The Liver and the The Liver and the Biliary TractBiliary Tract

Dr Dinah ParumsDr Dinah Parums

Principal HistopathologistPrincipal Histopathologist

July 2007July 2007

Normal LiverNormal Liver Average liver weight is 1,400

to 1,800 gms Lower border can be felt under

the right costal margin on deep inspiration

The right lobe is six times the size of the left

Dual blood supply - 40% hepatic artery - the rest by the hepatic portal vein

Bile drains in to the right and left hepatic ducts, into the common hepatic duct which joins with the cystic duct from the gallbladder, to form the common bile duct draining in to the duodenum via the Ampulla of Vater

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Normal LiverNormal Liver Histology of the liver shows a solid

mass of parenchyma composed of hepatocytes and cells lining the sinusoids pierced by portal tracts and tributaries of the hepatic veins

The liver lobule has an architecture defined by the liver vasculature

HV - the hepatic vein is at the centre of the liver lobule (sometimes called the Central Vein)

P - the portal tract - contains the portal triad

hepatic arteriole, bile duct and portal vein

Blood flow is from P to HV Bile flow is from HV to P The distance between the HV and

the P is 0.5 mm

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HV

P

Normal LiverNormal LiverThe Kupffer Cell and SinusoidsThe Kupffer Cell and Sinusoids

One type of cell lining the hepatic sinusoids, the Kupffer cell, is phagocytic and is a component of the mononuclear phagocyte system.

The Kupffer cell helps clear the blood of foreign substances and old erythrocytes.

The other major type of lining cell is a special endothelial cell containing numerous pores permitting free passage of plasma macromolecules between hepatocytes and blood. It is not phagocytic.

Finally, there are scattered lipocytes that store vitamin A and also are responsible for collagen synthesis in liver fibrosis.

Normal LiverNormal LiverBileBile

Bile, the exocrine product of the hepatocytes, is initially secreted into intercellular bile canaliculi and then passes into branches of the bile (hepatic) duct.

The bile canaliculi are tiny passageways between adjacent hepatocytes.

They are difficult to visualize with the light microscope unless they are selectively stained.

Apart from the connective tissue of the portal triads, the structural framework of hepatic lobules consists of reticular fibers which are arranged in small bundles located in the space between the endothelial cells lining the sinusoids and the hepatocytes. This space is called the space of Disse.

The space of Disse is too narrow to be seen with the light microscope

Hepatic InjuryHepatic Injury Inflammation = hepatitisInflammation = hepatitis

Portal tracts, lobulesPortal tracts, lobules DegenerationDegeneration

Damage from toxic or immunologic insultDamage from toxic or immunologic insult Accumulation of substances, e.g., steatosisAccumulation of substances, e.g., steatosis

Cell deathCell death Centrilobular, submassive, massive Centrilobular, submassive, massive

necrosisnecrosis FibrosisFibrosis

Usually irreversibleUsually irreversible CirrhosisCirrhosis

BileBile

Two major functionsTwo major functions Elimination of bilirubin, excess Elimination of bilirubin, excess

cholesterol, and xenobiotics that are cholesterol, and xenobiotics that are insufficiently water soluble to be insufficiently water soluble to be excreted in urineexcreted in urine

Emulsification of dietary fat in the gut Emulsification of dietary fat in the gut by bile acids (cholic acid, by bile acids (cholic acid, chenodeoxycholic acid)chenodeoxycholic acid)

Unconjugated Unconjugated → Conjugated→ Conjugated Reabsorbed in terminal ileum Reabsorbed in terminal ileum

(enterohepatic circulation)(enterohepatic circulation)

JaundiceJaundice Excessive production of bilirubinExcessive production of bilirubin

Hemolytic anemias, ineffective Hemolytic anemias, ineffective erythropoiesiserythropoiesis

Reduced hepatic uptakeReduced hepatic uptake Impaired conjugationImpaired conjugation

Physiologic jaundice of the newbornPhysiologic jaundice of the newborn Crigler-Najjar syndromes types I and IICrigler-Najjar syndromes types I and II Gilbert syndromeGilbert syndrome Viral or drug-induced hepatitis, cirrhosisViral or drug-induced hepatitis, cirrhosis

Decreased hepatocellular excretionDecreased hepatocellular excretion Dubin-Johnson syndrome, Rotor syndromeDubin-Johnson syndrome, Rotor syndrome

Impaired bile flowImpaired bile flow

CholestasisCholestasis Systemic retention of not only bilirubin Systemic retention of not only bilirubin

but also other solutes eliminated in but also other solutes eliminated in bile, particularly bile salts and bile, particularly bile salts and cholesterolcholesterol

Due to hepatocellular dysfunction or Due to hepatocellular dysfunction or biliary obstructionbiliary obstruction

Accumulation of bile pigment within Accumulation of bile pigment within the hepatic parenchyma – Kupffer cellsthe hepatic parenchyma – Kupffer cells

Bile ductular proliferationBile ductular proliferation Bile lakesBile lakes Portal tract fibrosisPortal tract fibrosis

Hepatic FailureHepatic Failure 80% to 90% of hepatic functional 80% to 90% of hepatic functional

capacity must to destroyedcapacity must to destroyed Massive hepatic necrosisMassive hepatic necrosis

Fulminant viral hepatitisFulminant viral hepatitis Drugs and chemicals, e.g., acetaminophen, Drugs and chemicals, e.g., acetaminophen,

carbon tetrachloride, mushroom poisoningcarbon tetrachloride, mushroom poisoning Chronic liver diseaseChronic liver disease Hepatic dysfunction without overt Hepatic dysfunction without overt

necrosisnecrosis Acute fatty liver of pregnancyAcute fatty liver of pregnancy Tetracycline toxicityTetracycline toxicity Reye syndromeReye syndrome

Clinical FeaturesClinical Features

JaundiceJaundice HypoalbuminaemiaHypoalbuminaemia HyperammonaemiaHyperammonaemia Fetor hepaticusFetor hepaticus Palmar erythaemaPalmar erythaema Spider angiomasSpider angiomas HypogonadismHypogonadism GynaecomastiaGynaecomastia

ComplicationsComplications Multiple organ failureMultiple organ failure CoagulopathyCoagulopathy Hepatic encephalopathyHepatic encephalopathy

Metabolic disorder of the CNS and Metabolic disorder of the CNS and NMSNMS

Elevated blood ammonia level and Elevated blood ammonia level and deranged neurotransmissionderanged neurotransmission

Rigidity, hyperreflexia, seizuresRigidity, hyperreflexia, seizures AsterixisAsterixis

Hepatorenal syndromeHepatorenal syndrome Idiopathic renal failureIdiopathic renal failure

CirrhosisCirrhosis Bridging fibrous septaBridging fibrous septa Parenchymal nodulesParenchymal nodules Disruption of the architecture of the Disruption of the architecture of the

entire liverentire liver AetiologiesAetiologies

Alcoholic liver disease 60% to 70%Alcoholic liver disease 60% to 70% Viral hepatitis 10%Viral hepatitis 10% Biliary diseases 5% to 10%Biliary diseases 5% to 10% Hereditary hemochromatosis 5%Hereditary hemochromatosis 5% Wilson disease rareWilson disease rare Cryptogenic cirrhosis 10% to 15%Cryptogenic cirrhosis 10% to 15%

Portal HypertensionPortal Hypertension PrehepaticPrehepatic

Occlusive thrombosis, narrowing of the Occlusive thrombosis, narrowing of the portal veinportal vein

IntrahepaticIntrahepatic CirrhosisCirrhosis Schistosomiasis, massive fatty change, Schistosomiasis, massive fatty change,

diffuse granulomatous diseases (sarcoidosis, diffuse granulomatous diseases (sarcoidosis, miliary TB)miliary TB)

PosthepaticPosthepatic Right-sided heart failure, constrictive Right-sided heart failure, constrictive

pericarditis, hepatic vein outflow obstructionpericarditis, hepatic vein outflow obstruction

Clinical SequelaeClinical Sequelae

AscitesAscites Portosystemic venous shuntsPortosystemic venous shunts

Oesophageal varices 65% of casesOesophageal varices 65% of cases HemorrhoidsHemorrhoids Caput medusaeCaput medusae

SplenomegalySplenomegaly Hepatic encephalopathyHepatic encephalopathy

Drug Induced Liver Drug Induced Liver DiseaseDisease

Liver is the major drug metabolizing Liver is the major drug metabolizing and detoxifying organ in the bodyand detoxifying organ in the body

Direct toxicityDirect toxicity Hepatic conversion of a xenobiotic to Hepatic conversion of a xenobiotic to

an active toxinan active toxin Immune mechanismsImmune mechanisms

Alcoholic Liver DiseaseAlcoholic Liver Disease Hepatic steatosisHepatic steatosis

Micro and Micro and macrovesicularmacrovesicular

Initially centrilobularInitially centrilobular Alcoholic hepatitisAlcoholic hepatitis

Hepatocyte swelling Hepatocyte swelling and necrosisand necrosis

Mallory bodiesMallory bodies Neutrophilic reactionNeutrophilic reaction FibrosisFibrosis

Alcoholic cirrhosisAlcoholic cirrhosis MicronodularMicronodular IrreversibleIrreversible

PathogenesisPathogenesis Shunting of normal substrates away Shunting of normal substrates away

from catabolism toward lipid from catabolism toward lipid biosynthesisbiosynthesis

Induction of cytochrome P-450Induction of cytochrome P-450 Free radicals generated by microsomal Free radicals generated by microsomal

ethanol oxidizing systemethanol oxidizing system Alcohol directly affects microtubular Alcohol directly affects microtubular

and mitochondrial functionand mitochondrial function Acetaldehyde induces lipid peroxidationAcetaldehyde induces lipid peroxidation Neutrophil infiltrationNeutrophil infiltration Immunologic attack of hepatocytesImmunologic attack of hepatocytes

Causes of DeathCauses of Death

Hepatic failureHepatic failure Massive GI hemorrhageMassive GI hemorrhage InfectionInfection Hepatorenal syndromeHepatorenal syndrome Hepatocellular carcinomaHepatocellular carcinoma

Nonalcoholic Fatty LiverNonalcoholic Fatty Liver

Elevated serum aminotransferase Elevated serum aminotransferase levelslevels

Low risk for development of hepatic Low risk for development of hepatic fibrosis or cirrhosisfibrosis or cirrhosis

Associated with obesity, type 2 DM, Associated with obesity, type 2 DM, hyperlipidemiahyperlipidemia

Need to exclude other causesNeed to exclude other causes

HemochromatosisHemochromatosis

Primary or hereditaryPrimary or hereditary HLA-linked autosomal recessive diseaseHLA-linked autosomal recessive disease

SecondarySecondary Transfusion dependentTransfusion dependent Chronic liver diseaseChronic liver disease

PathogenesisPathogenesis Total body iron pool 2 to 6 gmTotal body iron pool 2 to 6 gm Primary defect in regulation of Primary defect in regulation of

intestinal absorption of dietary iron, intestinal absorption of dietary iron, leading to a net iron accumulation of leading to a net iron accumulation of 0.5 to 1.0 g/yr0.5 to 1.0 g/yr

HFE gene on 6pHFE gene on 6p Interacts with transferrin receptor of Interacts with transferrin receptor of

intestinal enterocyte and modulates intestinal enterocyte and modulates interaction with transferrin-iron complexesinteraction with transferrin-iron complexes

C282Y – disulfide bridge disruptedC282Y – disulfide bridge disrupted H63DH63D Lipid peroxidation, collagen formation, Lipid peroxidation, collagen formation,

DNA interactionsDNA interactions

MorphologyMorphology Deposition of hemosiderin in the liver, Deposition of hemosiderin in the liver,

pancreas, myocardium, pituitary, adrenal, pancreas, myocardium, pituitary, adrenal, thyroid and parathyroid glands, joints, and skinthyroid and parathyroid glands, joints, and skin

Cirrhosis, micronodularCirrhosis, micronodular Pancreatic interstitial fibrosis and parenchymal Pancreatic interstitial fibrosis and parenchymal

atrophy atrophy → DM→ DM

Clinical FeaturesClinical Features M:F = 5-7:1M:F = 5-7:1 Symptoms usually appear in the fifth to Symptoms usually appear in the fifth to

sixth decades of life.sixth decades of life. Classic triad: cirrhosis with Classic triad: cirrhosis with

hepatomegaly, skin pigmentation, DM hepatomegaly, skin pigmentation, DM (late in course)(late in course)

Cardiac dysfunction, e.g., arrhythmias, Cardiac dysfunction, e.g., arrhythmias, cardiomyopathycardiomyopathy

Atypical arthritisAtypical arthritis HypogonadismHypogonadism Tx: phlebotomy, iron chelatorsTx: phlebotomy, iron chelators

Wilson DiseaseWilson Disease Autosomal recessive disorder of Autosomal recessive disorder of

copper metabolismcopper metabolism ATP7B on chr 13 ATP-dependent ATP7B on chr 13 ATP-dependent

metal ion transporter on the Golgi of metal ion transporter on the Golgi of hepatocyteshepatocytes

Failure to excrete copper into bileFailure to excrete copper into bile Copper causes progressive liver injuryCopper causes progressive liver injury Affects brain, cornea, kidneys, bones, Affects brain, cornea, kidneys, bones,

joints, and parathyroid glandsjoints, and parathyroid glands Dx: Dx: ↓ serum caeruloplasmin, ↑ hepatic ↓ serum caeruloplasmin, ↑ hepatic

copper content, ↑ urinary coppercopper content, ↑ urinary copper

MorphologyMorphology Liver – fatty change, Liver – fatty change,

acute hepatitis, acute hepatitis, chronic hepatitis, chronic hepatitis, cirrhosiscirrhosis Rhodanine stain for Rhodanine stain for

coppercopper Orcein stain for copper-Orcein stain for copper-

associated proteinassociated protein Brain – Basal ganglia Brain – Basal ganglia

(putamen) shows (putamen) shows atrophy and cavitationatrophy and cavitation

Eye – Kayser-Fleischer Eye – Kayser-Fleischer ringsrings

Aka hepatolenticular Aka hepatolenticular degenerationdegeneration

Clinical FeaturesClinical Features

Manifestations rare before 6 yrsManifestations rare before 6 yrs Acute or chronic liver disease – most Acute or chronic liver disease – most

commoncommon Neuropsychiatric manifestationsNeuropsychiatric manifestations Copper chelation therapy with D-Copper chelation therapy with D-

penicillaminepenicillamine Liver transplantationLiver transplantation

αα11-Antitrypsin Deficiency-Antitrypsin Deficiency

Autosomal recessive disorderAutosomal recessive disorder AAT is a protease inhibitor, AAT is a protease inhibitor,

particularly neutrophil elastase particularly neutrophil elastase released at sites of inflammationreleased at sites of inflammation

AAT gene on chr 14AAT gene on chr 14 M allele normal, Z allele abnormal M allele normal, Z allele abnormal → →

misfolding of the nascent polypeptide in misfolding of the nascent polypeptide in the hepatocyte ER, accumulation, the hepatocyte ER, accumulation, degradationdegradation

Leads to pulmonary emphysema due Leads to pulmonary emphysema due to tissue destructive enzymesto tissue destructive enzymes

MorphologyMorphology Round to oval Round to oval

cytoplasmic cytoplasmic inclusions of retained inclusions of retained AATAAT Periodic acid-Schiff Periodic acid-Schiff

(PAS) positive(PAS) positive Marked cholestasis Marked cholestasis

with hepatocyte with hepatocyte necrosis in newbornsnecrosis in newborns

Childhood cirrhosisChildhood cirrhosis Chronic hepatitis or Chronic hepatitis or

cirrhosis later in lifecirrhosis later in life Tx: liver Tx: liver

transplantationtransplantation

Neonatal HepatitisNeonatal Hepatitis

Not a specific entityNot a specific entity Not necessarily inflammatoryNot necessarily inflammatory

Extrahepatic biliary atresia (20%), Extrahepatic biliary atresia (20%), toxic, metabolic diseases, AAT toxic, metabolic diseases, AAT deficiency (1.5%), idiopathic (50% to deficiency (1.5%), idiopathic (50% to 60%)60%)

Neonatal cholestasis (prolonged Neonatal cholestasis (prolonged conjugated hyperbilirubinemia)conjugated hyperbilirubinemia)

Present with jaundice, dark urine, Present with jaundice, dark urine, light or acholic stools, hepatomegalylight or acholic stools, hepatomegaly

Marked Marked bilirubin stasis bilirubin stasis in hepatocytes, in hepatocytes, canaliculi, and canaliculi, and Kupffer cells in Kupffer cells in neonate with neonate with extrahepatic extrahepatic bile duct bile duct atresia.atresia.

Reye SyndromeReye Syndrome Rare disease characterized by fatty Rare disease characterized by fatty

change in the liver and change in the liver and encephalopathyencephalopathy

Children < 4 yoChildren < 4 yo 3 to 5 days after a viral illness3 to 5 days after a viral illness

Associated with salicylate (aspirin) useAssociated with salicylate (aspirin) use Present with vomiting, irritability or Present with vomiting, irritability or

lethargy, hepatomegalylethargy, hepatomegaly 25% progress to coma25% progress to coma Death due to progressive neurologic Death due to progressive neurologic

deterioration or liver failuredeterioration or liver failure Tx: symptomatic, supportiveTx: symptomatic, supportive

MorphologyMorphology

Liver – microvesicular steatosisLiver – microvesicular steatosis EM – mitochondrial enlargement with EM – mitochondrial enlargement with

disruption of cristaedisruption of cristae Brain – cerebral oedemaBrain – cerebral oedema

Astrocytes swollen, mitochondrial Astrocytes swollen, mitochondrial changeschanges

Skeletal muscles, kidneys, and heart Skeletal muscles, kidneys, and heart may have microvesicular steatosis.may have microvesicular steatosis.

Obstructive Obstructive Biliary Tract Biliary Tract

DiseaseDisease

Secondary Biliary Secondary Biliary CirrhosisCirrhosis

Most common cause is extrahepatic Most common cause is extrahepatic cholelithiasischolelithiasis

Biliary atresia, malignancies of the Biliary atresia, malignancies of the biliary tree and head of the biliary tree and head of the pancreas, and stricturespancreas, and strictures

CholestasisCholestasis Bile duct proliferation with Bile duct proliferation with

surrounding neutrophilssurrounding neutrophils Periportal fibrosisPeriportal fibrosis

Primary Biliary CirrhosisPrimary Biliary Cirrhosis

Middle-aged womenMiddle-aged women M:F = 1:10M:F = 1:10 Possibly autoimmunePossibly autoimmune

Autoantibodies to mitochondrial pyruvate Autoantibodies to mitochondrial pyruvate dehydrogenase 90%dehydrogenase 90%

Insidious onset, usually presenting Insidious onset, usually presenting with prurituswith pruritus

Hyperbilirubinemia, jaundice, Hyperbilirubinemia, jaundice, cirrhosis latecirrhosis late

↑ ↑ alkaline phosphatase, cholesterolalkaline phosphatase, cholesterol

NonsuppurativeNonsuppurative, granulomatous , granulomatous destruction of destruction of medium-sized medium-sized intrahepatic bile intrahepatic bile ducts = florid ducts = florid duct lesionduct lesion

Primary Sclerosing Primary Sclerosing CholangitisCholangitis

Inflammation, obliterative onion-skin Inflammation, obliterative onion-skin fibrosis, and segmental dilatation of the fibrosis, and segmental dilatation of the obstructed intrahepatic and obstructed intrahepatic and extrahepatic bile ductsextrahepatic bile ducts

String of beads on ERCPString of beads on ERCP 70% associated with inflammatory bowel 70% associated with inflammatory bowel

disease, particularly ulcerative colitisdisease, particularly ulcerative colitis M:F = 2:1, third through fifth decadesM:F = 2:1, third through fifth decades Progressive fatigue, pruritus, jaundiceProgressive fatigue, pruritus, jaundice Chronic courseChronic course Increased risk for cholangiocarcinomaIncreased risk for cholangiocarcinoma

Circulatory Circulatory DisordersDisorders

Hepatic Artery InflowHepatic Artery Inflow

Liver has dual blood supply.Liver has dual blood supply. Thrombosis of hepatic artery in Thrombosis of hepatic artery in

transplanted liver transplanted liver → loss of organ→ loss of organ

Portal Vein ObstructionPortal Vein Obstruction ExtrahepaticExtrahepatic

Peritoneal sepsis leads to phlebitisPeritoneal sepsis leads to phlebitis Lymphatic metastases to hilar lymph nodesLymphatic metastases to hilar lymph nodes Pancreatitis leads to splenic vein thrombosisPancreatitis leads to splenic vein thrombosis Postsurgical thrombosesPostsurgical thromboses Banti syndrome umbilical vein catheterizationBanti syndrome umbilical vein catheterization

Intrahepatic thrombus does not cause an Intrahepatic thrombus does not cause an ischemic infarction but results in an area ischemic infarction but results in an area of red-blue discoloration (infarct of Zahn).of red-blue discoloration (infarct of Zahn). Invasive carcinomaInvasive carcinoma Hepatoportal sclerosisHepatoportal sclerosis

Impaired Blood Flow Impaired Blood Flow Through the LiverThrough the Liver

CirrhosisCirrhosis Sickle cell diseaseSickle cell disease DIC – disseminated intravascular DIC – disseminated intravascular

coagulation - potentially fatal subcapsular coagulation - potentially fatal subcapsular haematoma in pts with eclampsiahaematoma in pts with eclampsia

Right-sided heart failure Right-sided heart failure → congestion of → congestion of centrilobular sinusoidscentrilobular sinusoids

Left-sided heart failure → hypoperfusion Left-sided heart failure → hypoperfusion and hypoxia → centrilobular necrosisand hypoxia → centrilobular necrosis

Peliosis hepatis – primary sinusoidal Peliosis hepatis – primary sinusoidal dilation associated with anabolic steroids, dilation associated with anabolic steroids, danazol, and oral contraceptivesdanazol, and oral contraceptives

Hepatic Vein ThrombosisHepatic Vein Thrombosis

Aka Budd-Chiari syndromeAka Budd-Chiari syndrome Hepatomegaly, weight gain, ascites, Hepatomegaly, weight gain, ascites,

abdominal painabdominal pain Polycythaemia vera or other Polycythaemia vera or other

myeloprolifera-tive disorders, pregnancy, myeloprolifera-tive disorders, pregnancy, the postpartum state, oral contraceptive the postpartum state, oral contraceptive use, PNH, intra-abdominal cancers, esp. use, PNH, intra-abdominal cancers, esp. HCCHCC

Massive intrahepatic abscess or parasitic Massive intrahepatic abscess or parasitic cystcyst

Centrilobular congestion and necrosisCentrilobular congestion and necrosis

Veno-Occlusive DiseaseVeno-Occlusive Disease

Shortly after bone marrow Shortly after bone marrow transplantationtransplantation

25% incidence25% incidence Subendothelial swelling and Subendothelial swelling and

reticulated collagenreticulated collagen Due to toxic endothelial injury Due to toxic endothelial injury

secondary to chemotherapy and secondary to chemotherapy and radiation therapyradiation therapy

Hepatic NeoplasmsHepatic Neoplasms

Metastatic carcinomas – most Metastatic carcinomas – most commoncommon ColonColon LungLung BreastBreast

Benign tumorsBenign tumors Primary liver carcinomaPrimary liver carcinoma

Hepatocellular carcinomaHepatocellular carcinoma CholangiocarcinomasCholangiocarcinomas Hepatoblastoma – childrenHepatoblastoma – children Angiosarcoma – associated with vinyl Angiosarcoma – associated with vinyl

chloride, arsenic, or Thorotrast exposurechloride, arsenic, or Thorotrast exposure

Benign TumorsBenign Tumors

Cavernous hemangioma – most Cavernous hemangioma – most commoncommon Well-circumscribed, subcapsular, < 2 Well-circumscribed, subcapsular, < 2

cmcm Focal nodular hyperplasiaFocal nodular hyperplasia

Young to middle aged adultsYoung to middle aged adults Poorly encapsulatedPoorly encapsulated Central fibrous scarCentral fibrous scar Response to local vascular injuryResponse to local vascular injury

Focal Nodular Focal Nodular HyperplasiaHyperplasia

Liver Cell AdenomaLiver Cell Adenoma Women of Women of

childbearing age who childbearing age who have used oral have used oral contraceptivescontraceptives

Often subcapsularOften subcapsular Sheets and cords of Sheets and cords of

hepatocyteshepatocytes Portal tracts are Portal tracts are

absentabsent Prominent vessels Prominent vessels

throughoutthroughout Risk for rupture, esp Risk for rupture, esp

during pregnancyduring pregnancy

Hepatocellular Hepatocellular CarcinomaCarcinoma

Annual incidenceAnnual incidence Americas, Northern Europe, Australia 3-7 Americas, Northern Europe, Australia 3-7

cases/100,000cases/100,000 Southern Europe 20 cases/100,000Southern Europe 20 cases/100,000 Southeast China, Taiwan 150 Southeast China, Taiwan 150

cases/100,000cases/100,000 HBV carrier since infancy = 200 fold riskHBV carrier since infancy = 200 fold risk

Cirrhosis in 85% to 90% vs 50%Cirrhosis in 85% to 90% vs 50% M:F = 3:1 vs 8:1M:F = 3:1 vs 8:1 Sixth to seventh decades vs third to Sixth to seventh decades vs third to

fifthfifth

PathogenesisPathogenesis Infection with HBVInfection with HBV

Genomic instability with integrated HBV Genomic instability with integrated HBV DNADNA

Integration pattern is clonalIntegration pattern is clonal HBV X-protein disrupts cell cycle controlHBV X-protein disrupts cell cycle control Certain HBV proteins inactivate p53Certain HBV proteins inactivate p53

Chronic liver disease, esp HCV and EtohChronic liver disease, esp HCV and Etoh Cirrhosis plays an important role.Cirrhosis plays an important role.

Hepatocarcinogens in food (aflatoxins Hepatocarcinogens in food (aflatoxins from the fungus from the fungus Aspergillus flavusAspergillus flavus))

Repeated cycles of cell death and Repeated cycles of cell death and regeneration, i.e., chronic hepatitis, regeneration, i.e., chronic hepatitis, with possible mutationswith possible mutations

MorphologyMorphology Unifocal, multifocal, or infiltrativeUnifocal, multifocal, or infiltrative Strong propensity for vascular invasionStrong propensity for vascular invasion

Portal vein or IVC involvementPortal vein or IVC involvement Well-differentiated – intracellular bileWell-differentiated – intracellular bile Scant stroma Scant stroma → soft→ soft Metastasizes to LN, lung, bone, adrenalMetastasizes to LN, lung, bone, adrenal Fibrolamellar carcinomaFibrolamellar carcinoma

20-40 yo, M=F20-40 yo, M=F No assoc. with cirrhosis or other risk No assoc. with cirrhosis or other risk

factorsfactors Tumor cells separated by dense collagenTumor cells separated by dense collagen Better prognosisBetter prognosis

HCCHCC

Clinical FeaturesClinical Features Rapid increase in liver sizeRapid increase in liver size Sudden worsening of ascitesSudden worsening of ascites Appearance of bloody ascites, fever, painAppearance of bloody ascites, fever, pain ↑ ↑ serum AFP, esp if > 1000 ng/mlserum AFP, esp if > 1000 ng/ml Median survival 7 monthsMedian survival 7 months Death due to GI or esophageal variceal Death due to GI or esophageal variceal

bleeding or liver failure with hepatic bleeding or liver failure with hepatic comacoma

Surgical resection for smaller tumorsSurgical resection for smaller tumors Recurrence rate 60% at 5 yrsRecurrence rate 60% at 5 yrs

Liver transplantationLiver transplantation

Disorders of the Disorders of the GallbladderGallbladder

CholelithiasisCholelithiasis Very commonVery common Cholesterol stones Cholesterol stones

Bile is supersaturated with cholesterolBile is supersaturated with cholesterol Gallbladder stasisGallbladder stasis F>MF>M ObesityObesity Advancing ageAdvancing age

Pigment stones – calcium bilirubinate Pigment stones – calcium bilirubinate saltssalts Asian more than WesternAsian more than Western Chronic hemolytic syndromesChronic hemolytic syndromes

Clinical FeaturesClinical Features AsymptomaticAsymptomatic Biliary colicBiliary colic CholecystitisCholecystitis Gallstone ileusGallstone ileus

CholecystitisCholecystitis

Acute calculousAcute calculous Obstruction of GB neck or cystic ductObstruction of GB neck or cystic duct RUQ pain radiating to right shoulderRUQ pain radiating to right shoulder Fever, nausea, leukocytosisFever, nausea, leukocytosis Potential surgical emergencyPotential surgical emergency

Acute acalculous – seriously ill ptsAcute acalculous – seriously ill pts ChronicChronic

Recurrent attacks of painRecurrent attacks of pain Nausea and vomitingNausea and vomiting Associated with fatty mealsAssociated with fatty meals

CholedocholithiasisCholedocholithiasis

Stones within the biliary treeStones within the biliary tree West – from gallbladderWest – from gallbladder Asia – primary ductal and Asia – primary ductal and

intrahepatic stone formationintrahepatic stone formation Symptoms due to:Symptoms due to:

Biliary obstructionBiliary obstruction PancreatitisPancreatitis CholangitisCholangitis Hepatic abscessHepatic abscess

CholangitisCholangitis Acute inflammation of bile ductsAcute inflammation of bile ducts Due to biliary obstruction, usually Due to biliary obstruction, usually

choledocholithiasischoledocholithiasis Bacterial infection from gut, i.e., Bacterial infection from gut, i.e.,

gram negative aerobesgram negative aerobes Fever, chills, abdominal pain, jaundiceFever, chills, abdominal pain, jaundice

Latin America and Near East: Latin America and Near East: Fasciola hepatica, schistosomiasisFasciola hepatica, schistosomiasis

Far East: Clonorchis sinensis, Far East: Clonorchis sinensis, Opisthorchis viverriniOpisthorchis viverrini

AIDS: cryptosporidiosisAIDS: cryptosporidiosis

Biliary AtresiaBiliary Atresia 1/3 of cases of neonatal cholestasis1/3 of cases of neonatal cholestasis 1 in 10,000 live births1 in 10,000 live births Complete obstruction of bile flow Complete obstruction of bile flow

caused by destruction or absence of caused by destruction or absence of all or part of the extrahepatic bile all or part of the extrahepatic bile ductsducts

Acquired inflammatory disorderAcquired inflammatory disorder Normal stools to acholic stoolsNormal stools to acholic stools Bile ductular proliferation on liver bxBile ductular proliferation on liver bx Cirrhosis by 3 to 6 months of age.Cirrhosis by 3 to 6 months of age. Require liver transplantationRequire liver transplantation

Gallbladder CarcinomaGallbladder Carcinoma

Seventh decadeSeventh decade F>MF>M Discovered at late stage, usually Discovered at late stage, usually

incidentalincidental Exophytic and infiltrating typesExophytic and infiltrating types AdenocarcinomaAdenocarcinoma Local extension into liver, cystic duct, Local extension into liver, cystic duct,

portahepatic LNsportahepatic LNs Mean 5 yr survival 1%Mean 5 yr survival 1%

CholangiocarcinomaCholangiocarcinoma

Older ptsOlder pts M>FM>F Painless jaundice, N/V, weight lossPainless jaundice, N/V, weight loss Opisthorchis sinensis (liver fluke), Opisthorchis sinensis (liver fluke),

PSC, inflammatory bowel diseasePSC, inflammatory bowel disease Tumors usually small at dx yet not Tumors usually small at dx yet not

resectableresectable Klatskin tumor – arises at bifurcationKlatskin tumor – arises at bifurcation AdenocarcinomaAdenocarcinoma Mean survival 6 to 18 monthsMean survival 6 to 18 months

Questions?Questions?