LIVER PATHOLOGY

LIVER
PATHOLOGY
- BY SURAJ DHARA

HISTOLOGY OFHISTOLOGY OF
THETHE LIVERLIVER
• HEPATICHEPATIC LOBULESLOBULES vs.vs. ACINIACINI
1 2 3
Portal
tract
Central
vein
Portal tract
Traditional conception of liver
histology, arbitrarily divided into
centrilobular, periportal
(peripheral) & midlobular zones
Acini are defined by micro-
circulatory layout of liver, with a
central axis (portal tract & its
afferent vessels), surrounded by 3
zones

THETHE LIVERLIVER
• Portal triads: contain aPortal triads: contain a
bile duct, a small hepaticbile duct, a small hepatic
artery and a portal veinartery and a portal vein
branch, surrounded bybranch, surrounded by
type I & III collagentype I & III collagen
• Central vein (tributaryCentral vein (tributary
of hepatic vein) withof hepatic vein) with
blood to hepaticblood to hepatic
parenchyma flowingparenchyma flowing
from the portal triads tofrom the portal triads to
the central veinsthe central veins

DISEASES OF
THETHE LIVERLIVER
• Hepatic injuryHepatic injury
• Jaundice & cholestasisJaundice & cholestasis
• Hepatic failureHepatic failure
• CirrhosisCirrhosis
• Inflammatory disorders: hepatitis, abscessesInflammatory disorders: hepatitis, abscesses
• Drug & toxin-related diseases: alcohol liverDrug & toxin-related diseases: alcohol liver
diseasedisease
• Inborn error of metabolism & pediatric liverInborn error of metabolism & pediatric liver
disease: Hemochromatosis, Wilsondisease: Hemochromatosis, Wilson’’s disease,s disease,
neonatal hepatitis & Reyeneonatal hepatitis & Reye’’s syndromes syndrome
• Intrahepatic biliary tract disease: PBC, PSCIntrahepatic biliary tract disease: PBC, PSC
• Circulatory disordersCirculatory disorders
• TumorsTumors

HISTOLOGIC PATTERNS OFHISTOLOGIC PATTERNS OF
HEPATIC INJURYHEPATIC INJURY
• Inflammation: acute or chronic hepatitis; portal
or lobular
• Degeneration: ballooning, foamy, steatosis
• Necrosis: coagulative or lytic (hydropic);
Councilman bodies; centrilobular, focal, piece-
meal, bridging, submassive, massive
• Fibrosis: portal, central, bridging
• Cirrhosis: regenerative nodules surrounded by
fibrosis

HISTOLOGIC PATTERNS OF HEPATIC INJURYHISTOLOGIC PATTERNS OF HEPATIC INJURY
STEATOSISSTEATOSIS
• Fat (neutral fat,Fat (neutral fat,
triglycerides) intriglycerides) in
liver cellsliver cells
indicates defect inindicates defect in
lipid metabolismlipid metabolism
or lipoproteinor lipoprotein
synthesis orsynthesis or
unusual amountsunusual amounts
of adipose orof adipose or
dietary lipidsdietary lipids
brought to liverbrought to liver

HISTOLOGIC PATTERNS OF HEPATIC INJURYHISTOLOGIC PATTERNS OF HEPATIC INJURY
HEPATOCYTE SWELLINGHEPATOCYTE SWELLING
• Swelling orSwelling or
hydropichydropic
change is achange is a
result ofresult of
defects indefects in
membranemembrane
and/orand/or
mitochondrialmitochondrial
functionfunction

Histologic patterns of
hepatic injury
NECROSISNECROSIS
• CoagulativeCoagulative
necrosis: poorlynecrosis: poorly
staining mummifiedstaining mummified
hepatocyteshepatocytes
• Councilman bodies:Councilman bodies:
dead hepatocytesdead hepatocytes
• Lytic necrosis:Lytic necrosis:
hepatocytes swell &hepatocytes swell &
rupturerupture

PHYSIOLOGY OF THE LIVER
BILIRUBIN METABOLISMBILIRUBIN METABOLISM
• Aging RBCs HEME MACROPHAGE
Heme
oxygenase
Biliverdin
reductase
BILIVERDIN
BILIRUBIN-
Albumin complex
BILIRUBIN
GLUCORONIDES
UDP
U
R
O
B
I
L
I
N
O
G
E
N
beta-glucuronidase

PHYSIOLOGY OF
THE LIVERTHE LIVER
• In addition toIn addition to bilirubinbilirubin, the liver secretes 12-36 g, the liver secretes 12-36 g
bile acidsbile acids/day: carboxylated steroid molecules/day: carboxylated steroid molecules
derived from cholesterol & hydroxyl groupsderived from cholesterol & hydroxyl groups
– Cholic acid & chenodeoxycholic acidCholic acid & chenodeoxycholic acid
– Secreted as taurine & glycine conjugatesSecreted as taurine & glycine conjugates
– 10-20% are deconjugated in ileum10-20% are deconjugated in ileum
– 0.2-0.6 g/d fecal loss matched by de novo liver synthesis0.2-0.6 g/d fecal loss matched by de novo liver synthesis
• Functions of hepatic bile:Functions of hepatic bile:
– 1) Primary pathway for elimination of water-insoluble1) Primary pathway for elimination of water-insoluble
bilirubin, excess cholesterol & xenobioticsbilirubin, excess cholesterol & xenobiotics
– 2) Emulsification of dietary fat in gut lumen2) Emulsification of dietary fat in gut lumen

PATHOLOGY OF THE LIVERPATHOLOGY OF THE LIVER
JAUNDICEJAUNDICE
• Jaundice:Jaundice: yellowish discoloration of skin & sclerayellowish discoloration of skin & sclera
(icterus) due to systemic retention of bilirubin (> 2(icterus) due to systemic retention of bilirubin (> 2
mg/dl)mg/dl)
• EquilibriumEquilibrium between bilirubin production &between bilirubin production &
clearance is disturbed:clearance is disturbed:
– 1) Excessive production1) Excessive production
– 2) Reduced hepatocellular uptake2) Reduced hepatocellular uptake
– 3) Impaired conjugation3) Impaired conjugation
– 4) Decreased hepatocellular excretion4) Decreased hepatocellular excretion
– 5) Impaired bile flow5) Impaired bile flow
• Kernicterus:Kernicterus: accumulation of bilirubin in brainaccumulation of bilirubin in brain

TYPES OF
JAUNDICEJAUNDICE
• UNCONJUGATEDUNCONJUGATED
BILIRUBINBILIRUBIN
– Water-insolubleWater-insoluble
– Tightly complexed toTightly complexed to
serum albuminserum albumin
– Cannot be excreted inCannot be excreted in
urineurine
– Free form is toxicFree form is toxic
– Lab test: TotalLab test: Total
bilirubin minus directbilirubin minus direct
bilirubinbilirubin
• CONJUGATEDCONJUGATED
BILIRUBINBILIRUBIN
– Water-solubleWater-soluble
– Loosely bound toLoosely bound to
serum albuminserum albumin
– Excess amounts areExcess amounts are
excreted in urineexcreted in urine
– NontoxicNontoxic
– Lab test: measuredLab test: measured
by direct bilirubinby direct bilirubin

LAB EVALUATION OF LIVER DISEASE
LIVER FUNCTION TESTSLIVER FUNCTION TESTS
• Tests of hepatocyte integrityTests of hepatocyte integrity
– ASL (SGOT)*ASL (SGOT)*
– ALT (SGPT)*ALT (SGPT)*
– LDHLDH
• Tests of biliary excretory functionTests of biliary excretory function
– Serum Bilirubin*Serum Bilirubin*
– Alkaline phosphatase*Alkaline phosphatase*
– Gamma-glutamyl transpeptidasGamma-glutamyl transpeptidas
• Tests of hepatocyte functionTests of hepatocyte function
– Albumin*Albumin*
– ProthrombineProthrombine time*time*
– AmmoniaAmmonia
– Aminopyrine breath test; galactose eliminationAminopyrine breath test; galactose elimination

PATHOLOGY OF THE LIVER
CHOLESTASISCHOLESTASIS
• SystemicSystemic retentionretention of bilirubin and other solutesof bilirubin and other solutes
eliminated in bile (e.g. bile salts & cholesterol)eliminated in bile (e.g. bile salts & cholesterol)
• Results from hepatocellular dysfunction & (intra-Results from hepatocellular dysfunction & (intra-
or extrahepatic) biliary obstructionor extrahepatic) biliary obstruction
• c/oc/o: Jaundice, pruritis, skin xanthomas, malabs.: Jaundice, pruritis, skin xanthomas, malabs.
• LabLab: Elevated bilirubin, alk. phosphatase, lipids: Elevated bilirubin, alk. phosphatase, lipids
• BxBx: bile pigment accumulation, foamy degenerat-: bile pigment accumulation, foamy degenerat-
ion, bile duct distension & proliferation, bile lakes,ion, bile duct distension & proliferation, bile lakes,
portal tract fibrosis, cholangitis & cholangiolitisportal tract fibrosis, cholangitis & cholangiolitis
• TypesTypes::
– IntrahepaticIntrahepatic
– ExtrahepaticExtrahepatic

PATHOLOGY OF
CHOLESTASISCHOLESTASIS
• Accumulation of bile pigment within hepatic parenchymaAccumulation of bile pigment within hepatic parenchyma
• Hepatocyte swelling and foamy degenerationHepatocyte swelling and foamy degeneration
• Bile duct proliferation secondary to biliary treeBile duct proliferation secondary to biliary tree
obstructionobstruction
• Hepatocyte necrosis, bile lakes, & portal tract fibrosisHepatocyte necrosis, bile lakes, & portal tract fibrosis

PEDIATRIC LIVER DISEASESPEDIATRIC LIVER DISEASES
NEONATAL CHOLESTASISNEONATAL CHOLESTASIS
• Prolonged conjugated hyperbilirubinemia in the newbornProlonged conjugated hyperbilirubinemia in the newborn
• Major causes:Major causes: EHBA & neonatal hepatitisEHBA & neonatal hepatitis
– Bile duct obstruction: Extrahepatic biliary atresiaBile duct obstruction: Extrahepatic biliary atresia
(EHBA)(EHBA)
– Neonatal infections: CMV, sepsis, UTI, syphilisNeonatal infections: CMV, sepsis, UTI, syphilis
– Toxic: drugs, parenteral nutritionToxic: drugs, parenteral nutrition
– Metabolic diseases: tyrosinemia, Niemann-PickMetabolic diseases: tyrosinemia, Niemann-Pick
disease, galactosemia, AAT deficiency, cysticdisease, galactosemia, AAT deficiency, cystic
fibrosis, ..fibrosis, ..
– Miscellaneous: shock, hypoperfusion, AlagilleMiscellaneous: shock, hypoperfusion, Alagille’’ss
syndrome (paucity of bile ducts), ..syndrome (paucity of bile ducts), ..
– Idiopathic neonatal hepatitisIdiopathic neonatal hepatitis

PEDIATRIC LIVER DISEASESPEDIATRIC LIVER DISEASES
NEONATAL CHOLESTASISNEONATAL CHOLESTASIS
• Clinical presentation is typical: jaundice, darkClinical presentation is typical: jaundice, dark
urine, light stools, hepatomegalyurine, light stools, hepatomegaly
• Neonatal hepatitis may be primary (idiopathic) orNeonatal hepatitis may be primary (idiopathic) or
secondarysecondary
• Idiopathic neonatal hepatitis (50-60%),Idiopathic neonatal hepatitis (50-60%),
extrahepatic biliary atresia (20%) & AATextrahepatic biliary atresia (20%) & AAT
deficiency (15%)deficiency (15%)
• Distinction between these disorders is essentialDistinction between these disorders is essential
because management is differentbecause management is different
• Liver biopsyLiver biopsy is important in the diagnosisis important in the diagnosis

HEPATIC FAILUREHEPATIC FAILURE
• Mostly due to progressive, or less often suddenMostly due to progressive, or less often sudden
massive hepatic destruction with loss of 80-90%massive hepatic destruction with loss of 80-90%
of hepatic functional capacityof hepatic functional capacity
• Causes:Causes:
– 1) Chronic liver diseases.1) Chronic liver diseases.
– 2) Massive hepatic necrosis (fulminant failure): viral2) Massive hepatic necrosis (fulminant failure): viral
hepatitis, drug & chemical toxicity (acetaminophen,hepatitis, drug & chemical toxicity (acetaminophen,
halothane, rifampicin, MOI antidepressants, CClhalothane, rifampicin, MOI antidepressants, CCl44,,
AmanitaAmanita mushroom toxinsmushroom toxins
– 3) Hepatic dysfunction without overt necrosis: viable3) Hepatic dysfunction without overt necrosis: viable
but nonfunctional hepatocytes, e.g. Reyebut nonfunctional hepatocytes, e.g. Reye’’s syndrome,s syndrome,
tetracycline toxicity, acute fatty liver of pregnancytetracycline toxicity, acute fatty liver of pregnancy

Table 18-2. Clinical Consequences of Liver Disease
Characteristic
signs
Hepatic dysfunction:
•Jaundice and cholestasis
•Hypoalbuminemia
•Hyperammonemia
•Hypoglycemia
•Fetor hepaticus
•Palmar erythema
•Spider angiomas
•Hypogonadism
•Gynecomastia
•Weight loss
•Muscle wasting
Portal hypertension from cirrhosis:
•Ascites
•Splenomegaly
•Hemorrhoids
•Caput medusae-abdominal skin

Life-threatening
complications •Hepatic failure
•Multiple organ failure
•Coagulopathy
•Hepatic encephalopathy
•Hepatorenal syndrome
•Portal hypertension from cirrhosis
•Esophageal varices, risk of
rupture
•Malignancy with chronic disease
•Hepatocellular carcinoma

HEPATIC FAILUREHEPATIC FAILURE
• Most cases are due to overwhelmingMost cases are due to overwhelming viralviral
hepatitishepatitis andand alcoholic liver diseasealcoholic liver disease
• Symptoms may occur within days with orSymptoms may occur within days with or
withoutwithout priorprior history of liver diseasehistory of liver disease
• A variety ofA variety of stressful eventsstressful events may contributemay contribute
to onset of failure:to onset of failure:
– GI bleedingGI bleeding
– Acute infectionsAcute infections
– Electrolyte disturbancesElectrolyte disturbances
– Major surgery, heart failure, shockMajor surgery, heart failure, shock
• TreatmentTreatment: not satisfactory: not satisfactory
• PxPx: 80% mortality rate: 80% mortality rate

HEPATIC ENCEPHALOPATHYHEPATIC ENCEPHALOPATHY
• A metabolic disorder of CNS & neuromuscularA metabolic disorder of CNS & neuromuscular
system associated with severe loss ofsystem associated with severe loss of
hepatocellular function & portosystemic shuntinghepatocellular function & portosystemic shunting
• The brain is exposed to anThe brain is exposed to an altered metabolicaltered metabolic
environmentenvironment (ammonia?) which impairs neuronal(ammonia?) which impairs neuronal
function & promotes generalized brain edemafunction & promotes generalized brain edema
• Patients exhibit aPatients exhibit a wide rangewide range of disturbances ofof disturbances of
consciousness: subtle behavioural changes,consciousness: subtle behavioural changes,
confusion, stupor, deep coma & deathconfusion, stupor, deep coma & death
• Other neurologic signs: Rigidity, hyperreflexia,Other neurologic signs: Rigidity, hyperreflexia,
EEG changes, seizures, asterixisEEG changes, seizures, asterixis
• Minor morphologic changes in brainMinor morphologic changes in brain

HEPATO-RENAL SYNDROMEHEPATO-RENAL SYNDROME
• Development of renal failure in patients withDevelopment of renal failure in patients with
severe liver disease,severe liver disease, withoutwithout presence of intrinsicpresence of intrinsic
morphologic or functional causes in the kidneymorphologic or functional causes in the kidney
• Excluded are cases of concomitant damage toExcluded are cases of concomitant damage to
liver & kidneys and acute tubular necrosisliver & kidneys and acute tubular necrosis
secondary to circulatory collapsesecondary to circulatory collapse
• PathogenesisPathogenesis: due to VC & decreased renal BF?: due to VC & decreased renal BF?
• c/oc/o: decrease in urine output: decrease in urine output
• Retained ability to concentrate urine:Retained ability to concentrate urine:
Hyperosmolar urine, protein -ve & low NaHyperosmolar urine, protein -ve & low Na
++
• LabLab: Increased blood urea and creatinine: Increased blood urea and creatinine
• PxPx: May hasten death or may persist for months: May hasten death or may persist for months

CIRRHOSISCIRRHOSIS
• IrreversibleIrreversible end stage of chronic liver disease,end stage of chronic liver disease,
which leads to parenchymal injury and fibrosiswhich leads to parenchymal injury and fibrosis
• 3 histologic features:3 histologic features:
– 1) Bridging fibrous septa1) Bridging fibrous septa
– 2) Disruption of2) Disruption of entireentire liver architectureliver architecture
– 3) Parenchymal nodules3) Parenchymal nodules

ETIOLOGIC CLASSIFICATION OF
CIRRHOSISCIRRHOSIS
• Viral hepatitisViral hepatitis
• Alcoholic liver diseaseAlcoholic liver disease
• Biliary diseasesBiliary diseases
• Genetic hemochromatosisGenetic hemochromatosis
• WilsonWilson’’s diseases disease
∀ αα11-antitrypsin deficiency-antitrypsin deficiency
• Drugs (Drugs (αα-methyldopa, acetaminophen-methyldopa, acetaminophen……))
• Ca, syphilisCa, syphilis
• Galactosemia, tyrosinosis..Galactosemia, tyrosinosis..
• ““Cardiac cirrhosisCardiac cirrhosis””
• Cryptogenic cirrhosisCryptogenic cirrhosis

Etiologic Factors Of Cirrhosis
Alcoholic liver disease 60% to 70%
Viral hepatitis 10%
Biliary diseases 5% to 10%
Primary hemochromatosis 5%
Wilson disease Rare
α1
-Antitrypsin deficiency Rare
Cryptogenic cirrhosis 10% to 15%

PATHOGENESIS OF
CIRRHOSISCIRRHOSIS
• Progressive fibrosis with collagen types I & IIIProgressive fibrosis with collagen types I & III
deposited in all portions of lobule. (Ito cell)deposited in all portions of lobule. (Ito cell)
• Collagen synthesis & deposition is stimulated by:Collagen synthesis & deposition is stimulated by:
– Chronic inflammation & cytokine productionChronic inflammation & cytokine production
(TNF, IL-1)(TNF, IL-1)
– Cytokine production by endogenous liver cellsCytokine production by endogenous liver cells
– Disruption of extracellular matrixDisruption of extracellular matrix
– Direct stimulation of Ito cells by toxinsDirect stimulation of Ito cells by toxins
• This is accompanied by alterations in sinusoidalThis is accompanied by alterations in sinusoidal
endothelial cellsendothelial cells
• > resulting in severe disruption of blood flow &> resulting in severe disruption of blood flow &
impaired diffusion of solutes & proteinsimpaired diffusion of solutes & proteins

PATHOLOGY OF
CIRRHOSISCIRRHOSIS
• MicronodularMicronodular
cirrhosiscirrhosis nodules &nodules &
scars of uniform sizescars of uniform size
• Macronodular cirrhosisMacronodular cirrhosis
nodules & scars ofnodules & scars of
variable sizevariable size

CLINICAL FEATURES OF
CIRRHOSISCIRRHOSIS
• Clinical features:Clinical features:
– May be asymptomaticMay be asymptomatic
– Nonspecific symptoms: malaise, anorexia, weightNonspecific symptoms: malaise, anorexia, weight
loss, weaknessloss, weakness
– Jaundice, ascites, peripheral edemaJaundice, ascites, peripheral edema
– serum transaminases, bilirubin, alk. phosph.serum transaminases, bilirubin, alk. phosph.
– serum protein (globulins, albumin, C.F.), Hbserum protein (globulins, albumin, C.F.), Hb
– Advanced disease: frank debilitationAdvanced disease: frank debilitation
– Hepatic failureHepatic failure
• Prognosis:Prognosis: ultimately will die of:ultimately will die of:
– Progressive hepatic failureProgressive hepatic failure
– Portal hypertensionPortal hypertension
– Hepatocellular carcinomaHepatocellular carcinoma

PORTAL HYPERTENSIONPORTAL HYPERTENSION
• == Increased resistance to portal blood flowIncreased resistance to portal blood flow
• Causes:Causes:
– I. Pre-hepatic:I. Pre-hepatic:
• Portal vein thrombosisPortal vein thrombosis
• Massive splenomegalyMassive splenomegaly
– II. Hepatic:II. Hepatic:
– III. Post-hepatic:III. Post-hepatic:
• Severe right-sided heart failureSevere right-sided heart failure
• Constrictive pericarditisConstrictive pericarditis
• Hepatic vein outflow obstructionHepatic vein outflow obstruction

LIVER CIRRHOSIS CAUSING
PORTAL HYPERTENSIONPORTAL HYPERTENSION
• Due to:Due to:
– Increased resistance to portal blood flow in sinusoidsIncreased resistance to portal blood flow in sinusoids
– Compression of central veins by perivenular fibrosis &Compression of central veins by perivenular fibrosis &
expanding parenchymal nodulesexpanding parenchymal nodules
– Anastomoses between arterial & portal systems inAnastomoses between arterial & portal systems in
fibrous bandsfibrous bands
• Consequences:Consequences:
– 1) Ascites1) Ascites
– 2) Portosystemic venous shunts2) Portosystemic venous shunts
– 3) Congestive splenomegaly3) Congestive splenomegaly
– 4) Hepatic encephalopathy4) Hepatic encephalopathy

COMPLICATIONS OF PORTAL HYPERTENSIONCOMPLICATIONS OF PORTAL HYPERTENSION
ASCITEASCITESS
• Excess (usually serous) fluid in abdominal cavityExcess (usually serous) fluid in abdominal cavity
• Fluid: albumin, solutes, few mesothelial cells,Fluid: albumin, solutes, few mesothelial cells,
mononuclear leukocytesmononuclear leukocytes
• Neutrophils=secondary infectionNeutrophils=secondary infection
• HydrothoraxHydrothorax
• Pathogenesis:Pathogenesis:
– Sinusoidal hypertension: increasedSinusoidal hypertension: increased
hydrostatic pressure & hypoalbuminemiahydrostatic pressure & hypoalbuminemia
– Percolation of hepatic lymph into peritonealPercolation of hepatic lymph into peritoneal
cavitycavity
– Renal retention of sodium & water secondaryRenal retention of sodium & water secondary
to hyperaldosteronismto hyperaldosteronism

COMPLICATIONS OF PORTALCOMPLICATIONS OF PORTAL HYPERTENSIONHYPERTENSION
PORTO-SYSTEMIC SHUNTSPORTO-SYSTEMIC SHUNTS
• Bypasses develop wherever the systemic &Bypasses develop wherever the systemic &
portal circulation share capillary bedsportal circulation share capillary beds
• Sites:Sites:
– RectumRectum
– Cardio-esophageal junctionCardio-esophageal junction
– RetroperitoneumRetroperitoneum
– Falciform ligament of liver (periumbilical &Falciform ligament of liver (periumbilical &
abdominal wall)abdominal wall)

COMPLICATIONS OF PORTALCOMPLICATIONS OF PORTAL HYPERTENSIONHYPERTENSION
SPLENOMEGALYSPLENOMEGALY
• Congestive splenomegalyCongestive splenomegaly
• May be massiveMay be massive
• Hypersplenism:Hypersplenism: removal of excessiveremoval of excessive
amounts of one or more of the formedamounts of one or more of the formed
blood elements:blood elements:
– AnemiaAnemia
– LeukopeniaLeukopenia
– ThrombocytopeniaThrombocytopenia

INFLAMMATIONS OF THE LIVERINFLAMMATIONS OF THE LIVER
INFECTIONSINFECTIONS• Pathways:Pathways:
– Arterial supplyArterial supply
– Portal veinPortal vein
– Ascending infection in the biliary tractAscending infection in the biliary tract
– Direct liver invasion from nearby infectionDirect liver invasion from nearby infection
– Penetrating injuryPenetrating injury
• Organisms:Organisms:
– Bacterial: Staphylococcal bacteremia,Bacterial: Staphylococcal bacteremia,
salmonelloses, miliary TBsalmonelloses, miliary TB
– Viral: infectious mononucleosisViral: infectious mononucleosis
– Protozoal: malaria, amebiasis, echinococcusProtozoal: malaria, amebiasis, echinococcus

VIRAL HEPATITISVIRAL HEPATITIS
• EBVEBV
• CMVCMV
• HSVHSV
• Arbovirus (Yellow fever)Arbovirus (Yellow fever)
• RubellaRubella
• AdenovirusAdenovirus
• EnterovirusEnterovirus
• Hepatotropic (Hepatitis) viruses: A, B,Hepatotropic (Hepatitis) viruses: A, B,
C, D, E, GC, D, E, G

CLINICAL SYNDROMES OFCLINICAL SYNDROMES OF
VIRAL HEPATITISVIRAL HEPATITIS
• Carrier stateCarrier state
• Asymptomatic infectionAsymptomatic infection
• Acute hepatitisAcute hepatitis
• Chronic hepatitisChronic hepatitis
• Fulminant hepatitisFulminant hepatitis

CLINICAL SYNDROMES OF VIRAL HEPATITISCLINICAL SYNDROMES OF VIRAL HEPATITIS
CARRIER STATECARRIER STATE
• Reservoir of infectionReservoir of infection
• ““healthyhealthy”” carriercarrier
• asymptomatic chronic liver diseaseasymptomatic chronic liver disease
• essentially normal liver biopsyessentially normal liver biopsy
• HBV:HBV:
– 90-95% of early life infections; vertical transmission90-95% of early life infections; vertical transmission
– 1-10% of infections in adulthood1-10% of infections in adulthood
– individuals with impaired immunityindividuals with impaired immunity
– ““ground-glassground-glass”” hepatocytes,hepatocytes, ““sandedsanded”” nucleinuclei
• HCV:HCV:
– 0.2-1% of blood donors0.2-1% of blood donors
– chronic hepatitis usually present histologicallychronic hepatitis usually present histologically
• HDV:HDV:
– 1-10% of drug addicts; in conjunction with HBV

ASYMPTOMATIC INFECTIONASYMPTOMATIC INFECTION
• Serologic hepatitisSerologic hepatitis
• Identified incidentally by laboratoryIdentified incidentally by laboratory
teststests
– Elevated liver enzymesElevated liver enzymes
– Positive viral antibodiesPositive viral antibodies

ACUTE HEPATITISACUTE HEPATITIS
• 1) Incubation period: peak infectivity1) Incubation period: peak infectivity
• 2) Symptomatic pre-icteric state: nonspecific2) Symptomatic pre-icteric state: nonspecific
constitutional symptoms (malaise, generalconstitutional symptoms (malaise, general
fatigability, nausea, loss of appetite, weight loss,fatigability, nausea, loss of appetite, weight loss,
fever, headache, muscle & joint aches, vomiting,fever, headache, muscle & joint aches, vomiting,
diarrheadiarrhea
• 3) Symptomatic icteric state: jaundice3) Symptomatic icteric state: jaundice
(conjugated hyperbilirubinemia), dark-colored(conjugated hyperbilirubinemia), dark-colored
urine, light-colored stools, pruritis.urine, light-colored stools, pruritis.
• Usual with adult HAV, half of HBV, but notUsual with adult HAV, half of HBV, but not
children HAV and HCVchildren HAV and HCV
• 4) Convalescence: few weeks-months4) Convalescence: few weeks-months

ACUTE HEPATITISACUTE HEPATITIS
• Histology of acute hepatitis:Histology of acute hepatitis:
– Ballooning degenerationBallooning degeneration
– Cholestasis (bile plugs)Cholestasis (bile plugs)
– Steatosis (HCV)Steatosis (HCV)
– Hepatocyte necrosisHepatocyte necrosis
• dropped out cells surrounded by macrophagesdropped out cells surrounded by macrophages
(Councilman bodies)(Councilman bodies)
• apoptotic cellsapoptotic cells
– Kuppfer cell hypertrophy & hyperplasiaKuppfer cell hypertrophy & hyperplasia
– Portal tracts infiltration by inflammatory cells withPortal tracts infiltration by inflammatory cells with
spill over to parenchyma (interface hepatitis)spill over to parenchyma (interface hepatitis)
• Px:Px: 1% fulminant; 5-10% chronic hepatitis ( HBV)1% fulminant; 5-10% chronic hepatitis ( HBV)
• 85% chronic hepatitis;15% resolution (HCV)85% chronic hepatitis;15% resolution (HCV)

ACUTE HEPATITISACUTE HEPATITIS• DiffuseDiffuse
swellingswelling
• HepatocyteHepatocyte
necrosisnecrosis

CHRONIC HEPATITISCHRONIC HEPATITIS
• Symptomatic, biochemical or serologic evidenceSymptomatic, biochemical or serologic evidence
of continuing or relapsing hepatic disease forof continuing or relapsing hepatic disease for
more than 6 months, with histologicallymore than 6 months, with histologically
documented inflammation and necrosisdocumented inflammation and necrosis
• Viral & non-viral causes (WilsonViral & non-viral causes (Wilson’’s disease,s disease, αα1-AT1-AT
deficiency, alcoholism, drugs, autoimmunity)deficiency, alcoholism, drugs, autoimmunity)
• Etiology rather than histologic pattern is singleEtiology rather than histologic pattern is single
most important factor determining probability ofmost important factor determining probability of
developing progressive chronic hepatitisdeveloping progressive chronic hepatitis

• Histology of chronic hepatitisHistology of chronic hepatitis::
– Variable in severityVariable in severity
– Some of the changes seen in acute hepatitisSome of the changes seen in acute hepatitis
– Portal inflammation +/-spill over, bridgingPortal inflammation +/-spill over, bridging
inflammation & necrosisinflammation & necrosis
– Bile duct epithelial proliferationBile duct epithelial proliferation
– Lymphoid aggregates (HCV)Lymphoid aggregates (HCV)
– Fibrosis (portal, periportal, bridging)Fibrosis (portal, periportal, bridging)
– CirrhosisCirrhosis
• Lab findings:Lab findings: ↑↑ PT, bilirubin, alk. ph. , decrease inPT, bilirubin, alk. ph. , decrease in
globulins.globulins.
• Clinical featuresClinical features are highly variable & not predictive ofare highly variable & not predictive of
outcomeoutcome
• PxPx is highly variableis highly variable

• Portal inflammation:Portal inflammation:
mildest form of chronicmildest form of chronic
hepatitis withhepatitis with
inflammatory cells limitedinflammatory cells limited
to portal tractsto portal tracts
• With more severeWith more severe
inflammation,inflammation,
inflammatory cells spillinflammatory cells spill
over into parenchymaover into parenchyma
causing periportalcausing periportal
necrosis (piecemealnecrosis (piecemeal
necrosis) occurs.necrosis) occurs.

FULMINANT HEPATITISFULMINANT HEPATITIS
• Hepatic insufficiency that progresses from onsetHepatic insufficiency that progresses from onset
of symptoms to hepatic encephalopathy within 2-of symptoms to hepatic encephalopathy within 2-
3 weeks, or up to 3 months (subfulminant)3 weeks, or up to 3 months (subfulminant)
• 50-65% due to viral hepatitis: HBV>HCV>>> HDV-50-65% due to viral hepatitis: HBV>HCV>>> HDV-
HBV, HAV, HEV, HSVHBV, HAV, HEV, HSV……
• 25-30% due to drugs & chemicals, e.g.25-30% due to drugs & chemicals, e.g.
acetominophen, INH, MOI antidepressants,acetominophen, INH, MOI antidepressants,
halothane, methyldopa,halothane, methyldopa, Amanita phalloidesAmanita phalloides
mycotoxinsmycotoxins ……
• Rarely due to hepatic vein obstruction, WilsonRarely due to hepatic vein obstruction, Wilson’’ss
disease, malignancy, autoimmune hepatitis,disease, malignancy, autoimmune hepatitis,
hyperthermia, microvesicular steatosishyperthermia, microvesicular steatosis
syndromes ...syndromes ...

• Histology of fulminant hepatitis:Histology of fulminant hepatitis:
– Focal or diffuse liver destructionFocal or diffuse liver destruction
– Little or massive inflammatory reactionLittle or massive inflammatory reaction
– +/-regeneration:+/-regeneration:
• orderlyorderly
• post-necrotic cirrhosispost-necrotic cirrhosis
• Clinical features:Clinical features: Jaundice, fetor hepaticus,Jaundice, fetor hepaticus,
stigmata of chronic liver diseasestigmata of chronic liver disease
• Life threatening complications:Life threatening complications: coagulopathycoagulopathy
with bleeding, CV instability, RF, ARDS,with bleeding, CV instability, RF, ARDS,
electrolyte & acid-base disturbances, sepsiselectrolyte & acid-base disturbances, sepsis
• Px:Px: Mortality 90%, except if liver transplantationMortality 90%, except if liver transplantation
is performed (25%)is performed (25%)

• ExtensiveExtensive
liverliver
destructiondestruction
with collapsewith collapse
of normalof normal
architecture,architecture,
presence ofpresence of
residualresidual
hepatocytes &hepatocytes &
inflammatoryinflammatory
cellscells

AUTOIMMUNE HEPATITISAUTOIMMUNE HEPATITIS
• Chronic hepatitis of variable severity, histologicallyChronic hepatitis of variable severity, histologically
indistinguishable from chronic viral hepatitisindistinguishable from chronic viral hepatitis
• Patients have variety of immunologic abnormalitiesPatients have variety of immunologic abnormalities
• Female predominance (70%)Female predominance (70%)
• No serologic viral markersNo serologic viral markers
• Elevated serum IgG >2.5 gm/dlElevated serum IgG >2.5 gm/dl
• High titers of autoantibodies (80%) including ANA, anti-smoothHigh titers of autoantibodies (80%) including ANA, anti-smooth
muscles.muscles.
• Increased frequency of HLA-B8 or HLA-DRwIncreased frequency of HLA-B8 or HLA-DRw
• Other forms of autoimmune diseases may be present (60%), e.g.Other forms of autoimmune diseases may be present (60%), e.g.
RA, SjogrenRA, Sjogren’s syndrome’s syndrome
• Overall risk for cirrhosis is 5%Overall risk for cirrhosis is 5%
• Rx: good response to immunosuppressive therapyRx: good response to immunosuppressive therapy

TOXIN-INDUCED LIVER DISEASETOXIN-INDUCED LIVER DISEASE
ALCOHOLIC LIVER DISEASEALCOHOLIC LIVER DISEASE
• Alcohol is the fifth leading cause of death in theAlcohol is the fifth leading cause of death in the
U.S. (many related to automobile accidents)U.S. (many related to automobile accidents)
• Alcohol has adverse effects onAlcohol has adverse effects on liverliver,, GITGIT (ulcers,(ulcers,
gastritis),gastritis), CNSCNS (peripheral neuropathy &(peripheral neuropathy &
Wernicke- Korsakaff syndrome secondary toWernicke- Korsakaff syndrome secondary to
thiamine deficiency, cerebral atrophy, cerebellarthiamine deficiency, cerebral atrophy, cerebellar
degenerationdegeneration ……),), CVSCVS (cardiomyopathy,(cardiomyopathy,
hypertension, HDL),hypertension, HDL), pancreaspancreas (pancreatitis),(pancreatitis),
pregnancypregnancy (fetal alcohol syndrome)(fetal alcohol syndrome)
• 3 forms of alcoholic liver disease:3 forms of alcoholic liver disease:
– 1) Hepatic steatosis1) Hepatic steatosis
– 2) Alcoholic hepatitis2) Alcoholic hepatitis
– 3) Alcoholic cirrhosis3) Alcoholic cirrhosis

PATHOGENESIS OFPATHOGENESIS OF
• Alcohol-induced hepatocellular steatosis:Alcohol-induced hepatocellular steatosis:
– 1) Generation of excess NADH by alcohol1) Generation of excess NADH by alcohol
dehydrogenase & acetaldehyde dehydrogenase leadingdehydrogenase & acetaldehyde dehydrogenase leading
to increased lipid biosynthesisto increased lipid biosynthesis
– 2) Impaired assembly & secretion of lipoproteins2) Impaired assembly & secretion of lipoproteins
– 3) Increased peripheral catabolism of fat3) Increased peripheral catabolism of fat
• Alcohol-induced hepatocellular damage:Alcohol-induced hepatocellular damage:
– 1) Induction of cytochrome P- 4501) Induction of cytochrome P- 450
– 2) Generation of free radicals2) Generation of free radicals
– 3) Direct effect on microtubular & mitochondrial3) Direct effect on microtubular & mitochondrial
function & memebrane fluidityfunction & memebrane fluidity

PATHOGENESIS OFPATHOGENESIS OF
• Alcohol-induced hepatocellular damage:Alcohol-induced hepatocellular damage:
– 4) Acetaldehyde induces lipid peroxidation &4) Acetaldehyde induces lipid peroxidation &
acetaldehyde-protein adduct formation, furtheracetaldehyde-protein adduct formation, further
disrupting cytoskelatal & membrane functiondisrupting cytoskelatal & membrane function
– 5) Antigenic alteration of hepatocytes & hepatic5) Antigenic alteration of hepatocytes & hepatic
proteins, inducing an immunologic attackproteins, inducing an immunologic attack
• Alcohol-induced fibrosis:Alcohol-induced fibrosis:
– Multifactorial and poorly understoodMultifactorial and poorly understood
• Other mechanisms:Other mechanisms:
– Malnutrition & vitamin deficienciesMalnutrition & vitamin deficiencies
– Impaired digestive function (chronic gastric & intestinalImpaired digestive function (chronic gastric & intestinal
mucosal damage & pancreatitis)mucosal damage & pancreatitis)

HEPATIC SHEPATIC STEATOSISTEATOSIS
• Lipid dropletsLipid droplets
accumulate inaccumulate in
hepatocyteshepatocytes
• 2 histologic types:2 histologic types:
– MicrovesicularMicrovesicular
– MacrovesicularMacrovesicular
• Initially centrilobularInitially centrilobular
• Later panlobularLater panlobular
• Large (4-6 kg) softLarge (4-6 kg) soft
yellow greasyyellow greasy
appearanceappearance
• Completely reversible ifCompletely reversible if

ALCOHOLIC HEPATITISALCOHOLIC HEPATITIS
• Hepatocyte swellingHepatocyte swelling
(ballooning) due to(ballooning) due to
accumulation of fat &accumulation of fat &
water, and cell necrosiswater, and cell necrosis
• Mallory bodies:Mallory bodies:
characteristic eosinophiliccharacteristic eosinophilic
cytoplasmic inclusionscytoplasmic inclusions
(cytokeratin intermediate(cytokeratin intermediate
filaments)filaments)
• Neutrophilic reactionNeutrophilic reaction
• FibrosisFibrosis

ALCOHOLIC HEPATITISALCOHOLIC HEPATITIS
• Mallory bodies:Mallory bodies:
characteristiccharacteristic
eosinophiliceosinophilic
cytoplasmiccytoplasmic
inclusionsinclusions
(cytokeratin(cytokeratin
intermediateintermediate
filaments)filaments)

HEPATIC CIRRHOSISHEPATIC CIRRHOSIS
• Initially, the liver is yellow-Initially, the liver is yellow-
tan, fatty & enlargedtan, fatty & enlarged
• Eventually, it becomesEventually, it becomes
brown, shrunken & non-brown, shrunken & non-
fattyfatty
• Fibrous septa becomeFibrous septa become
thicker & extend throughthicker & extend through
sinusoidssinusoids
• Regenerative nodules withRegenerative nodules with
entrapped hepatocytesentrapped hepatocytes

CLINICAL FEATURES OFCLINICAL FEATURES OF
• Hepatic steatosisHepatic steatosis
– AsymptomaticAsymptomatic
– MildMild ↑↑ serum bilirubin & alk. phosphataseserum bilirubin & alk. phosphatase
• Alcoholic hepatitisAlcoholic hepatitis
– Minimal to severe manifestationsMinimal to severe manifestations
– Nonspecific symptomsNonspecific symptoms
– Increase in serum bilirubin, alk. phosphatase, WBCsIncrease in serum bilirubin, alk. phosphatase, WBCs
• Alcoholic cirrhosisAlcoholic cirrhosis
– Similar to other forms of cirrhosisSimilar to other forms of cirrhosis

TOXIN-INDUCED LIVER DISEASETOXIN-INDUCED LIVER DISEASE

PROGNOSIS OFPROGNOSIS OF
• VariableVariable outcome depending on severity ofoutcome depending on severity of
histologic changeshistologic changes
• 5 years survival approaches 90% in abstainers5 years survival approaches 90% in abstainers
who are free of jaundice, ascites, orwho are free of jaundice, ascites, or
hematemesis, but drops to 50-60% in those whohematemesis, but drops to 50-60% in those who
continue to drinkcontinue to drink
• Immediate causes of death:Immediate causes of death:
– 1) hepatic failure1) hepatic failure
– 2) massive GI hemorrhage2) massive GI hemorrhage
– 3) intercurrent infection3) intercurrent infection
– 4) hepatorenal syndrome4) hepatorenal syndrome
– 5) hepatocellular carcinoma5) hepatocellular carcinoma

METABOLIC LIVER DISEASES
NONALCOHOLIC FATTY LIVER DISEASE(NAFLD)
• The most common metabolic liver disease & most
common cause of incidental elevation of serum
transaminases.
• A condition in which fatty liver develops in individuals
who do not drink alcohol.
• May present as steatosis or as nonalcoholic steatohepatitis
(NASH) which is similar to ASH.
• Is considered as a significant contributar to the group of
patients with cryptogenic cirrhosis.
• NAFLD & NASH are consistently associated with insulin
resistance .

• Other conditions associated with NAFLD:
1) Type 2 D.M.
2) Obesity.
3) Dyslipidemia ( increase triglycerides, low
HDL, high LDL).

Pathogenesis & clinical features:
• Insulin resistance results in accummlation of TGs
in hepatocytes.
• Fat-laden hepatocytes are sensitive to lipid
peroxidation products leading to liver damage &
inflammation.
• Pt. with steatosis are asymptomatic.
• Pt. with NASH may be asymptomatic, but some
have fatigue, malaise, right upper discomfort or
even symptoms of chronic liver disease.

Prognosis:Prognosis:
The frequancy of progression fromThe frequancy of progression from
steatosis to NASH , and from NASH tosteatosis to NASH , and from NASH to
cirrhosis, seems to be low.cirrhosis, seems to be low.

TUMORS & TUMOR-LIKETUMORS & TUMOR-LIKE
CONDITIONS OF THE LIVERCONDITIONS OF THE LIVER
• The most common hepatic neoplasms are metastaticThe most common hepatic neoplasms are metastatic
tumors, most commonly from colon, lung, and breast.tumors, most commonly from colon, lung, and breast.
• May be single or multipleMay be single or multiple
• Asymptomatic or symptomaticAsymptomatic or symptomatic
• ClassificationClassification::
– BenignBenign
• Non-neoplastic: Cysts (simple, congenital, choledochal,Non-neoplastic: Cysts (simple, congenital, choledochal,
polycystic), focal nodular hyperplasiapolycystic), focal nodular hyperplasia
• Neoplastic: hemangioma, adenomaNeoplastic: hemangioma, adenoma
– MalignantMalignant
• Primary: Hepatocellular carcinoma, cholangiocarcinomaPrimary: Hepatocellular carcinoma, cholangiocarcinoma
• Secondary: metastatic carcinoma, sarcoma, lymphomaSecondary: metastatic carcinoma, sarcoma, lymphoma

TUMORS OF THE LIVERTUMORS OF THE LIVER
LIVER CELL ADENOMALIVER CELL ADENOMA
• Mostly in young women with history of oralMostly in young women with history of oral
contraceptive pills (OCP) use.contraceptive pills (OCP) use.
• Well-demarcated yellow-tan frequently bile-stainedWell-demarcated yellow-tan frequently bile-stained
nodule(s), often located beneath capsule, usually smallnodule(s), often located beneath capsule, usually small
in size but may reach up to 30 cm.in size but may reach up to 30 cm.
• Histology:Histology: sheets & cords of cells that resemble normalsheets & cords of cells that resemble normal
hepatocytes with minimal pleomorphism.hepatocytes with minimal pleomorphism.
• Clinical significance:Clinical significance:
– 1) Misdiagnosed as hepatocellular carcinoma1) Misdiagnosed as hepatocellular carcinoma
– 2) May rupture & cause serious intra-abdominal2) May rupture & cause serious intra-abdominal
hemorrhagehemorrhage
• May regress on discontinuance of OCPsMay regress on discontinuance of OCPs

PRIMARY MALIGNANT TUMORSPRIMARY MALIGNANT TUMORS
• Hepatocellular carcinoma (hepatoma)Hepatocellular carcinoma (hepatoma)
• CholangiocarcinomaCholangiocarcinoma
• Tumors of mixed cell typesTumors of mixed cell types
• HepatoblastomaHepatoblastoma
– Aggressive tumor of childrenAggressive tumor of children
• AngiosarcomaAngiosarcoma
– Association with exposure to vinyl chloride,Association with exposure to vinyl chloride,
arsenic & Thorotrastarsenic & Thorotrast
• Primary lymphomas, sarcomas, ...Primary lymphomas, sarcomas, ...

HEPATOCELLULAR CARCINOMAHEPATOCELLULAR CARCINOMA
• Malignant tumor arrising from hepatocytesMalignant tumor arrising from hepatocytes
• Wide variation in geographic distributionWide variation in geographic distribution
• ChronicChronic HBVHBV carrier state: a 200x increased riskcarrier state: a 200x increased risk
• HCC is frequently associated withHCC is frequently associated with cirrhosiscirrhosis
• M:F ratio ranges from 3:1 to 8:1; adulthoodM:F ratio ranges from 3:1 to 8:1; adulthood
• Pathogenesis:Pathogenesis: several factors areseveral factors are
– Viruses: HBV, HCVViruses: HBV, HCV
– Chemicals: alcohol, food hepatocarcinogensChemicals: alcohol, food hepatocarcinogens
(e.g.(e.g. Aspergillus flavusAspergillus flavus aflatoxins Baflatoxins B11))
– Chronic liver diseaseChronic liver disease

HEPATOCELLULAR CARCINOMAHEPATOCELLULAR CARCINOMA
• The HBV link:The HBV link:
– HBV genome does not contain any oncogenicHBV genome does not contain any oncogenic
sequences, & there is no selective site ofsequences, & there is no selective site of
integrationof viral DNA into host enomeintegrationof viral DNA into host enome
– Repeated cycles of cell death & regenerationRepeated cycles of cell death & regeneration
leads to accumulation of mutations & genomicleads to accumulation of mutations & genomic
instabilityinstability
– HBV genome encode the X-protein, aHBV genome encode the X-protein, a
transcriptional activator of many genes whichtranscriptional activator of many genes which
may disrupt normal growth control bymay disrupt normal growth control by
activating host cell protooncogenesactivating host cell protooncogenes
– HBV proteins bind & inactivate p53HBV proteins bind & inactivate p53

CLINICAL FEATURESCLINICAL FEATURES OFOF
PRIMARY HEPATIC CARCINOMAPRIMARY HEPATIC CARCINOMA
• Asymptomatic hepatomegalyAsymptomatic hepatomegaly
• Patients with cirrhosis:Patients with cirrhosis:
– Rapid increase in liver sizeRapid increase in liver size
– Sudden worsening of ascitesSudden worsening of ascites
– Appearance of bloody ascitesAppearance of bloody ascites
– Fever & painFever & pain
• Lab:Lab: alpha-fetoprotein: nonspecific tumoralpha-fetoprotein: nonspecific tumor
marker; >1000 ng/ml is highly suggestive of HCCmarker; >1000 ng/ml is highly suggestive of HCC
• Px:Px: grim. Death within 6 mths - 1 yr due to: 1)grim. Death within 6 mths - 1 yr due to: 1)
Severe cachexia, 2) GI bleeding, 3) liver failure &Severe cachexia, 2) GI bleeding, 3) liver failure &
4) tumor rupture4) tumor rupture
• Rx:Rx: Complete surgical resectionComplete surgical resection

PATHOLOGY OFPATHOLOGY OF
HEPATOCELLULHEPATOCELLUL
ARAR
CARCINOMACARCINOMA
• Unifocal, multifocal orUnifocal, multifocal or
diffusely infiltrativediffusely infiltrative
tumor involving entiretumor involving entire
liverliver
• Cirrhosis ofCirrhosis of
surrounding liversurrounding liver
parenchyma isparenchyma is
frequently presentfrequently present
• Strong propensity forStrong propensity for
invasion of vascularinvasion of vascular
channelschannels

HISTOPATHOLOGY OFHISTOPATHOLOGY OF
HEPATOCELLULARHEPATOCELLULAR
CARCINOMACARCINOMA
• Range from well-Range from well-
differentiated todifferentiated to
anaplasticanaplastic
• Neoplastic cells ofNeoplastic cells of
well-differentiatedwell-differentiated
tumors resembletumors resemble
hepatocytes & mayhepatocytes & may
show intra-show intra-
cytoplasmic bilecytoplasmic bile
globulesglobules
• FibrolamellarFibrolamellar
variant: better pxvariant: better px

CHOLANGIOCARCINOMACHOLANGIOCARCINOMA
• Malignant epithelial neoplasms of bile duct originMalignant epithelial neoplasms of bile duct origin
• Less common than hepatocellular carcinomaLess common than hepatocellular carcinoma
• Not associated with etiologic factors related to HCCNot associated with etiologic factors related to HCC
• Etiology:Etiology:
– Majority of cases are not associated with any knownMajority of cases are not associated with any known
risk factorrisk factor
– Radiologic contrast material: Thorostrast exposureRadiologic contrast material: Thorostrast exposure
– Opisthorchis sinensis infestation of biliary tractOpisthorchis sinensis infestation of biliary tract
– Primary sclerosing cholangitisPrimary sclerosing cholangitis

CHOLANGIO-CHOLANGIO-
CARCINOMACARCINOMA
• Usually single tumorUsually single tumor
with a firm grittywith a firm gritty
consistencyconsistency
• May be located inMay be located in
liver or biliary treeliver or biliary tree
• Papillary, intra-Papillary, intra-
ductal or diffuseductal or diffuse
• Klatskin tumor:Klatskin tumor:
present in thepresent in the
junction of hepatic &junction of hepatic &
common bile ductscommon bile ducts

HISTOPATHOLOGY OFHISTOPATHOLOGY OF
CHOLANGI-CHOLANGI-
CARCINOMACARCINOMA
• Usually well-Usually well-
differentiated,differentiated,
forming glandsforming glands
and tubularand tubular
structuresstructures
• DesmoplasticDesmoplastic
stromastroma
• Bile pigment notBile pigment not
presentpresent
• May mimicMay mimic
metastaticmetastatic
adenocarcinomaadenocarcinoma

THE BILIARY TRACTTHE BILIARY TRACT
• Disorders of the gallbladderDisorders of the gallbladder
– CholelithiasisCholelithiasis
– CholecystitisCholecystitis
– TumorsTumors
• Disorders of extrahepatic bile ductsDisorders of extrahepatic bile ducts
– CholedocholithiasisCholedocholithiasis
– Ascending cholangitisAscending cholangitis
– Extrahepatic biliary atresiaExtrahepatic biliary atresia
– TumorsTumors

PATHOLOGY OFPATHOLOGY OF THE GALLBLADDERTHE GALLBLADDER
CHOLELITHIASISCHOLELITHIASIS
• Common disease affecting 10-20% of adultsCommon disease affecting 10-20% of adults
• >80% are asymptomatic>80% are asymptomatic
• Two main types of gall stones:Two main types of gall stones:
– 1) Cholesterol stones1) Cholesterol stones
– 2) Bilirubin calcium salts (pigment) stones2) Bilirubin calcium salts (pigment) stones
• Pathogenesis:Pathogenesis:
– 1) bile supersaturation with cholesterol1) bile supersaturation with cholesterol
– 2) nucleation: promoted by calcium salts2) nucleation: promoted by calcium salts
– 3) gall bladder stasis with cholesterol crystals3) gall bladder stasis with cholesterol crystals
remaining long enough to aggregateremaining long enough to aggregate

• AppearanceAppearance
– Cholesterol stonesCholesterol stones: exclusively in GB, ovoid firm,: exclusively in GB, ovoid firm,
single or multiple, multi-faceted, most aresingle or multiple, multi-faceted, most are
radiolucentradiolucent
• PurePure: pale yellow: pale yellow
• MixedMixed: gray white to black, containing cacium: gray white to black, containing cacium
carbonate, phosphates & bilirubincarbonate, phosphates & bilirubin
– Pigment stonesPigment stones: anywhere in biliary tree, contain: anywhere in biliary tree, contain
calcium salts of unconjugated bilirubin, calciumcalcium salts of unconjugated bilirubin, calcium
salts, mucin glycoproteins & cholesterolsalts, mucin glycoproteins & cholesterol
• BlackBlack: in sterile GB bile, small, numerous, friable,: in sterile GB bile, small, numerous, friable,
50-75% are radioopaque50-75% are radioopaque
• BrownBrown in infected intra- or extrahepatic ducts,in infected intra- or extrahepatic ducts,
single or few, soft & greasy, radiolucentsingle or few, soft & greasy, radiolucent

RISK FACTORS OFRISK FACTORS OF
• Risk factors for cholesterol stonesRisk factors for cholesterol stones
– AgeAge: elderly> young adults: elderly> young adults
– Gender:Gender: femalesfemales
– Oral contraceptives (Oral contraceptives (OCPOCPs), pregnancys), pregnancy
– Demography:Demography: WesternWestern World; Native AmericansWorld; Native Americans
– GallbladderGallbladder stasisstasis
– Inborn disordersInborn disorders of bile acid metabolismof bile acid metabolism
– ObesityObesity
– HyperlipidemiaHyperlipidemia
– Rapid weight lossRapid weight loss
– Treatment with the hypocholesterolemic agentTreatment with the hypocholesterolemic agent
clofibrateclofibrate

RISK FACTORS OFRISK FACTORS OF
• Risk factors for pigment stonesRisk factors for pigment stones
– Demography:Demography: AsiansAsians, rural areas, rural areas
– ChronicChronic hemolytichemolytic syndromessyndromes
– BiliaryBiliary infectioninfection
– Gastrointestinal disordersGastrointestinal disorders::
• Ileal disease, e.g. CrohnIleal disease, e.g. Crohn’’s diseases disease
• Ileal resection or bypassIleal resection or bypass
• Cystic fibrosis with pancreaticCystic fibrosis with pancreatic
insufficiencyinsufficiency

• Clinical presentation:Clinical presentation:
– 70-80% are asymptomatic70-80% are asymptomatic
– Biliary pain, constant or colicky from anBiliary pain, constant or colicky from an
obstructed gallbladder or biliary treeobstructed gallbladder or biliary tree
– Associated with inflammation of gallbladderAssociated with inflammation of gallbladder
• Complications:Complications:
• EmpyemaEmpyema
• PerforationPerforation
• FistulaeFistulae
• Inflammation of biliary treeInflammation of biliary tree
• Obstructive cholestasisObstructive cholestasis
• PancreatitisPancreatitis
• Intestinal obstruction (Intestinal obstruction (““gallstone ileusgallstone ileus””))

CHOLECYSTITISCHOLECYSTITIS
• Inflammation of the gallbladderInflammation of the gallbladder
• Almost always associated with gallstonesAlmost always associated with gallstones
• One of the most common indications forOne of the most common indications for
abdominal surgeryabdominal surgery
• Epidemiologic distribution similar toEpidemiologic distribution similar to
cholelithiasischolelithiasis
• Classification:Classification:
– Acute calculousAcute calculous
– Acute acalculousAcute acalculous
– ChronicChronic
– Acute & chronicAcute & chronic

TYPES OFTYPES OF
ACUTE CHOLECYSTITISACUTE CHOLECYSTITIS
• Acute calculous cholecystitis:Acute calculous cholecystitis: caused by obstructioncaused by obstruction
of GB neck or cystic duct by stonesof GB neck or cystic duct by stones
– Chemical irritation & inflammation of GB wallChemical irritation & inflammation of GB wall
• Mucosal phospholipases hydrolyze biliary lecithin toMucosal phospholipases hydrolyze biliary lecithin to
lysolecithinlysolecithin
• Disruption of protective glycoprotein mucous layerDisruption of protective glycoprotein mucous layer
• Prostaglandin release within GB wallProstaglandin release within GB wall
• BF compromise due to GB distension & pressureBF compromise due to GB distension & pressure
– Symptoms may be mild or sudden & severeSymptoms may be mild or sudden & severe
• Acute acalculous cholecystitis:Acute acalculous cholecystitis: 5-12% of cases5-12% of cases
– Seen inSeen in 1) post-operative states, 2) severe trauma,1) post-operative states, 2) severe trauma,
3) severe burns, 4) sepsis & 5) postpartum3) severe burns, 4) sepsis & 5) postpartum
– Factors:Factors: 1) dehydration, 2) GB stasis & sludging, 3)1) dehydration, 2) GB stasis & sludging, 3)
vascular compromise, 5)vascular compromise, 5) bacterial contaminationbacterial contamination

ACUTE CHOLECYSTITISACUTE CHOLECYSTITIS
• Enlarged (2-3x), tense GB with discolorationsEnlarged (2-3x), tense GB with discolorations
due to subserosal hemorrhages.due to subserosal hemorrhages.
• Serosal fibrinous or suppurative exudateSerosal fibrinous or suppurative exudate
• Stones obstructing GB neck or cystic duct inStones obstructing GB neck or cystic duct in
90%90%
• GB lumen filled with turbid bile, +/- fibrin,GB lumen filled with turbid bile, +/- fibrin,
hemorrhage & pushemorrhage & pus
• Empyema of gallbladder: full of pusEmpyema of gallbladder: full of pus
• Thickened edematous hyperemic wallThickened edematous hyperemic wall
• Gangrenous cholecystitis: black necrotic GBGangrenous cholecystitis: black necrotic GB
• Histology: edema, WBC infiltration, congestionHistology: edema, WBC infiltration, congestion
& necrosis& necrosis

CHRONIC CHOLECYSTITISCHRONIC CHOLECYSTITIS
• +/- history of acute cholecystitis+/- history of acute cholecystitis
• Gall stonesGall stones almost always present, but stones &almost always present, but stones &
obstruction do not play major role in initiation ofobstruction do not play major role in initiation of
inflammationinflammation
• Supersaturation of bile predisposes to chronicSupersaturation of bile predisposes to chronic
inflammation & stone formationinflammation & stone formation
• BacteriaBacteria are isolated in 1/3 of casesare isolated in 1/3 of cases
• Variable morphologic appearance: minimalVariable morphologic appearance: minimal
changes, contraction, enlargment, mucosalchanges, contraction, enlargment, mucosal
ulceration or wall thickeninigulceration or wall thickeninig
• Histology:Histology: lymphocytic infiltration, fibrosislymphocytic infiltration, fibrosis

CHOLECYSTITISCHOLECYSTITIS
• Acute & chronic calculous cholecystitis haveAcute & chronic calculous cholecystitis have
similar & variable symptoms: minimal nonspecificsimilar & variable symptoms: minimal nonspecific
symptoms to biliary colics to severe RUQ painsymptoms to biliary colics to severe RUQ pain
• Fever, nausea, leukocytosis & prostrationFever, nausea, leukocytosis & prostration
• Conjugated hyperbilirubinemiaConjugated hyperbilirubinemia
• Acute acalculous cholecystitis: symptomsAcute acalculous cholecystitis: symptoms
obscured by general conditionobscured by general condition
• Dx: UltrasonographyDx: Ultrasonography
• Complications: cholangitis, sepsis, GBComplications: cholangitis, sepsis, GB
perforation, abscess, rupture, cholecyst-entericperforation, abscess, rupture, cholecyst-enteric
fistula, intestinal ileus, ...fistula, intestinal ileus, ...

TUMORS OF THE BILIARY TRACTTUMORS OF THE BILIARY TRACT
GALLBLADDER CARCINOMAGALLBLADDER CARCINOMA
• Commonest extrahepatic biliary tract cancerCommonest extrahepatic biliary tract cancer
• Slightly commoner in women; peak 7th decadeSlightly commoner in women; peak 7th decade
• Due to recurrent trauma and inflammation: usuallyDue to recurrent trauma and inflammation: usually
associated with stones; pyogenic or parasitic dis.associated with stones; pyogenic or parasitic dis.
• Pathology:Pathology: Infiltrating or fungating growth patternInfiltrating or fungating growth pattern
• Most areMost are adenocarcinomaadenocarcinoma; 5% have squamous; 5% have squamous
differentiation; minority are carcinoid tumorsdifferentiation; minority are carcinoid tumors
• At dx, most have invaded liver, +/- cystic & biliary ducts,At dx, most have invaded liver, +/- cystic & biliary ducts,
portahepatic LNportahepatic LN
• Seeding to peritoneum, GIT, and lungsSeeding to peritoneum, GIT, and lungs
• Insidious symptoms similar to cholelithiasisInsidious symptoms similar to cholelithiasis
• If obstruction develops early: early Dx & RxIf obstruction develops early: early Dx & Rx
• Px:Px: dismal. 5 year survival: 1%dismal. 5 year survival: 1%

INTRAHEPATIC BILIARY TRACT DISEASEINTRAHEPATIC BILIARY TRACT DISEASE
• Biliary tract diseases are divided into:Biliary tract diseases are divided into:
– 1)1) IntrahepaticIntrahepatic diseasesdiseases
– 2)2) ExtrahepaticExtrahepatic diseasesdiseases
• Intrahepatic biliary tract disease:Intrahepatic biliary tract disease:
– I. Due to general liver diseaseI. Due to general liver disease
• a) Drug toxicitya) Drug toxicity
• b) Viral hepatitisb) Viral hepatitis
• c) Liver transplantationc) Liver transplantation
– II. Due to biliary tract diseaseII. Due to biliary tract disease
• a)a) Biliary cirrhosisBiliary cirrhosis
– PrimaryPrimary
– SecondarySecondary
• b)b) Primary sclerosing cholangitisPrimary sclerosing cholangitis

PATHOLOGY OF THE EXTRAHEPATIC BILE DUCTSPATHOLOGY OF THE EXTRAHEPATIC BILE DUCTS
CHOLEDOCHOLITHIASISCHOLEDOCHOLITHIASIS
• Stones present within the biliary treeStones present within the biliary tree
• Stones may be:Stones may be:
– 1) Derived from gallbladder1) Derived from gallbladder
– 2) Primary ductal & intrahepatic stone2) Primary ductal & intrahepatic stone
formationformation
• Stones do not necessarily obstruct major bileStones do not necessarily obstruct major bile
ductsducts
• Asymptomatic in 10%Asymptomatic in 10%
• Symptoms due to:Symptoms due to: 1) biliary obstruction, 2)1) biliary obstruction, 2)
pancreatitis, 3) cholangitis, 4) hepatic abscess,pancreatitis, 3) cholangitis, 4) hepatic abscess,
5) chronic liver disease with secondary biliary5) chronic liver disease with secondary biliary
cirrhosis, or 6) acute acalculous cholecystitiscirrhosis, or 6) acute acalculous cholecystitis

EXTRAHEPATIC BILIARY ATRESIAEXTRAHEPATIC BILIARY ATRESIA
• Major cause (1/3) of neonatal cholestasisMajor cause (1/3) of neonatal cholestasis
• 1:10,000 live births1:10,000 live births
• Complete bile flow obstruction due toComplete bile flow obstruction due to destructiondestruction
or absenceor absence of all or part of extrahepatic bile ductsof all or part of extrahepatic bile ducts
• Not a true atresiaNot a true atresia: an acquired inflammatory: an acquired inflammatory
disorder of unknown causedisorder of unknown cause
• Slight female preponderanceSlight female preponderance
• Normal birth weight infantsNormal birth weight infants
• Lab:Lab: conjugated hyperbilirubinemiaconjugated hyperbilirubinemia
• BiopsyBiopsy is essential for diagnosisis essential for diagnosis

EXTRAHEPATIC BILIARY ATRESIAEXTRAHEPATIC BILIARY ATRESIA
• Pathology:Pathology:
– 1) inflammation & fibrosing stricture of hepatic1) inflammation & fibrosing stricture of hepatic
or common bile ducts, with progressiveor common bile ducts, with progressive
destruction of intrahepatic biliary treedestruction of intrahepatic biliary tree
– 2) Periductal inflammation of intrahepatic ducts2) Periductal inflammation of intrahepatic ducts
– 3) Liver: marked bile duct proliferation, portal3) Liver: marked bile duct proliferation, portal
tract edema & fibrosis, parenchymaltract edema & fibrosis, parenchymal
cholestasis & giant multinucleated hepatocytes.cholestasis & giant multinucleated hepatocytes.
– 4) Periportal fibrosis & cirrhosis within 3-64) Periportal fibrosis & cirrhosis within 3-6
monthsmonths
• Px:Px: death within 2 years of birthdeath within 2 years of birth
• Rx:Rx: liver transplatationliver transplatation

PRIMARY BILIARYPRIMARY BILIARY CIRRHOSISCIRRHOSIS
• Chronic progressiveChronic progressive & often fatal cholestatic& often fatal cholestatic
liver disease, characterized byliver disease, characterized by destructiondestruction ofof
intra-hepatic bile ducts, portalintra-hepatic bile ducts, portal inflammationinflammation &&
scarringscarring
• Primary feature: nonsuppurativePrimary feature: nonsuppurative granulomasgranulomas

PRIMARY BILIARY CIRRHOSISPRIMARY BILIARY CIRRHOSIS
• Disease ofDisease of middle-aged womenmiddle-aged women, onset 20-80 yrs, onset 20-80 yrs
• InsidiousInsidious onset: pruritis; later jaundice appearsonset: pruritis; later jaundice appears
• CirrhosisCirrhosis & hepatic failure develops over 2 or& hepatic failure develops over 2 or
more decades, with s & s of portal hypertension &more decades, with s & s of portal hypertension &
hepatic encephalopathyhepatic encephalopathy
• Lab:Lab: alk. phosph. & cholesterol; bilirubin is a latealk. phosph. & cholesterol; bilirubin is a late
development, indicating hepatic decompensationdevelopment, indicating hepatic decompensation
• Autoantibodies:Autoantibodies: anti-mitochondrial Ab in >90% ofanti-mitochondrial Ab in >90% of
patients (mitochondrial pyruvate dehydrogenase)patients (mitochondrial pyruvate dehydrogenase)
• Associated extra-hepatic conditions:Associated extra-hepatic conditions: SjogrenSjogren’’s,s,
scleroderma, thyroiditis, RA, celiac diseasescleroderma, thyroiditis, RA, celiac disease ……
• Rx:Rx: Liver transplantationLiver transplantation

PRIMARY BILIARY CIRRHOSISPRIMARY BILIARY CIRRHOSIS
• AutoimmuneAutoimmune disease involving lymphocyte-mediateddisease involving lymphocyte-mediated
destruction of bile duct epitheliumdestruction of bile duct epithelium

PRIMARY SCLEROSING CHOLANGITISPRIMARY SCLEROSING CHOLANGITIS
• InflammationInflammation, obliterative, obliterative fibrosisfibrosis & segmental& segmental
dilationdilation of the obstructed intrahepatic & extrahepaticof the obstructed intrahepatic & extrahepatic
bile ductsbile ducts

PRIMARY SCLEROSING CHOLANGITISPRIMARY SCLEROSING CHOLANGITIS
• Irregular strictures & dilations of affected bileIrregular strictures & dilations of affected bile
ducts produces characteristicducts produces characteristic ““beadingbeading”” picturepicture
in barium contrast radiographyin barium contrast radiography
• 70% of patients have associated70% of patients have associated ulcerative colitisulcerative colitis
• About 4% of UC patients have PSCAbout 4% of UC patients have PSC
• 3rd-5th decades;3rd-5th decades; M:F=2:1M:F=2:1
• Clinical picture:Clinical picture: progressive fatigue, pruritis &progressive fatigue, pruritis &
jaundice; s & s of chronic liver diseasejaundice; s & s of chronic liver disease
• Lab:Lab: alkaline phosphatasealkaline phosphatase
• Autoantibodies:Autoantibodies: <10% of patients<10% of patients
• Px:Px: protracted course over many years;protracted course over many years;
increased risk of cholangiocarcinomaincreased risk of cholangiocarcinoma
• Rx:Rx: Liver transplantationLiver transplantation

PATHOLOGY OF INTRAHEPATICPATHOLOGY OF INTRAHEPATIC
BILIARY TRACT DISEASEBILIARY TRACT DISEASE
Primary biliary
cirrhosis
Secondary biliary
cirrhosis
Primary sclerosing
cholangitis
Pre-cirrhosis:
Florid duct lesion with
granulomas,
lymphocytes,
macrophages, plasma
cells & eosinophils;
bile duct proliferation,
inflammation &
necrosis of periportal
hepatic parenchyma
Pre-cirrhosis:
Prominent bile stasis
in bile ducts, bile
duct proliferation
with surrounding
neutrophils, portal
tract edema.
Coarse fibrous septa
with distended ducts
embedded in septa.
Pylephlebitis &
cholangitic abscess
Pre-cirrhosis:
Fibrosing
cholangitis of bile
ducts; concentric
"onion skin"
fibrosis, progressive
duct atrophy &
luminal obliteration

SECONDARY BILIARY CIRRHOSISSECONDARY BILIARY CIRRHOSIS
• Prolonged obstruction to extrahepatic biliary treeProlonged obstruction to extrahepatic biliary tree
results in profound damage to the liverresults in profound damage to the liver
• Causes:Causes:
– 1) Extrahepatic cholelithiasis1) Extrahepatic cholelithiasis
– 2) Biliary atresia2) Biliary atresia
– 3) Tumors of biliary tree & pancreas head3) Tumors of biliary tree & pancreas head
– 4) Strictures secondary to previous surgery4) Strictures secondary to previous surgery
• Pathology:Pathology:
– Initially, reversible features of cholestasisInitially, reversible features of cholestasis
– Periportal fibrosis, scarring, & nodulePeriportal fibrosis, scarring, & nodule formationformation
• Subtotal obstruction causes secondary ascendingSubtotal obstruction causes secondary ascending
cholangitis, mostly due to coliforms & enterococcicholangitis, mostly due to coliforms & enterococci

ASCENDING CHOLANGITISASCENDING CHOLANGITIS
• Acute iflammation of the wall of bile ductsAcute iflammation of the wall of bile ducts
• Causd by any lesion obstructing bile flowCausd by any lesion obstructing bile flow::
– 1) Choledocholithiasis1) Choledocholithiasis
– 2) Tumors2) Tumors
– 3) Indwelling catheters or stents3) Indwelling catheters or stents
– 4) Acute pancreatits4) Acute pancreatits
– 5) Benign strictures5) Benign strictures
– 6) Microorganisms: fungi, viruses, protozoa &6) Microorganisms: fungi, viruses, protozoa &
bacteriabacteria
• Fever, chills, abdominal pain, jaundiceFever, chills, abdominal pain, jaundice
• Suppurative cholangitis: risk of liver abscessSuppurative cholangitis: risk of liver abscess
• Complications:Complications: SepsisSepsis

CARCINOMA OF EXTRAHEPATIC DUCTSCARCINOMA OF EXTRAHEPATIC DUCTS
• CholangiocarcinomaCholangiocarcinoma arising in extrahepatic ductsarising in extrahepatic ducts
• Insidious behaviour, producing painlessInsidious behaviour, producing painless
progressive jaundiceprogressive jaundice
• Older individuals, more in malesOlder individuals, more in males
• Causes:Causes:
– Association with stones is not convincingAssociation with stones is not convincing
– Biliary tract fluke infections (ClonorchisBiliary tract fluke infections (Clonorchis
sinensis)sinensis)
– Pre-existing primary sclerosing cholangitisPre-existing primary sclerosing cholangitis
• Periampullary carcinomas:Periampullary carcinomas: arising in immediatearising in immediate
vicinity of Ampula of Vatervicinity of Ampula of Vater

CARCINOMA OF EXTRAHEPATIC DUCTSCARCINOMA OF EXTRAHEPATIC DUCTS
• At time of diagnosis, these tumors tend to beAt time of diagnosis, these tumors tend to be
small in size.small in size.
• Most are firm nodules within bile duct wallMost are firm nodules within bile duct wall
• Some are diffusely infiltrative lesionsSome are diffusely infiltrative lesions
• A few are papillary polypoid lesionsA few are papillary polypoid lesions
• Adencarcinomas. Squamous features areAdencarcinomas. Squamous features are
uncommonuncommon
• Jaundice, light stools, nausea, vomitingJaundice, light stools, nausea, vomiting
• Hepatomegaly & palpable gall bladderHepatomegaly & palpable gall bladder
• Elevated alk. phosphatase & transaminases, PTElevated alk. phosphatase & transaminases, PT……
• Dx:Dx: endoscopyendoscopy
• Px:Px: despite small size, most are not surgicallydespite small size, most are not surgically
resectable at time of diagnosisresectable at time of diagnosis

CIRCULATORY DISORDERSCIRCULATORY DISORDERS
• Disturbances in the vascular supply or venousDisturbances in the vascular supply or venous
drainage of liver are extremely commondrainage of liver are extremely common
• Classification:Classification:
– Impaired blood flow into the liverImpaired blood flow into the liver
• Hepatic artery inflowHepatic artery inflow
• Portal vein obstructionPortal vein obstruction
– Impaired blood flow through the liverImpaired blood flow through the liver
• Passive congestion & centrilobular necrosisPassive congestion & centrilobular necrosis
• Peliosis hepatisPeliosis hepatis
– Hepatic venous outflow obstructionHepatic venous outflow obstruction
• Hepatic vein thrombosis (Budd-Chiary syndrome)Hepatic vein thrombosis (Budd-Chiary syndrome)
• Veno-occlusive diseaseVeno-occlusive disease

CIRCULATORY DISORDERS OF THE LIVERCIRCULATORY DISORDERS OF THE LIVER
IMPAIRED BLOOD INFLOWIMPAIRED BLOOD INFLOW
• Hepatic artery inflow:Hepatic artery inflow: Causes:Causes:
– Thrombosis, embolismThrombosis, embolism
– Vascular disease, e.g. polyarteritis nodosaVascular disease, e.g. polyarteritis nodosa
– Compression by neoplasiaCompression by neoplasia
– SepsisSepsis
• Liver infarctsLiver infarcts are rare, due to theare rare, due to the doubledouble bloodblood
supply to the liversupply to the liver
• Interruption of main hepatic artery does notInterruption of main hepatic artery does not
always produce ischemic necrosis of liver due toalways produce ischemic necrosis of liver due to
the presence of accessory vessels & the portalthe presence of accessory vessels & the portal
venous systemvenous system
• Ischemic (anemic or hemorrhagic) necrosisIschemic (anemic or hemorrhagic) necrosis
usually produses small & localized infarcts;usually produses small & localized infarcts;
complete organ loss is rare (liver transplantation)complete organ loss is rare (liver transplantation)

• Portal vein obstruction:Portal vein obstruction: CausesCauses::
– ExtrahepaticExtrahepatic portal vein obstruction:portal vein obstruction:
• PeritonealPeritoneal sepsissepsis & subsequent pylephlebitis& subsequent pylephlebitis
• LymphaticLymphatic metastasismetastasis with enlarged hilar LNwith enlarged hilar LN
• Pancreatitis withPancreatitis with splenic vein thrombosissplenic vein thrombosis
• HypercoagulabilityHypercoagulability; Post-surgical thromboses; Post-surgical thromboses
• BantiBanti’’s syndromes syndrome: subclinical portal vein thrombosis: subclinical portal vein thrombosis
due todue to neonatal omphalitisneonatal omphalitis oror umbilical veinumbilical vein
catheterizationcatheterization produces fibrotic partially recanalizedproduces fibrotic partially recanalized
blood vesselblood vessel
– IntrahepaticIntrahepatic portal vein radicle obstruction:portal vein radicle obstruction:
• Vascular invasion byVascular invasion by cancercancer in liverin liver
• HypercoagulableHypercoagulable statesstates

• Obstruction of Portal vein or its radicles:Obstruction of Portal vein or its radicles:
• Infarct of Zahn:Infarct of Zahn: sharply demarcated area of red-sharply demarcated area of red-
blue discoloration, due to hepatocellular atrophyblue discoloration, due to hepatocellular atrophy
secondary to marked sinusoidal congstionsecondary to marked sinusoidal congstion
• Clinical manifestations:Clinical manifestations:
– Symptoms are variableSymptoms are variable
– Portal hypertension (ascites, esophagealPortal hypertension (ascites, esophageal
varices, splenomegaly),varices, splenomegaly),
– Intestinal congestion & pain, due to obstructionIntestinal congestion & pain, due to obstruction
of portal vein or its major radiclesof portal vein or its major radicles
– Bowel infarction if visceral blood flow isBowel infarction if visceral blood flow is
impairedimpaired
– Multiple liver abscesses (in pylephlebitis)Multiple liver abscesses (in pylephlebitis)

IMPAIRED BLOOD FLOWIMPAIRED BLOOD FLOW
THROUGH THE LIVERTHROUGH THE LIVER
• Causes:Causes:
– 1)1) CirrhosisCirrhosis: causes portal blood flow: causes portal blood flow
obstruction due to copmression of sinusoids &obstruction due to copmression of sinusoids &
central veins leading to increased resistance tocentral veins leading to increased resistance to
portal flow at the level of the sinusoidsportal flow at the level of the sinusoids
– 2)2) Physical occlusion of hepatic sinusoidPhysical occlusion of hepatic sinusoid::
• Sickle cell anemiaSickle cell anemia
– 3)3) Systemic circulatory compromiseSystemic circulatory compromise: DIC: DIC
–Eclampsia of pregnancy: associated withEclampsia of pregnancy: associated with
DIC, and may result in extensiveDIC, and may result in extensive
subcapsular hepatic hematomasubcapsular hepatic hematoma

• Passive congestion & centrilobular necrosisPassive congestion & centrilobular necrosis
– Manifestations of systemic circulatory collapseManifestations of systemic circulatory collapse
– Right-sided heart failureRight-sided heart failure: leads to passive: leads to passive
congestion of liver [Centrilobular congestion]congestion of liver [Centrilobular congestion]
– Left-sided heart failure or shockLeft-sided heart failure or shock: leads to: leads to
hepatic hypoperfusion & hypoxia [Centrilobularhepatic hypoperfusion & hypoxia [Centrilobular
necrosis]necrosis]
– Combined Rt & Lt heart failureCombined Rt & Lt heart failure: leads to: leads to
centrilobular hemorrhagic necrosis (centrilobular hemorrhagic necrosis (““nutmegnutmeg””
liver)liver)
– Cardiac sclerosis (Cardiac sclerosis (““cardiac cirrhosiscardiac cirrhosis””):):
centrilobular fibrosis; uncommon complicationcentrilobular fibrosis; uncommon complication
of sustained chronic severe congestive heartof sustained chronic severe congestive heart
failurefailure

• Peliosis hepatis:Peliosis hepatis:
– Rare condition characterized by sinusoidalRare condition characterized by sinusoidal
dilation formingdilation forming blood filled cavitiesblood filled cavities withinwithin
hepatic parenchymahepatic parenchyma
– Associated withAssociated with anabolic steroidsanabolic steroids, OCPs,, OCPs,
corticosteroids, danazol,corticosteroids, danazol, ……
– Also associated with marasmus, bacterialAlso associated with marasmus, bacterial
endocarditis, lymphoproliferative dis., &endocarditis, lymphoproliferative dis., & AIDSAIDS
(bacillary angiomatosis-(bacillary angiomatosis- Rochalimaea henselaeRochalimaea henselae))
– Unknown pathogenesisUnknown pathogenesis
– Usually asymptomaticUsually asymptomatic
– ComplicationsComplications of advanced peliosis: intra-of advanced peliosis: intra-
abdominal hemorrhage, hepatic failureabdominal hemorrhage, hepatic failure

HEPATIC VENOUS OUTFLOWHEPATIC VENOUS OUTFLOW
OBSTRUCTIONOBSTRUCTION
• Hepatic vein thrombosis (Budd-Chiari syndrome)Hepatic vein thrombosis (Budd-Chiari syndrome)
– May be:May be:
• Acute : usually fatalAcute : usually fatal
• SubacuteSubacute
• ChronicChronic
– Associated with:Associated with:
• Polycythemia veraPolycythemia vera
• PregnancyPregnancy
• Post-partum statePost-partum state
• Oral contraceptive useOral contraceptive use
• Paroxysmal nocturnal hemoglobinuriaParoxysmal nocturnal hemoglobinuria
• Intra-abdominal cancers, particularly hepatocellularIntra-abdominal cancers, particularly hepatocellular
carcinomacarcinoma
• 30% of cases are idiopathic30% of cases are idiopathic

HEPATIC VENOUSHEPATIC VENOUS
OUTFLOW OBSTRUCTIONOUTFLOW OBSTRUCTION
• Hepatic vein thrombosis (Budd-Chiari syndrome)Hepatic vein thrombosis (Budd-Chiari syndrome)
– Clinical manifestations:Clinical manifestations:
• HepatomegalyHepatomegaly
• AscitesAscites
• Abdominal pain & distensionAbdominal pain & distension
• JaundiceJaundice
• DeathDeath
– Thrombosis in major hepatic veins or inferiorThrombosis in major hepatic veins or inferior
vena cavavena cava
– Swollen red-purple liver with tense capsuleSwollen red-purple liver with tense capsule
– Severe hepatic centrilobular congestion &Severe hepatic centrilobular congestion &
necrosis; centrilobular fibrosis in chronic casesnecrosis; centrilobular fibrosis in chronic cases
– Px:Px: acute form has a high mortality; chronicacute form has a high mortality; chronic
formform
– Rx: surgical

HEPATIC VENOUS OUTFLOWHEPATIC VENOUS OUTFLOW
OBSTRUCTIONOBSTRUCTION
• Veno-occlusive diseaseVeno-occlusive disease
– Associated with:Associated with:
• Drinking of Pyrrolizidine alkaloid-containingDrinking of Pyrrolizidine alkaloid-containing bush teabush tea
• Bone marrow transplantationBone marrow transplantation followed by graft-followed by graft-
versus-host disease:versus-host disease:
– Up to 25% of allogenic bone marrow transplant patientsUp to 25% of allogenic bone marrow transplant patients
– 30% mortality rate30% mortality rate
– Chemotherapy & radiotherapy induced toxic endothelialChemotherapy & radiotherapy induced toxic endothelial
injuryinjury
– Small hepatic vein radicles are obliterated bySmall hepatic vein radicles are obliterated by
subebdothelial swelling & collagen depositionsubebdothelial swelling & collagen deposition
– Clinical pictureClinical picture is indistinguishable from Budd-is indistinguishable from Budd-
Chiari syndromeChiari syndrome
– Centrilobular congestion & necrosis +/-Centrilobular congestion & necrosis +/-
sclerosissclerosis

LIVER PATHOLOGY

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