The liver
- dual body supply
o portal vein: 60-70%
o hepatic artery: 30-40%
- porta hepatis – the hilum thru which the portal v.
and hepatic a. enter the liver; transverse fissure in
inferior surface
- portal tracts – consist of portal veins, hepatic
arteries, bile ducts; travel together parallel
Hepatic microarchitecture
- lobular model
o 1-2 mm hexagonal lobules oriented around
terminal tributaries of the hepatic v. w/ portal
tracts at periphery
o centrilobular hepatocytes = in vicinity of
terminal hepatic v.
o periportal hepatocytes = near portal tract
- acinar model
o hepatocytes near terminal hepatic veins are
apices
o penetrating septal venules from the portal
vein are the bases
o triangle w/ 3 zones; zone 1 closest to blood
supply
- zonation of the parenchyma is IMPORTANT
o gradient of activity displayed by many hepatic
enzymes
o zonal distribution of certain types of hepatic
injuries
- hepatocytes are arranged in sheets
- sinusoids between the sheets
- most richly perfused cells in the body
- sinusoids lined by discontinuous endothelial cells
- space of Disse – lies deep to endothelial cells;
protrude microvilli of hepatocytes
- Kupffer cells – mononuclear phagocytes attached
to luminal face of endothelial cells
- Hepatic stellate cells (HSCs) – fat containing cells
in space of Disse
- bile canaliculi drain into  canals of Hering  bile
ductules  terminal bile ducts
- lymphocytes
General features of hepatic diseases
- liver dz is insidious because of enormous
functional reserve (except fulminant hepatic
failure)
Lab evaluation of liver disease
- hepatocyte integrity
o AST, ALT, LDH
- biliary excretory function
o bilirubin – total, direct, delta
o urine bilirubin
o bile salts
o AP, GGTP, 5” nucleotidase
- hepatocyte function
o albumin, PT, ammonia
o aminopyrine breath test
o galactose elimination
Patterns of liver injury
- hepatocyte degeneration & intracellular
accumulations
- hepatocyte necrosis
- inflammation
- regeneration
- fibrosis
- syndromes
o hepatic failure
o cirrhosis
o portal HTN
o disturbances of bilirubin metabolism
(jaundice, cholestasis)
Hepatic failure
- acute liver failure
o assoc. w/ encephalopathy w/in 6 mo. of dx
o massive hepatic necrosis
o drugs or toxins
o In US:
 50% acetaminophen
 14% other toxins (mushrooms)
 4% hepatitis A
 8% hepatitis B
 15% autoimmune & unknown
- chronic liver disease – cirrhosis
- hepatic dysfunction w/o overt necrosis
o hepatocytes viable but unable to perform
normal metabolic function
o tetracycline toxicity
o acute fatty liver of pregnancy
- clinical:
o jaundice
o hypoalbuminemia  peripheral edema
o hyperammonemia  cerebral dysfunction
o fetor hepaticus  portosystemic shunting
o impaired estrogen metabolism
 palmar erythema
 spider angiomas
 males – hypogonadism, gynecomastia
o coagulopathy
o hepatic encephalopathy
 spectrum of disturbances in
consciousness
 rigidity, hyper-reflexia, asterixis
 disorder of neurotransmission in CNS &
neuromuscular system
 minor morphologic changes in brain
 reversible
 assoc. w/ elevated ammonia lvls
o hepatorenal syndrome
 appearance of renal failure in pts w/
severe chronic liver dz
 8% per year among pts w/ cirrhosis and
ascites
 precipitating stress factor
 poor prognosis
o hepatopulmonary syndrome
 triad = chronic liver dz, hypoxemia,
intrapulmonary vascular dilations
 diffusion-perfusion defect
 enhanced production of NO by the lung =
key mediator of dz
 pts respond to O2 therapy
Cirrhosis
- chief worldwide causes:
o alcohol abuse
o viral hepatitis
o NASH (non-alcoholic steatohepatitis)
- 3 main morphologic characteristic
o bridging fibrous septa
o parenchymal nodules (cycles of hepatocyte
regen/scarring)
o disruption of the architecture of the entire
liver
- pathogenesis:
o death of hepatocytes
o ECM deposition
o vascular reorganization
- types I & III collagen deposited in space of Disse 
loss of fenestrations of sinusoidal endothelial cells
(capillarization of sinusoids)
- vascular architecture is disrupted  formation of
new vascular channels in fibrotic septa shunting
of blood from parenchyma
- mechanism of fibrosis = proliferation of HSCs and
their activation into highly fibrogenic cells
- stimulus for HSC proliferation:
o chronic inflammation
o cytokine & chemokine production by Kupffer
cells, endothelial cells, hepatocytes, and bile
duct epithelial cells
o disruption of the ECM
o direct stimulation of the stellate cell by toxins
- surviving hepatocytes stimulated to regenerate as
nodules
- result = fibrotic nodular liver
o delivery of blood to hepatocytes compromised
o ability of hepatocytes to secrete substances
into plasma is compromised
o biliary channels obliterated
- clinical:
o nonspecific – anorexia, weight loss, weakness
o signs of hepatic failure
- mechanism of death in most:
o progressive liver failure
o complication related to portal HTN
o development of HCC
Portal HTN
- prehepatic
o obstructive thrombosis
o narrowing of the portal v.
o massive splenomegaly
- intrahepatic
o cirrhosis
- posthepatic
o severe R-sided heart failure
o constrictive pericarditis
o hepatic v. outflow obstruction
- pathophysiology:
-
-
-
-
o increased resistance to flow at the lvl of
sinusoids
o increase in portal venous blood flow resulting
from hyperdynamic circulation
 arterial vasodilation (splanchnic)
 NO = major cause of splanchnic arterial
vasodilation
major clinical consequences:
o ascites
o formation of portosystemic venous shunts
o congestive splenomegaly
o hepatic encephalopathy
pathogenesis of ascites:
o sinusoidal HTN
o percolation of hepatic lymph into peritoneal
cavity
o splanchnic vasodilation and hyperdynamic
circulation
portosystemic shunts
o rise in portal system pressure  reversed
flow from portal to systemic circulation
o venous bypass locations
 rectum  hemorrhoids
 esophagogastric junction  varices
(massive hematemesis & death)
 retroperitoneum
 falciform ligament of liver (periumbilical
& abdominal wall)  caput medusa
(hallmark of portal HTN)
splenomegaly
o massive congestion
o secondary thrombocytopenia or pancytopenia
Jaundice
- common causes of jaundice:
o bilirubin overproduction
o hepatitis
o obstruction of the flow of bile
- 2 major functions of bile:
o emulsification of fat in gut thru detergent
action of bile salts
o elimination of bilirubin, excess cholesterol,
xenobiotics, & other waste that aren’t water
soluble enough to be excreted by kidney
- metabolism of bilirubin
o uptake from circulation
o intracellular storage
o conjugation w/ glucouronic acid
o biliary excretion
- bilirubin & bile formation:
o bilirubin = end-product of heme degredation
o heme  biliverdin via heme oxygenase
o biliverdin  bilirubin via biliverdin reductase
o bound to albumin & transported to liver
o uptake by hepatocytes  conjugated by UDPglucuronic transferase  excreted into bile
o deconjugated in bowel by bacteria to
urobilinogens  excreted in feces
o enterohepatic circulation (20% of
urobilinogen is reabsorbed in ileum and
colon)
o hepatic conjugating enzyme UGT1A1
 product of UGT1 gene
 responsible for bilirubin glucuronidation
 mutation in UGT1A1 can cause CriglerNajjar syndrome type I & II and Gilbert
syndrome
o bile acids = highly effective detergents
 human bile acids = cholic &
chenodeoxycholic acid
- pathophysiology:
o unconjugated bilirubin
 insoluble in H2O at physiologic pH
 exists in tight complexes w/ albumin
(can’t be excreted in urine)
o small amt exists as albumin-free anion in
plasma
 can increase if becomes unbound from
albumin by protein-binding drugs or in
severe hemolytic dz
 can diffuse into tissues
 kernicterus – neurologic damage from
erythroblastosis fetalis  accumulation
of unconjugated bilirubin in brain
o conjugated bilirubin
 soluble, non-toxic, and only loosely
bound to albumin
 excess can be excreted in urine
o delta bilirubin
 covalently bound to albumin if there is
prolonged elevated conjugated
hyperbilirubinemia
o jaundice occurs when equilibrium btwn
bilirubin production & clearance is disturbed
by:
 unconjugated
 excessive extrahepatic production
o hemolytic anemias
o resorption of blood from
internal hemorrhage
o ineffective erythropoiesis
 reduced hepatocyte uptake
o drug interference w/
membrane carrier system
o some cases of Gilbert syndrome
 impaired conjugation
o physiologic jaundice of the
newborn
o breast milk jaundice
o genetic deficiency of UGT1A1
activity
o Gilbert syndrome
o diffuse hepatocellular dz
 conjugated
 decreased hepatocellular excretion
(deficiency of canalicular
membrane transporters)
 impaired bile flow
Hereditary hyperbilirubinemias
o unconjugated
 Crigler-Najjar syndrome
 type I – hepatic UGT1A1 completely
absent; severe jaundice & icterus;
fatal w/o surgery
 type II – UGT1A1 activity greatly
reduced; very yellow skin
 Gilbert syndrome – decreased UGT1A1
activity; mild hyperilirubinemia;
o conjugated
 Dubin-Johnson syndrome – mutation in
canalicular multidrug resistance protein
2 (MRP2); impaired biliary excretion;
liver darkly pigmented
 Rotor syndrome – asymptomatic;
multiple defects in hepatocellular uptake
& excretion of bilirubin pigments
Cholestasis
- impaired bile formation and flow
- extra-hepatic or intrahepatic obstruction of bile
channels
- defects in hepatocyte bile secretion
- clinical:
o jaundice, pruritus, skin xanthomas,
malabsorption, fat-soluble vitamin deficiency
o  AP, GGTP
- morphology:
o accumulation of bile pigment in hepatic
parenchyma
o feathery degeneration
o bile lakes
- progressive familial intrahepatic cholestasis
o PFIC-1
 begins in infancy
 severe pruritus from high serum bile
acid lvls
 liver failure b4 adulthood
o PFIC-2
 mutation in hepatocyte cannalicular bile
salt export pump (BSEP)
 severely impaired bile salt secretion into
bile
 extreme pruritus, growth failure,
progression to cirrhosis in 1st decade of
life
 risk for cholangiocarcinoma
o PFIC-3
 cholestasis w/ high serum GGT
 toxic destruction of biliary tree epithelia
Infectious disorders
Hepatitis A
- benign, self-limited dz
- incubation 3-6 weeks
- ssRNA, fecal-oral, raw shellfish
- never causes chronic liver dz
- sporadic febrile dz
- vaccine available
Hepatitis B
- acute hepatitis w/ recovery
- incubation 1-4 mo.
- partially dsDNA; parenteral, sexual, perinatal
- HBV can cause:
o nonprogressive chronic hepatitis
o progressive chronic dz ending in cirrhosis
o fulminant hepatitis w/ massive liver necrosis
o asymptomatic carrier state
- 10%  chronic liver dz
- chronic liver dz can cause HCC
- vaccine available
- highest carrier rate is in perinatally acquired
infection
- HBV genome codes for: core protein, envelope
glycoproteins, polymerase, HBx protein
- host immune response is prime determinant of
outcome of infection
- acute infection:
- chronic infection:
Hepatitis C
- MC chronic blood-borne infection
- ssRNA; enveloped; parenteral; intranasal cocaine
- incubation 7-8 weeks
- 80% of chronic liver dz
- MC cause of chronic liver dz in US
- MC reason for liver transplant
- risk factors:
o IV drug use (54%)
o multiple sex partners
o surgery within last 6 mo.
o needle stick injury
o multiple contacts w/ HCV-infected person
o employment in medical/dental field
o unknown (32%)
- inherently unstable = multiple genotypes &
subtypes; quasispecies in one person (hampered
vaccine efforts)
- elevated titers of anti-HCV IgG occurring after
active infection do not consistently confer effective
immunity
- characteristic feature of HCV infection = repeated
bouts of hepatic damage (result of reactivation of a
preexisting infection or emergence of an
endogenous, newly mutated strain)
- incubation 6-12 weeks
- persistent infection & chronic hepatitis are
hallmarks of HCV infection
- 85% acute infection is asymptomatic
- HCV RNA to assess viral replication; RNA persists
in many pts with chronic HCV infection
- characteristic of chronic HCV infection = episodic
elevation in serum aminotransferases, with
intervening normal periods
- fulminant hepatic failure rare
- acute:
- chronic:
Hepatitis D
- circular defective ssRNA
- dependent on HBV for life cycle
- 2 types:
o acute coinfection – HBV established first
o superinfection of chronic carrier – may cause
severe acute hepatitis
o helper-independent latent inf. in liver
transplant
Hepatitis E
- unenveloped ssRNA; fecal-oral; zoonotic
- incubation 4-5 weeks
- no chronic liver dz
- high mortality rate in pregnant women (20%)
Hepatitis G
- not hepatogropic; doesn’t cause rise in serum
aminotransferase
- blood and sexual contact
- replicates in bone marrow and spleen
- no human dz
- protective against HIV if coninfects with HIV+
Clinicopathologic syndromes of viral hepatitis
- acute asymptomatic hepatitis w/ recovery
(serologic evidence only)
- acute symptomatic hepatitis w/o recovery
(anicteric or icteric)
- chronic hepatitis w/ or w/o progression to
cirrhosis
o MC = HCV
o fatigue, spider angiomas, palmar erythema,
mild hepatomegaly, hepatic tenderness, mild
splenomegaly
o younger age at infection = higher chance of
chronicity
- fulminant hepatitis w/ massive to submassive
hepatic necrosis
- carrier state
Morphology of HBV infected hepatocytes
- cytoplasm packed w/ spheres & tubules of HBsAg
- ground glass hepatocytes
Morphology of HCV infected hepatocytes
- lymphoid aggregates within portal tracts
- focal lobular regions of hepatocyte macrovesicular
steatosis
Morphology of acute hepatitis
- ballooning degeneration
- cholestasis
- macrophage aggregates
- apoptosis
- bridging necrosis
- Kupffer cells  hypertrophy + hyperplasia
- portal tracts infiltrated w/ mix of inflammatory
cells
- interface hepatitis
- ductular rxn
Morphology of chronic hepatitis
- smoldering hepatocyte apoptosis
- lymphoid aggregates
- bile duct reactive changes
- macrovesicular steatosis (MC in HCV genotype 3
infections)
- interface hepatitis
- bridging necrosis
- deposition of fibrous tissue = hallmark
Fulminant hepatic failure
- hepatic insufficiency  hepatic encephalopathy
within 2-3 wks in individuals w/o chronic liver dz
- causes:
o viral hepatitis (12%)
o acetaminophen toxicity
o unknown
- morphology
o HBV induced = massive apoptosis
o entire liver or only random areas may be
involved
o massive loss of mass  limp red organ
covered by wrinkled capsule
o necrotic areas = mushy appearance w/
hemorrhage
- survival may cause proliferation & differentiation
of stem cell population  ductular rxn
Other liver infections
- TSS – S. aureus
- Typhoid fever – Salmonella typhi
- Syphilis – T. pallidum
- ascending cholangitis
- parasitic infections – malaria, schistosomiasis,
strongyloidiasis, cryptosporidiosis, leishmaniasis,
echinococcosis, liver flukes
- liver abscesses
o common in developing countries
o caused by echinococcal and amebic infections
o in developed countries – usually pyogenic
o organisms reach liver by:
 portal vein
 arterial supply
 ascending infection in biliary tract
 direct invasion from nearby source
 penetrating injury
o clinical: fever, RUQ pain, tender hepatomegaly,
jaundice
Autoimmune hepatitis
- chronic & progressive hepatitis of unknown
etiology
- triggers:
o viral infections
o drugs (minocycline, atorvastatin, simvastatin,
methyldopa, interferons, nitrofuantoin,
pemoline)
o herbal products (black cohosh)
- occurs concurrently w/ other autoimmune
disorders
o celiac, SLE, RA, thyroiditis, Sjögren, ulcerative
colitis
- female predominance (young & perimenopausal)
- Type 1 (MC)
o ANA (anti-nuclear)
o SMA (anti-smooth muscle)
o AAA (anti-actin)
o anti-SLA/LP (soluble liver antigen/liverpancreas antigen)
o HLA-DR3 serotype
- Type 2
o ALKM-1 (anti-liver kidney microsome)
o ACL-1 (anti-liver cytosol)
- clusters of plasma cells in the interface of portal
tracts and hepatic lobules = characteristic
- Tx – immunosuppresives; transplant (recurrence
in 22-42%)
Drug and toxin-induced liver disease
- drug-induced liver injury
o 10% of adverse drug rxns
o MC cause of fulminant hepatitis in US
- injury from:
o direct toxicity
o hepatic conversion of xenobiotic  active
toxin
o immune mechanisms
- acetaminophen = leading cause of drug-induced
acute liver failure
- antibiotics, isoniazid, non-steroidal analgesics,
anti-seizure meds = MC Rx drugs causing
idiosyncratic injury
- Reye syndrome
o mitochondrial dysfunction in liver, brain, and
elsewhere
o accumulation of fat in hepatocytes
(microvesicular steatosis)
o aspirin in febrile illness
- exposure to a toxin or therapeutic agent should
always be included in the ddx of liver dz
Alcoholic liver disease
- 3 forms of alcoholic liver dz:
o hepatic steatosis (fatty liver dz)
 reversible if abstention from EtOH
 results from:
 shunting away from catabolism to
lipid biosynthesis
 impaired assembly and secretion of
lipoproteins
 increased peripheral catabolism of
fat
 microvesicular lipid droplets 
macrovesicular globules
 soft yellow greasy organ
o alcoholic hepatitis
 hepatocyte swelling & necrosis
 mallory bodies
 neutrophilic rxn
 fibrosis
 acetaldehyde (metabolite of EtOH)
induces lipid peroxidation &
acetaldehyde-protein adduct formation
 disrupt cytoskeletal & membrane fxn
 cyt P450 produce ROS
 malnutrition & vitamin (thiamine) def.
 release of bacterial endotoxin from gut
 inflammatory response
 release of endothelins from sinusoidal
endothelial cells  decrease in
sinusoidal perfusion
o cirrhosis
 final & irreversible form of alcoholic liver
dz
 yellow-tan, fatty, enlarged  brown,
shrunk, nonfatty
 scattered larger nodules = hobnail
appearance on surface
- pathogenesis:
o exposure to EtOH causes steatosis,
dysfunction of mitochondrial & cellular
membranes, hypoxia, and oxidative stress
- clinical:
o hepatic steatosis – hepatomegaly, mild
hyperbilirubinemia & alkaline phosphatase
o alcoholic hepatitis – acute symptoms after
bout of heavy drinking; malaise, anorexia,
weight loss, upper abdominal pain, tender
hepatomegaly, hyperbilirubinemia, elevated
alkaline phosphatase, neutrophilic
leukocytosis; repeated bouts  cirrhosis
o alcoholic cirrhosis –elevated
aminotransferase, hyperbilirubinemia,
elevated serum AP, hypoproteinemia, anemia
- risk factors:
o women more susceptible to hepatic injury but
majority of are men
o rates higher for African Americans
o strong family association
o iron overload & infections w/ HCV & HBV
increase severity
Metabolic liver disease
Non-alcoholic fatty liver disease (NAFLD)
- MC acquired metabolic disorder
- hepatic steatosis in those who don’t drink
- MC cause of chronic liver dz in US
- NAFLD includes: hepatic steatosis, steatosis
accompanied by minor non-specific inflammation,
and non-alcoholic steatohepatitis (NASH)
- NASH
o hepatocyte ballooning
o lobular inflammation
o steatosis
o progressive dz  fibrosis
o strongly assoc. w/ obesity & metabolic
syndrome (dyslipidemia, hyperinsulinemia,
insulin resistance)
- pathogenesis (two hit model):
o (1) hepatic fat accumulation
o (2) hepatic oxidative stress
- clinical:
o serum AST and ALT elevated
o AST/ALT ratio <1
o symptoms related to obesity & metabolic
syndrome
- morphology:
o steatosis involves >5% of hepatocytes;
droplets of fat (TGs) accumulate in
hepatocytes
o NASH characterized by steatosis & multifocal
parenchymal inflammation (Mallory bodies,
ballooning degeneration, apoptosis), fibrosis
Hemachromatosis
- excessive accumulation of iron  deposition in
parenchymal organs
- abnormal regulation of intestinal absorption of
dietary iron
- characteristic features:
o micronodular cirrhosis (all pts)
o DM (75-80%)
o skin pigmentation (75-80%)
o injury is slow & progressive (5th-6th decade)
o males >females
- hepcidin – main regulator of iron absorption
o encoded by HAMP gene
o txn of hepcidin is increased by inflammatory
cytokines & iron
o txn decreased by iron deficiency, hypoxia, and
ineffective erythropoiesis
o binds to cellular iron efflux channel
ferroportin  internalization & proteolysis of
the channel  prevents iron from intestinal
cells & macrophages
o hepcidin lowers plasma iron; deficiency
causes iron overload
o mutations causing lack of hepcidin expression
cause hemochromatosis
o HFE mutation = MC form of hereditary adult
hemochromatosis
o HJV mutation = severe juvenile hereditary
hemochromatosis
- morphology:
o deposition of hemosiderin in liver, pancreas,
myocardium, pituitary, adrenal, thyroid,
parathyroid, joints, skin
o cirrhosis
o pancreatic fibrosis
o liver slightly larger than normal, dense,
chocolate brown
o biochemical determination of hepatic tissue
iron conc. is standard for quantitating hepatic
iron content
o pancreas – intensely pigmented, diffuse
fibrosis, parenchymal atrophy
o heart – enlarged, hemosiderin granules,
striking brown color
o skin – pigmentation due to deposition &
increased epidermal melanin production;
slate-gray color
o joint – hemosiderin deposition in synovial
linings; synovitis may develop; may develop
pseudo-gout
o testes – small and atrophic
- clinical:
o principally dz of males
o classic triad = pigment cirrhosis with
hepatomegaly, skin pigmentation, DM
o abdominal pain, cardiac dysfunction, atypical
arthritis
o 200-fold increase in risk of HCC; Tx doesn’t
remove risk
o removal of excess iron can reverse the toxic
changes if cells are not fatally injured
Neonatal hemochromatosis
- unknown origin
- severe liver dz + extrahepatic hemosiderin
deposition
- not inherited
- liver injury begins in utero
- no treatment
- major function of their protein is inhibition of
proteases released from neutrophils
- w/o it, emphysema and liver dz develop
- cutaneous panniculitis, arterial aneurysm,
bronchiectasis, Wegener’s granulomatosis can
occur as well
- morphology:
o presence of round-to-oval cytoplasmic
globular inclusions in hepatocytes; acidophilic
o PAS positive and diastase resistant
- clinical:
o neonatal hepatitis w/ cholestatic jaundice in
10-20% of newborns w/ deficiency
o HCC develops in 2-3%
o in pts with pulmonary dz, smoking avoidance
is crucial because it will markedly accelerate
emphysema
Hemosiderosis
- secondary hemochromatosis; parenteral iron
overload
- ineffective erythropoiesis (severe thalassemia &
myeodysplastic syndromes)
- excess iron from transfusions + increased
absorption
- Bantu siderosis – iron overload from ingesting
large quantities of alcohol fermented in iron
utensils
- congenital atransferrinemia
- chronic liver dz
Neonatal cholestasis
- primary conjugated hyperbilirubinemia
- 1/2500 live births
- major conditions causing it:
o cholangiopathies (primary biliary atresia)
o neonatal hepatitis
- major causes:
o bile duct obstruction
o neonatal inf.
o toxic
o metabolic dz
o miscellaneous
o idiopathic
- important to differentiate biliary atresia (needing
surgery)
- affected infants have jaundice, dark urine, light
stools, hepatomegaly
- multinucleated giant hepatocytes
Wilson disease
- AR mutation of ATP7B gene (majority are
compound heterozygotes)
- impaired copper excretion into bile
- failure to incorporate copper into ceruloplasmin
- toxic lvls of copper in brain, liver, eye
- morphology:
o liver – steatosis; acute/chronic hepatitis
o brain – basal ganglia (putamen) shows
atrophy & cavitation
o eyes – Kayser Fleischer rings (green/brown
deposits of Cu in Descemet’s membrane in
limbus)
- clinical:
o average age onset = 11.4 years
o MC presentation = acute or chronic liver dz
o neuropsychiatric symptoms (behavioral
changes, frank psychosis, Parkinson-like
syndrome – tremor)
-  in serum ceruloplasmin
-  in hepatic Cu content (most sensitive & accurate
test)
-  urinary excretion of copper
- chelation therapy or zinc-based therapy very
successful if recognized early
α1-antitrypsin deficiency
- AR
- very low lvls of α1-antitrypsin
Intrahepatic biliary tract disease
Secondary biliary cirrhosis
- prolonged obstruction of the extrahepatic biliary
tree
- MC cause = extrahepatic cholelithiasis
- other causes = malignancy, strictures
- in children = biliary atresia, CF, choledochal cysts,
paucity of bile ducts
- subtotal obstruction can cause ascending
cholangitis (gram neg. enteric organisms)
- morphology
o end-stage obstructed liver = yellow-green
o coarse fibrous septa that subdivide liver in
jigsaw-like pattern
o proliferation of smaller bile ductules
o feathery degeneration
o bile lakes
Primary biliary cirrhosis
- nonsuppurative, inflammatory destruction of
medium-sized intrahepatic bile ducts
- females > males 6:1
- antimitochondrial antibodies
- morphology:
o small-duct biliary fibrosis and cirrhosis
o dense accumulation of lymphocytes,
macrophages, plasma cells, & occasional
eosinophils
o liver weight is increased  becomes
decreased
- clinical:
o fatigue
o pruritus
o hepatomegaly
o hyperpigmentation
o eyelid xanthelasmas
o arthropathy
o increased risk of HCC
- extrahepatic manifestations: Sjögren syndrome,
systemic sclerosis, thyroiditis, RA, Raynaud’s,
membranous GN, celiac
- Tx: ursodeoxycholic acid; mechanism unknown,
remission and prolonged survival in 25-30%
Primary sclerosing cholangitis
- inflammation & obliterative fibrosis of intrahepatic
& extrahepatic bile ducts, w/ dilation of preserved
segments
- “beading” of contrast in radiographs of biliary tree
- commonly associated with IBD (ulcerative colitis)
- atypical p-ANCA found in 80%
- onion-skin fibrosis of affected ducts  solid
cordlike fibrous scars
- 7% develop cholangiocarcinoma
Anomalies of the biliary trees
- Von meyenburg complexes
o bile duct hamartomas
o common; no clinical significance
- Polycystic liver dz
o multiple diffuse cystic lesions in liver
- Congenital hepatic fibrosis
o portal tracts enlarged by irregular, broad
bands of collagenous tissue
o due to persistence of embryonic form of
biliary tree
o may develop portal HTN
o  risk for cholangiocarcinoma
- Caroli dz
o larger ducts of intrahepatic biliary tree are
segmentally dilated
o  risk for cholangiocarcinoma
- all above can be assoc. w/ polycystic kidney dz
- Alagille syndrome (paucity of bile ducts)
o AD; mutation or deletion of Jagged1
o 5 major clinical features:
 chronic cholestasis
 peripheral stenosis of pulmonary a.
 butterfly-like vertebral arch defects
 posterior embryotoxon (eye defect)
 peculiar hypertelic facies
Circulatory disorders
Impaired blood flow
- hepatic a. compromise  localized infarct
- portal v. obstruction & thrombosis
o extrahepatic portal v. obstruction can be
caused by:
 umbilical catheter
 intra-abdominal sepsis
 hypercoagulable disorders
 trauma
 pancreatitis/pancreatic CA
 HCC
 cirrhosis
o intrahepatic portal v. radicles may be
obstructed by acute thrombosis  infarct of
Zahn
o noncirrhotic portal fibrosis is common in
India; presents w/ upper GI bleeding
o idiopathic portal HTN has female
predominance; presents w/ splenomegaly
Impaired intrahepatic blood flow
- MC is cirrhosis
- sinusoid occlusion can occur in sickle cell, DIC,
eclampsia, metastases
- R-sided cardiac decompensation = passive
congestion of liver  enlarged, tense, cyanotic w/
round edges
- L-sided cardiac failure/shock = hepatic
hypoperfusion  centrilobular necrosis
- centrilobular hemorrhagic necrosis
o hypoperfusion + retrograde congestion
o nutmeg liver
- peliosis hepatis
o primary sinusoid dilation
o Bartonella species involved in AIDS assoc.
o assoc. w/ CA, TB, AIDS, post-transplant
Hepatic vein outflow obstruction
- Budd-Chiari syndrome
o obstruction of 2+ major hepatic veins
o liver swollen & red-purple w/ tense capsule
o centrilobular congestion & necrosis
- hepatic vein thrombosis is assoc. w/
o 1 myeloproliferative disorders (polycythemia
vera)
o inherited coagulopathies
o antiphosphlipid syndrome
o paroxysmal nocturnal hemoglobinuria
o intra-abdominal CA (HCC)
- obliterative hepatocavopathy
o inferior vena cava obstruction at hepatic
portion
o caused by inferior vena cava thrombosis
o endemic in Nepal (assoc. w/ infections)
- sinusoidal obstruction syndrome (veno-occlusive
disease)
o Jamaican bush tea drinkers
o occurs primarily following allogenic bone
marrow transplant
o can occur in CA pts receiving chemo
o obliteration of hepatic vein radicles
o arises from toxic injury to sinusoidal
endothelium  slough off wall & embolize
downstream, obstructing bloodflow
Hepatic complications of organ or bone marrow
transplantation
Acute graft-vs-host disease
- 10-50 days after bone marrow transplantation
- donor lymphocytes attack epithelial cells of liver
 hepatitis
Chronic hepatic graft-vs-host disease
- >100 days after transplantation
- portal tract inflammation, selective bile duct
destruction, fibrosis
- endothelitis present (subendothelial lymphocytic
infiltrate lifts endothelium from BM)
Acute rejection of transplanted livers
- infiltration of mixed population of inflammatory
cells
- endothelitis
- BANFF scheme – grading scale for severity of
rejection
Chronic rejection
- obliterative arteritis of small & larger arterial
vessels (arteriopathy)  ischemic changes in liver
parenchyma
- bile ducts progressively destroyed
Hepatic disease associated with pregnancy
- viral hepatitis is MC cause of jaundice in pregnancy
- HEV inf. runs severe course (10-20% mortality)
Preeclampsia/eclampsia
- maternal HTN, proteinuria, peripheral edema,
coagulation abnormalities, DIC
- HELLP syndrome – hemolysis, elevated liver
enzymes, low platelets
- periportal sinusoids contain fibrin deposits w/
hemorrhage into space of Disse
- hepatic hematoma
- dissection of blood under Glisson’s capsule may
lead to rupture
- eclampsia = preeclampsia + hyper-reflexia and
convulsions; life-threatening
Acute fatty liver of pregnancy (AFLP)
- spectrum of mild hepatic dysfunction to hepatic
failure, coma, death
- present in latter half of pregnancy
- primary Tx = termination of pregnancy
- fetuses are deficient in mitochondrial long-chain 3hydroxyacyl CoA dehydrogenase  metabolites
produced by fetus cause hepatic toxicity in mother
Intrahepatic cholestasis of pregnancy
- onset of pruritus in 3rd trimester, darkening of
urine, light stools, jaundice
- pruritus extremely distressing for pregnant
mother
Benign neoplasms
Cavernous hemangiomas
- MC benign liver tumor
- BV tumor
- discrete red-blue soft nodules directly beneath
capsule
Hepatic adenoma
- MC occur in women on OC (regress if OC stopped)
- may be mistaken for HCC
- subcapsular adenomas have tendency to rupture
(esp in pregnancy)
- may transform into carcinomas (esp. in glycogen
storage dz)
- mutation in txn factor HNF1α and β-catenin
- morphology:
o pale, yellow-tan bile-stained nodules
o often beneath capsule
o well demarcated
o steatosis commonly present
o no portal tracts
Malignant tumors
Angiosarcoma of the liver
- assoc. w/ vinyl chloride, arsenic, or Thorotras
- metastasize widely and kill w/in a year
Hepatoblastoma
- MC liver tumor of childhood
- fatal w/in few years if not treated
- epithelial type
o made of small polygonal fetal cells or smaller
embryonal cells
o form acini, tubules, or papillary structures
- mixed epithelial & mesenchymal type
o contains foci of mesenchymal differentiation
- frequent activation of WNT/β-catenin signaling
pathway
- assoc. w/ FAP and Beckwith-Wiedmann syndrome
Hepatocellular carcinoma (HCC)
- 3rd most frequent cause of CA deaths
- males > females
- 4 major etiologic factors:
o chronic viral infection (HBV, HCV, 200-fold
increased risk for vertical transmission of
HBV)
o chronic alcoholism
o NASH
o food contaminants (aflatoxins from A. flavus in
peanuts/grains)
- tyrosinemia – 40% develop HCC
- cirrhosis is prerequisite to emergence of HCC in
Western countries
- repeated cycles of cell death & regeneration
- morphology:
o unifocal, multifocal, or diffusely infiltrative
o strong propensity for invasion of vascular
structures (may be long snakelike mass of
tumor invading portal vein or IVC extending
into R-side of heart)
o satellite nodules
- fibrolamellar carcinoma
o 5% of HCCs
o young male & female adults
o no underlying hepatic dz
o single large, hard “scirrhous” tumor w/
fibrous bands
- clinical:
o elevated serum AFP in 50%
o death due to cachexia, GI bleed, liver failure
w/ coma, rupture of tumor w/ hemorrhage
Cholangiocarcinoma (CCA)
- 2nd MC hepatic malignant tumor
- malignancy of biliary tree outside liver
- highest in Hispanics in US
- risk factors:
o primary sclerosing cholangitis
o congenital fibropolycystic dz of biliary system
o HCV infection
o exposure to Thorotrast
o liver fluke (Opisthorchis sinensis)
- Extrahepatic form (90% of CCAs)
o Klatskin tumors – perihilar; junction of R & L
hepatic ducts
o periampullary carcinomas are grouped w/
adenocarcinomas of duodenum & pancreatic
carcinomas
- Intrahepatic form
o not usually detected until late in course
- morphology:
o extrahepatic CCAs
 small firm gray nodules w/in bile duct
wall
 most are adenocarcinomas
 Klatskin tumors have slower growth w/
prominent fibrosis
o intrahepatic CCAs
 occur in noncirrhotic liver
 track along intrahepatic portal tract =
treelike tumorous mass
 extensive intrahepatic metastasis
 extremely firm & gritty
 lymph node & hematogenous metastases
to lungs, bone (vertebrae), adrenals,
brain
Metastatic tumors
- more common than primary liver cancers
- MC = colon, breast, lung, pancreas
- multiple nodular metastases w/ striking
hepatomegaly
- amazing amt of involvement before lab evidence of
hepatic dysfunction
Biliary tract
- 95% of biliary dz attributable to cholelithiasis
- 1 liter of bile secreted by liver each day
- GB has capacity of 50 ml
- not essential for biliary function
Biliary tract congenital anomalies
- GB absent, duplicated, bilobed or aberrantly
located
- folded fundus is MC anomaly; creates Phrygian cap
- agenesis of all/portion of hepatic or common bile
ducts
- hypoplastic narrowing of biliary channels (true
biliary atresia)
Disorders of the gallbladder
Cholelithiasis
- vast majority silent
- 2 main types: cholesterol (90%) & pigment
(bilirubin calcium salts)
- risk factors:
o cholesterol stones
 northern europeans, N & S Americans,
Native Americans
 advancing age
 female sex hormones
 obesity & metabolic syndrome
 rapid weight reduction
 gallbladder stasis
 inborn errors of bile acid metabolism
 hyperlipidemia syndromes
o pigment stones
 Asians, rural
 chronic hemolytic syndromes
 bacterial infection of biliary tree
 parasitic infestations
 GI disorders
- cholesterol gallstone formation involves 4
simultaneous conditions:
o supersaturation of bile
o GB hypomotility
o cholesterol nucleation (crystallization)
o hypersecretion of mucus in gallbladder trap
crystals  aggregation into stones
- morphology:
o cholesterol stones
 pure cholesterol stones = pale yellow,
round to ovoid, finely granular hard
external surface
 mostly radiolucent
 10-20% cholesterol stones radiopaque
o pigment stones
 black stones in sterile GB bile; 50-75%
are radioopaque
 brown stones in infected intra or
extrahepatic ducts; radiolucent
- clinical:
o biliary pain – excruciating & constant or
“colicky”
o GB inflammation – painful
o complications – empyema, perforation,
fistulas, obstructive cholestasis or
pancreatitis, gallstone ileus (Bouveret’s
syndrome), risk for carcinoma
Acute cholecystitis
Calculous
- precipitated 90% of time by obstruction of neck or
cystic duct
- results from chemical irritation & inflammation of
obstructed GB
- protective mucus layer disrupted  expose
epithelium to bile salts
- GB dysmotility develops  compromised blood
flow to mucosa  bacterial contamination may
later develop
- frequently develops in diabetic pts w/
symptomatic gallstones
- clinical:
o RUQ or epigastric pain
o fever, anorexia, tachycardia, sweating, nausea,
vomiting
o jaundice = obstruction of common bile duct
o leukocytosis, increased serum alkaline
phosphatase
o symptoms appear w/ remarkable suddenness
Acalculous
- results from ischemia
- cystic artery has no collateral circulation
- contributing factors:
o inflammation & edema of wall, compromising
blood flow
o GB stasis
o accumulation of microcrystals of cholesterol
(biliary sludge), viscous bile, and GB mucus 
cystic duct obstruction
- risk factors:
o sepsis w/ hypotension & multisystem organ
failure
o immunosuppression
o major trauma & burns
o DM
o infections
- clinical:
o more inisidous than calculous cholecystitis
o incidence of gangrene & perforation much
higher than calculous
Chronic cholecystitis
- associated with cholelithiasis in >90%
- supersaturation of bile predisposes to
inflammation as well as stone formation
- microorganisms (E. coli and enterococci) can be
cultured from bile in 1/3 of cases
- obstruction of GB outflow is not requisite
- morphology:
o fibrous adhesions
o variable degrees of inflammation
o Rokitansky-Aschoff sinuses (outpouchings of
mucosal epithelium through wall)
o porcelain GB (extensive calcification)
o xanthogranulomatous cholecystitis (thickened
wall)
o hydrops of GB (obstructed atrophic GB w/
clear secretions)
- clinical:
o recurrent attacks of steady or colicky
epigastric or RUQ pain
o n/v
o intolerance for fatty foods
- complications:
o bacterial superinfection w/ cholangitis or
sepsis
o GB perforation & local abscess formation
o GB rupture w/ diffuse peritonitis
o biliary enteric fistula
o aggravation of preexisting medical illness
o porcelain GB (increased risk of CA)
Disorders of extrahepatic bile ducts
Choledocholithiasis
- presence of stones w/in bile ducts of biliary tree
- higher incidence in Asia
- may be asymptomatic or cause symptoms:
o obstruction
o pancreatitis
o cholangitis
o hepatic abscess
o secondary biliary cirrhosis
o acute calculous cholecystitis
Cholangitis
- bacterial infection of bile ducts
- MC from choledocholithiasis and biliary strictures
- Sphincter of Oddi is MC entry point
- ascending cholangitis – infection of intrahepatic
biliary radicles; usually enteric gram neg. aerobes
(E. coli, Klebsiella, Interococcus, Enterobacter)
- presents with fever, chills, abdominal pain,
jaundice
Biliary atresia
- complete or partial obstruction of lumen of
extrahepatic biliary tree w/in 3 months of life
- 1/3 of infants with neonatal cholestasis
- 1:12,000 live births
- MC cause of death from liver dz in children
- progressive inflammation and fibrosis of intra or
extrahepatic bile ducts
- 2 forms:
o fetal (20%) – commonly assoc. w/ other
anomalies (malrotation of viscera, interrupted
IVC, polysplenia, congenital heart dz)
o perinatal form (MC) – presumed normal tract
is destroyed following birth; viral (reovirus,
rotavirus, CMV) or autoimmune
- Kasai procedure – for type I (common duct) or
type II (hepatic bile ducts)
- 90% of pts have type III biliary atresia
(obstruction at or above porta hepatis)
Choledochal cysts
- congenital dilations of common bile duct
- present most often in children <10 years old
- present with jaundice and/or recurrent abdominal
pain
- predispose to stone formation, stenosis and
stricture, pancreatitis, and obstructive biliary
complications within liver
- risk of bile duct carcinoma in older pts
Tumors
- derive from epithelium lining of biliary tree
- adenomas
o benign epithelial tumors
o tubular, papillary, or tubulopapillary
- inflammatory polyps
o sessile mucosal projections with surface
stroma infiltrated w/ chronic inflammatory
cells and lipid-laden macrophages
- adenomyosis of GB
o hyperplasia of muscle layer, containing
intramural hyperplastic glands
Carcinoma of the gallbladder
- MC malignancy of extrahepatic biliary tract
- women>men; occurs mostly in 7th decade of life
- gallstones = most important risk factor
- carcinogenic derivatives of bile acids may play role
- morphology
o infiltrating pattern is MC; poorly defined area
of diffuse thickening and induration of GB wall
o exophytic pattern growns into lumen as
irregular, cauliflower mass while invading
underlying wall
o MC sites of involvement are fundus and neck;
20% involve lateral walls
o most are adenocarcinomas
o most invade liver centrifugally at time of
discovery; many have extended to cystic duct
and adjacent bile ducts and portal-hepatic
lymph nodes