcAg
▪ Can be highlighted by anti-HBc immunohistochemical stain
▪ Extensive nuclear staining for anti-HBc indicates active HBV viral replication and
may suggest immunosuppression status
! • Fibrosing cholestatic hepatitis B
◦ Variant of viral hepatitis B that often has more progressive course and worse outcome
◦ Pathogenesis is thought to be due to viral cytopathic effect
◦ Occurs following orthotopic liver transplantation
◦ Also occurs in other immunosuppression status, such as chemotherapy
◦ Occurrence is less common nowadays due to better prevention and antiviral regimens
◦ Unique histopathology
▪ Hepatocytic swelling due to cholestasis
▪ Canalicular and bile ductal cholestasis
▪ Marked bile ductular reaction
▪ Extensive fibrosis beginning from portal tracts, surrounding hepatocytes within
sinusoidal spaces, with "serpiginous pattern"
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Semiquantitative Grading and Staging
• Grading denotes inflammatory activity while staging indicates degree of fibrosis
◦ Ishak score
▪ Modified from Knodell (histologic activity index) scoring system
▪ Composite score of portal inflammation, interface hepatitis, parenchymal injury,
and confluent necrosis appropriate for evaluation of large cohorts of patients
▪ Fibrosis score from 1-6
◦ Batts and Ludwig system
▪ Simple scoring system appropriate for management of individual patients
▪ Grading activity from 1-4 based on overall portal and lobular inflammatory activity
combined
▪ Staging fibrosis from 1-4

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Histologic Features of Hep C Infection
• Variably dense portal inflammatory cell infiltrates
◦ Portal inflammation includes predominantly lymphocytes
◦ Periportal interface activity
▪ Lymphocytes disrupt limiting plate and surround nearby hepatocytes, causing
hepatocyte injury and necrosis
• Scattered lobular collections of inflammatory cells with or without acidophil bodies
• Cholestatic hepatitis in some cases
 • Mild duct injury dubbed "Paulsen lesions"
• Mild, patchy steatosis may be seen, particularly in genotype 3b
• Progressive fibrosis begins in portal areas and extends outward in stellate fashion
• Histologic features are scored
◦ Grade: Extent and severity of interface activity and lobular inflammation and injury
◦ Stage: Extent of fibrosis
◦ Several grading and staging systems available
• Acute infection rarely recognized clinically and rarely biopsied
◦ Usually relatively mild lobular hepatitis
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CLASSIFICATION OF IRON OVERLOAD
o Hereditary
o HFE mutations
o HJV mutations
o Secondary
o Parenteral iron overload
o Anemia
o SCD
o Leukemias
o Myelodysplastic syndromes
o Ineffective erythropoesis with increased EPO
o Increased oral iron intake
o Chronic liver disease
o Porphyria
o Congenital
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CLASSIFICATION OF SYNDROMES WITH PAUCITY OF BILE DUCTS – bile duct:portal tract ratio < 0.5
o Syndromic
o Alagille syndome
o Non-syndromic
o Neonatal
▪ Bile duct atresia
▪ Non-syndromic paucity of bile ducts
o Adult
▪ PBC
▪ PSC
▪ Secondary due to chronic extrahepatic obstructions
▪ Overlap syndrome
▪ Sarcoidosis with intrahepatic cholestasis
▪ Idiopathic
▪ Rejection
▪ GVHD
▪ Drug induced
▪ Secondary to neoplasia (HL, LCH)
▪ Mucoviscidosis
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CYSTIC LESIONS OF THE BILIARY TREE
o Von Meyenberg complexes
o Small subcapsular, produce bile or mucin
 o Polycystic liver disease
o Congenital hepatic fibrosis
o Multiple ductal plate malformations with fibrosis
o Strongly associated with AR PCKD
o Caroli disease
o The larger ducts of the intrahepatic biliary tree are dilated
o Usually associated with congenital hepatic fibrosis
o AD PCKD can be associated with any of the above syndromes
o Alagille syndrome
o Rare AD disorder characterized by absence of bile ducts in the portal tracts
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Cystic Masses of the Liver (Sternberg)
Abscesses
Amebic
Pyogenic
Parasitic (echinococcal) cysts
Nonparasitic (nonneoplastic) cysts
Solitary (unilocular) biliary
Fibropolycystic diseases
Adult polycystic kidney disease (ADPKD)
Polycystic liver disease w/o ADPKD
Caroli disease
Caroli syndrome
Congenital hepatic fibrosis (ARPKD)
Multiple hilar cysts
Mesenchymal hamartoma
Alimentary tract-related cysts
Pseudocysts (trauma, ischemia, pancreatic origin)
Neoplastic cysts
Biliary cystadenoma/cysadenocarcinoma
Mucinous type
Serous (microcystic, glycogen rich) type
Teratoma

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MAJOR VASCULAR DISORDERS OF THE LIVER
o Impaired Blood Flow Into Liver
o Hepatic Artery Compromise
▪ thrombosis or compression of intrahepatic arterial branches → localized pale
infarct
o Portal Vein Obstruction and Thrombosis
▪ Intraabdominal sepsis resulting in pyelophlebitis of the splanchnic system
▪ Acquired or Inherited Hypercoagulable disorders
▪ Trauma
▪ Pancreatitis and pancreatic cancer (initiate splanchnic thrombosis)
▪ Extension of HCC into the portal vein
 ▪ Cirrhosis associated with portal vein thrombosis in 25%
! o Impaired Intrahepatic Blood Flow
o Cirrhosis (most important cause)
o Sinusoid occlusion
▪ Sarcoidosis
▪ Metastatic tumors
▪ Sickle cell disease
▪ DIC
o Passive Congestion and Centrilobular Necrosis
▪ Systemic hypoperfusion (shock)
▪ Superimposed HF or pericarditis → centrilobular hemorrhagic necrosis
▪ protracted HF →cardiac sclerosis
o Peliosis Hepatitis (reversible sinusoidal dilation assoc with several disorders)
o Nodular Regenerative Hyperplasia
▪ can lead to non cirrhotic portal HTN
! o Hepatic Venous Outflow Obstruction
o Hepatic vein thrombosis and Inferior Vena Cava Thrombosis
▪ Budd-Chiari - when 2+ major hepatic veins are obstructed → hepatic damage form
increased intrahepatic blood pressure
▪ Primary myeloproliferative disorders
▪ Disorders of coagulation
▪ Antiphospholipid antibody syndrome
▪ PNH
▪ Cancers – HCC
▪ Pregnancy
▪ OCP use
▪ Idiopathic
o Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease)
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HEPATIC COMPLICATIONS OF ORGAN OR BONE MARROW TRANSPLANTATION
! o GVHD: direct lymphocyte attack on liver cells, esp bile duct epithelium
o Acute – hepatitis (parecnhymal inflammation and hepatocyte necrosis), chronic vascular
inflammation and intimal proliferation (endothelialitis) and bile duct destruction
o Chronic – >100 days post transplant, PT inflammation, bile duct destruction and fibrosis,
endothelialitis may be seen
! o LIVER REJECTION
o Acute – mixed inflammatory cells, hepatitis, bile duct injury, endothelialitis
o Chronic – months to years post transplant - obliterative arteritis resulting in ischemia to the
parenchyma, progressive loss of bile ducts, eventual graft failure
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Banff Criteria for Grading Acute Liver Allograft Rejection
Global Assessment Criteria
Indeterminate portal inflammatory infiltrate that fails to meet criteria for dx of acute rejection
Mild infiltrate in minority of triads that is generally mild and confined within portal spaces
Moderate infiltrate expands t most or all of triads
 Severe as aobve for moderate, with spillover into periportal areas and mod to severe perivneular inflammation that
extends into hepatic parenchyma and is assoc with perivenular hepatocyte necrosis

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Banff Criteria for Chornic Liver Allograft Rejection (CR)
Structure Early CR Late CR
Small bile ducts • degen Δ’s involving majority of ducts • degen Δ’s in remaining bile ducts
•eo’c transofrmaiton of cytoplasm • loss in ≥50% of PT’s
•↑ N:C
•nuclear hyperchromasia
•uneven nuclear spacing
•ducts only partially lined by
biliary epithelial cells
• bile duct loss in <50% Pt’s
Terminal hepatic venules and • intimal/luminal inflammation • focal obliteration
zone 3 hepatocytes • lytic zone 3 necrosis and • varibale inflammation
inflammation • severe (bridign) fibrosis
• mild perivenular fibrosis
PT hepatic arterioles • occ’l loss involving <25% PT’s • loss involving >25% PT’s
Other • so-called transition hepatitis with • sinusoidal foam cell accumulation
spotty necrosis of hepatocytes • marked cholestasis
Larger perihilar hepatic artery • intimal inflammation, focal foam cell • luminal narrowing by subintiaaml foam
branches deposition w/o luminal compromise cells
• fibrointimal prolifertation
Large perihilar bile ducts • inflammation damage and focal foam • mural fibrosis
cell deposition

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HEPATIC DISEASE IN PREGNANCY
o Preeclampsia
o Fibrin thrombi in the sinusoids and hemorrhage in space of disse
o Hepatocellular necrosis
o Hepatic hematoma
o Acute fatty liver of pregnancy
o Microvesicular fatty transformation of the hepatocytes
o Severe cases can resemble acute hepatitis
o Intrahepatic cholestasis of pregnancy – generally runs a benign course
o Viral hepatitis
o HEV runs a more severe course in pregnant patients – fatality 10-20%
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Scoring system for NAFLD
o Steatosis
o Lobular inflammation
o Hepatocyte ballooning
o Stage the fibrosis
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Grading and Staging of Nonalcoholic Fatty Liver Disease (NAFLD)
Component scores for grading
Steatosis Lobular Inflammation Hepatocellular ballooning
0: <5% 0: None 0: None
1: 5-33% 1: <2/20x field 1: Mild, few
2: 34-66% 2: 2-4/20x field 2: Moderate-marked, many
3: >66% 3: >4/20x field
NAFLD activity score:NAS 0-8 (steatosis + lobular inflammation + hepatocellular ballooning
Fibrosis Scoring: Based on Masson trichrome stain
0: None
1a: Delicate Zone 3 perisinusoidal fibrosis, req trichrome stain
1b: Dense Zone 3 perisinusoidal fibrosis, visible on H and E
1c: Portal/periportal fibrosis
2: Zone 3 perisinusoidal and portal fibrosis
3: Bridging
4: Cirrhosis

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NODULES AND TUMORS
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CLASSIFICATION
o NON-NEOPLASTIC -
o Bile Duct Hamartoma: benign, non-encapsulated “angulated/dilated” glands
o no mitoses, angulated/dilated lumen; fibrous stroma; +ve bile; non-infiltrative; lymphocytes
present; usually small
o may have potential syndromic assoc with ADPKD
o Bile Duct Adenoma: benign, non-encapsulated “ductular reaction”
o no mits, hard to find lumen; fibrous stroma; NO bile; non-infiltrative; lymphocytes, usually
small
o helpful stain (rarely needed): mucin (intracytoplasmic), CEA, EMA, keratin, PAS highlights
BM;s
o Nodular Hyperplasias
o are solitary or multiple benign hepatocellular nodules in absence of cirrhosis
o cause thought to be from focal hepatic vascular obliteration with compensatory hypertrophy
of adjacent well-vascularized lobules
▪ FNH: “cirrhosis that is focal”
• mass lesion in non-cirrhotic liver
• young to middle aged adults; irreg, unencapsulated mass containing central
stellate scar
• central dysplastic artery, daughter arteries and ductules in septae; not NO bile
duct and benign heptocytes
▪ NRH – nodules in the absence of fibrosis, can lead to portal hypertension, associated
with renal transplantation, bone marrow transplantation, vasculitis, HIV, CTD
o Partial nodular transformation – generally occurs at the hilum, associated with RA
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o NEOPLASTIC
o Benign
• Hepatic adenomas: occur only in non-cirrhotic livers
• F>M, assoc with prolonged use of oral contraceptives, men on anabolic steroid use,
certain metabolic disorders (eg. some glycogensoes, MODY3, tyrosinosis)and
obesity; no RF for chronic liver disease; some may have familial link
• those arising in background of metabolic disorder → inc risk to HCC
• usually solitary; consist of bland hepatocytes 1 - 3 cell layers thick with minimal
nuclear pleomorphism
• small unaccomp arteries and sinusoids are present but no PT’s and bile ducts
• may or may not be encapsulated
• must differentiate from normal liver, HCC and FNH
• possible outcomes: rupture/hem’g; malignant transformation
! 4 genetic subtypes:
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1. HNF1α mutation (35-40%)
o characterized by steatosis, more likely to be multifocal cf other subtypes
o LOSS of staining for LFABP
o gene reguated the FABP1 gene that codes for LFABP (liver fatty acid binding
protein)
o low risk of malig progression (7%)
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2. β-catenin activated adenomas (10-15%)
o nuclear and cyto β-catenin and unregulated expression of glutamine
synthetase (diffuse) by IHC
o may have borderline histology, incl pseudoacinar architecture
 o more common in men than other subtypes; also in glycogenoses and FAP pts
o assoc with highest risk of progression to HCC (46%)
! 3. Inflammatory, non-mutated (IA) (45-60%);
o previously called telangiectatic FNH
o due to mutation of gp130 (target site for IL-6) and over expression of inflame
markers SAA and CRP by IHC, also shows CK7+
o assoc with obesity and EtOH use
o often hemorrhagic with foci of sinusoidal dilatation and peliosis and abN
vessels
o chronic inflame infiltrates common along fibrovasc setae with periseptal
ductular reaction
o up to 10% of these also show β-catenin
o 0% risk to HCC
! 4. Unclassified; Non-mutated, non-inflammatory (10%)
o has no defined genotyipc or phenotypic features
▪ Mesenchymal – hemangioma, paraganglioma
! o Malignant
▪ HCC
▪ Hepatoblastoma – may be associated with FAP and BW syndrome
• activation of Wnt/β-catenin signalling pathway
▪ Cholangiocarcinoma
• Intrahepatic (10%)
• Extrahepatic (90%)
▪ Mesenchymal – hemangioendothelioma, angiosarc, mesenchymal sarc
▪ Metastatic tumors
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• Helpful histologic features of HCC:
• hepatocellular differentiation WITH:
• variation from background
• thick plates (CD34+ sinusoids due to neovasc, Reticulin)
• unpaired arteries
• reticulin deficiency
• portal tract or sinusoidal infiltration
• vascular invasion
• N:C ratio
• nuclear atypia

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NB: Fibrolamellar variant:
• young adults
• no underlying chronic liver disease
• can be very large and vascular invasive
• large tumor cells; large nucleoli; abundant eo’c cytoplasm; lamellar fibrosis
• CK7+ and HepPar1+, CK19- (ONLY HCC that is CK7 pos!)
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PRENEOPLASTIC LESIONS: DYSPLASTIC NODULES:
• DN’s are nodular lesions displaying some degree of cytologic or architectural atypia but lacking definitive
histologic features of malignancy.
• further subdivided into low and high grades, depending on the degree of histologic abnormality.
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Features of dysplastic nodules in liver
Feature LG-DN HG-DN
Nuclear stypia minimal hyperchromasia and pleomorphism
Small cell change rare may be present
Clone-like growth pattern (uniform present Present; may have nodule-within-nodule
population of hepatocytes with growth pattern suggestive of subclone
map-like growth pattern evolution
Liver cell plates 1-2 cell layers thick focal areas >2 cells thick
Unpaired arteries rare common

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HEPATOCELLULAR CARCINOMA
o Risk factors
o Modifiable
▪ HBV, HCV, NASH, NAFLD, alcohol and food contaminants
o Genetic
▪ Males, tyrosinemia (40% of individuals develop HCC), glycogen storage diseases,
hereditary hemochromatosis, AAT deficiency, age
o Cirrhosis is typically absent in carriers of HBV
o Cirrhosis is typically present in non-HBV associated HCC
o Aflatoxin gives a signature mutation in p53
o Grossly may be unifocal, multifocal, of diffusely infiltrative
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CHOLANGIOCARCINOMA
o Risk factors
o Modifiable
▪ HCV infection
o Environmental
▪ Thorotrast exposure
o Non-modifiable/genetic
▪ PSC
▪ Congenital fibrocystic conditions (Caroli’s, PCLD, PCKD, congenital hepatic
fibrosis, choledochal cysts)
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THE BILIARY TRACT
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Classification of Gallstones
o Cholesterol stones
o Older
o Females – all the F’s
o Oral contraceptives
o Pregnancy
o Rapid weight loss
o Hyperlipidemia
o Pigment stones
o Asians
o Hemolysis
o Biliary infection – liver flukes, Ascaris
▪ Microbial beta-glucuronidases lead to increased unconjugated bilirubin
o GI disorders
o Mixed stones
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CHOLECYSTITIS
o Acute
o Most cases are secondary to stone impaction and the etiology is thought to be ischemic
o Primary bacterial infection can occur but is rare
o Chronic
o Results from multiple attacks of acute cholecystitis
o Complications
o Bacterial superinfection – cholangitis or sepsis
o Perforation with abscess formation
o Biliary enteric fistula – gallstone ileus
o Aggravation of pre-existing disease
o Carcinoma
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• Ascending cholangitis: results from any lesion that causes obstruction of biliary drainage – most
frequently choledocholithiasis and strictures.
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Classification of Biliary Atresia
o Fetal (20%) – associated with other anomalies
o Perinatal – a normally developed biliary tree is destroyed after birth, viral infection and
autoimmunity may play a role
o Type I – limited to common duct
o Type II – limited to common and hepatic ducts
o Type III (90%) – obstruction at or above the porta hepatis
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Classification of choledochal cysts
• Type I: Most common variety (80-90%) involving saccular or fusiform dilatation of a portion or entire
common bile duct (CBD) with normal intrahepatic duct.
• Type II: Isolated diverticulum protruding from the CBD.
• Type III or Choledochocele: Arise from dilatation of duodenal portion of CBD or where pancreatic duct
meets.
• Type IVa: Characterized by multiple dilatations of the intrahepatic and extrahepatic biliary tree.
• Type IVb: Multiple dilatations involving only the extrahepatic bile ducts.
• Type V or Caroli’s disease: Cystic dilatation of intra hepatic biliary ducts.
o More common in females
o Predispose to:
 o Stone formation
o Stenosis
o Strictures
o Pancreatitis
o Obstructive biliary complications
o Carcinoma in the elderly
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