Chapter 18 Liver and Biliary Tract

THE LIVER Hepatocyte degeneration and

has a dual blood supply: the intracellular accumulations
portal vein provides 60% to
Hepatocyte necrosis and
70% of hepatic blood flow, and
apoptosis
the hepatic artery supplies 30%
to 40%
Inflammation
two different concepts: the
hepatic lobule and the hepatic
Regeneration
acinus
Centrilobular - hepatocytes in
the vicinity of the terminal Fibrosis
hepatic vein
TABLE 18-1 -- Laboratory
Periportal - those near the
Evaluation of Liver Disease
portal tract
3 zones: Test
zone 1 being closest to Categor
y Serum Measurement[*]
the vascular supply
zone 3 abutting the Hepatocy Cytosolic
terminal hepatic venule te hepatocellular
and most remote from integrity enzymes[]
the afferent blood supply Serum aspartate
zone 2 being aminotransferase
intermediate (AST)
Classical hexagonal
Serum alanine
Portal triangular
aminotransferase
Kp-1 (CD68) kuppfers cells (ALT)
Low molecular wt. keratin bile
duct cells Serum lactate
dehydrogenase
EMA/CEA canaliculi cells
(LDH)
Space of Disse where fat-
containing hepatic stellate cells Biliary Substances normally
(HSCs) are found
secreted in bile[]
Canals of Hering - connect the
bile canaliculi to bile ductules in Serum bilirubin
the periportal region Total:
unconjugated
General Features of Hepatic plus
Disease conjugated
The major primary diseases of Direct:
the liver: conjugated
viral hepatitis only
alcoholic liver disease Delta:
nonalcoholic fatty liver covalently
disease (NAFLD) linked to
hepatocellular carcinoma albumin
(HCC)
Urine bilirubin
PATTERNS OF HEPATIC INJURY
 Chapter 18 Liver and Biliary Tract

Test End-stage liver disease may

Categor occur by insidious destruction of
y Serum Measurement[*] hepatocytes or by repetitive
discrete waves of parenchymal
Serum bile acids damage
The alterations that cause liver
Plasma membrane failure fall into three categories:
enzymes (from Acute liver failure -
damage to bile associated with
canaliculus)[] encephalopathy within 6
Serum alkaline months after the initial
phosphatase diagnosis.
Serum -glutamyl - fulminant liver failure
transpeptidase when the encephalopathy develops
rapidly, within 2 weeks of the
Serum 5- onset of jaundice, and as sub-
nucleotidase fulminant liver failure when the
encephalopathy develops within 3
Hepatocy Proteins secreted into months of the onset of jaundice
te the blood Chronic liver disease - the
function Serum albumin[] most common route to
Prothrombin hepatic failure
time[] (factors V, - the end point of
VII, X, relentless chronic
prothrombin, hepatitis ending in
fibrinogen) cirrhosis
Hepatic dysfunction
Hepatocyte without overt necrosis
metabolism
Serum ammonia[] Clinical Features:
Aminopyrine Jaundice
breath test Hypoalbuminemia, which
(hepatic predisposes to peripheral
demethylation)[] edema
hyperammonemia, which plays
Galactose
a major role in cerebral
elimination
dysfunction
(intravenous
Fetor hepaticus is a
injection)[]
characteristic body odor that is
variously described as musty
HEPATIC FAILURE or sweet and sour
The most severe clinical Impaired estrogen metabolism
consequence of liver disease and consequent
result of sudden and massive hyperestrogenemia are the
hepatic destruction (fulminant putative causes of palmar
hepatic failure) erythema
the end stage of progressive severely impaired liver function,
chronic damage to the liver patients are highly susceptible
 Chapter 18 Liver and Biliary Tract
to encephalopathy and failure
of multiple organ systems
Three particular complications
associated with hepatic failure merit
separate consideration:
Hepatic encephalopathy -
manifested by a spectrum of
disturbances in consciousness,
ranging from subtle behavioral
abnormalities, to marked
confusion and stupor, to deep
coma and death
- regarded as a disorder
of neurotransmission in the
central nervous system and
neuromuscular system
Hepatorenal syndrome -
refers to the appearance of
renal failure in individuals with
severe chronic liver disease in
whom there are no intrinsic
morphologic or functional
causes for the renal failure
Hepatopulmonary syndrome
(HPS) - characterized by the
clinical triad of chronic liver
disease, hypoxemia, and intra-
pulmonary vascular dilations
(IVPD)
CIRRHOSIS
Causes: alcohol abuse, viral
hepatitis, and non-alcoholic
steatohepatitis (NASH)
three main morphologic
characteristics:
Bridging fibrous septa
* Fibrosis is the
key feature of
progressive damage
to the liver
Parenchymal nodules
containing hepatocytes
encircled by fibrosis
Disruption of the
architecture of the entire
liver
Pathogenesis:
The central pathogenic
processes in cirrhosis are death
of hepatocytes, extracellular
matrix (ECM) deposition, and
vascular reorganization.[
types I and III collagen are
deposited in the space of Disse,
creating fibrotic septal tracts
The predominant mechanism of
fibrosis is the proliferation of
hepatic stellate cells and their
activation into highly fibrogenic
cells
Clinical features:
The ultimate mechanism of deaths in
most cirrhotic patients is (1)
progressive liver failure, (2) a
complication related to portal
hypertension, or (3) the development
of hepatocellular carcinoma
PORTAL HYPERTENSION
The major prehepatic conditions
are obstructive thrombosis,
narrowing of the portal vein
before it ramifies within the
liver, or massive splenomegaly
with increased splenic vein
blood flow
The main post-hepatic causes
are severe right-sided heart
failure, constrictive pericarditis,
and hepatic vein outflow
obstruction.
The dominant intrahepatic
cause is cirrhosis
The four major clinical
consequences of portal
hypertension are:
Ascites - the
accumulation of excess
fluid in the peritoneal
cavity
Portosystemic Shunts -
the flow is reversed from
portal to systemic
 Chapter 18 Liver and Biliary Tract
circulation by dilation of
collateral vessels and
development of new
vessels
Splenomegaly
Hepatic encephalopathy
JAUNDICE AND CHOLESTASIS
The common causes of jaundice
are bilirubin overproduction,
hepatitis, and obstruction of the
flow of bile
2 major functions of hepatic
bile:
emulsification of dietary
fat
of bilirubin, excess
cholesterol, xenobiotics
jaundice and icterus - yellow
discoloration of the skin and
sclera respectively
cholestatis - retention of not
only bilirubin but also other
solutes eliminated in bile
Bilirubin and Bile Formation
Bilirubin is the end product of
heme degradation; from
breakdown of senescent red
cells by the mononuclear
phagocytic system
Bile acids - the major catabolic
products of cholesterol; act as
highly effective detergents
Pathophysiology of Jaundice
Both unconjugated bilirubin and
conjugated bilirubin (bilirubin
glucuronides) may accumulate
systemically
Unconjugated bilirubin -
virtually insoluble in water at
physiologic pH and exists in
tight complexes with serum
albumin. This form cannot be
excreted in the urine even
when blood levels are high
*kernicterus - accumulation of
unconjugated bilirubin in the
brain
conjugated bilirubin - water-
soluble, nontoxic, and only
loosely bound to albumin;
excess conjugated bilirubin in
plasma can be excreted in urine
Jaundice becomes evident when
the serum bilirubin levels rise
above 2.0 to 2.5 mg/dL
Two conditions result from specific
defects in hepatocellular bilirubin
metabolism:
Neonatal Jaundice - transient
and mild unconjugated
hyperbilirubinemia, termed
neonatal jaundice or physiologic
jaundice of the newborn
Hereditary Hyperbilirubinemias
Crigler-Najjar
syndrome type I
hepatic UGT1A1 -
completely absent, and
the colorless bile contains
only trace amounts of
unconjugated bilirubin
Crigler-Najjar
syndrome type II - a
less severe, nonfatal
disorder in which UGT1A1
enzyme activity is greatly
reduced, and the enzyme
is capable of forming only
monoglucuronidated
bilirubin
Gilbert syndrome is a
relatively common,
benign, inherited
condition presenting with
mild, fluctuating
hyperbilirubinemia, in the
absence of hemolysis or
liver disease
Dubin-Johnson
syndrome - an
autosomal recessive
disorder characterized by
 Chapter 18 Liver and Biliary Tract

chronic conjugated across the canalicular

hyperbilirubinemia. It is membrane
caused by a defect in
hepatocellular excretion
of bilirubin glucuronides