THE LIVER • Blood traverses the sinusoids and exits into the terminal
Normal
• The liver and biliary tree and the gallbladder occupy the
right upper quadrant of the abdomen.
• The liver resides between the digestive tract and the rest
of the body and functions as a way station between the
splanchnic and systemic circulation
• The liver has the critical job of maintaining the body's
metabolic homeostasis. This includes:
a. the processing of dietary amino acids,
carbohydrates, lipids, and vitamins;
b. removal of microbes and toxins in splanchnic blood
en route to the systemic circulation;
c. synthesis of many plasma proteins; and
detoxification and excretion into bile of endogenous
waste products and pollutant xenobiotics.
• The mature liver lies in the right hypochondrium under
the rib cage and extends from the right fifth intercostal
space at the midclavicular line to just below the costal
margin.
• It projects slightly below the costal margin at the right
intercostal line and under the xyphoid process in the
midline.
• The physiologic or functional right and left lobes are
defined by the distribution of the right and left portal vein
systems.
• The watershed between these two vascular beds
corresponds to a plane that passes superiorly through
the left side of the sulcus of the inferior vena cava to the
middle of the gallbladder fossa inferiorly.
• The quadrate lobe and the greater part of the caudate
lobe on the posterior aspect of the liver belong
functionally to the left hemiliver.
Microarchitecture
• The liver has been divided into 1- to 2-mm diameter
hexagonal lobules oriented around the terminal
tributaries of the hepatic vein (terminal hepatic veins),
with portal tracts at the periphery of the lobule.
• Accordingly, the hepatocytes in the vicinity of the
terminal hepatic vein are called "centrilobular" (or
centrolobular); those near the portal tract are
"periportal."
• However, since hepatocytes near the terminal hepatic
veins are most remote from the blood supply, it has
been argued that they are at the distal apices of roughly
triangular acini, with the bases formed by penetrating
septal venules from the portal vein extending out from
the portal tracts.
• In the "acinus," the parenchyma is divided into three
zones, zone 1 being closest to the vascular supply, zone
3 abutting the terminal hepatic venule, and zone 2 being
intermediate.
• The hepatic parenchyma is organized into cribiform,
anastomosing sheets or "plates" of hepatocytes, seen in
microscopic sections as cords of cells.
• Hepatocytes immediately abutting the portal tract are
referred to as the limiting plate, forming a discontinuous
rim around the mesenchyme of the portal tract.
• There is a radial orientation of the hepatocyte cords
around the terminal hepatic vein.
• Hepatocytes exhibit minimal variation in overall size, but
nuclei may vary in size, number, and ploidy, particularly
with advancing age.
• Uninucleate, diploid cells tend to be the rule, but with
increasing age, a significant fraction are binucleate, and
the karyotype may range up to octaploidy.
• Between the cords of hepatocytes are vascular
sinusoids.
hepatic vein through innumerable orifices in the vein
wall.
• Hepatocytes are thus bathed on two sides by well-mixed
portal venous and hepatic arterial blood, placing
hepatocytes among the most richly perfused cells in the
body.
• The sinusoids are lined by fenestrated and
discontinuous endothelial cells, which demarcate an
extrasinusoidal space of Disse, into which protrude
abundant microvilli of hepatocytes.
• Scattered Kupffer cells of the mononuclear phagocyte
system are attached to the luminal face of endothelial
cells, and scattered fat-containing perisinusoidal stellate
cells are found in the space of Disse.
• These stellate cells play a role in the storage and
metabolism of vitamin A and are transformed into
collagen-producing myofibroblasts when there is
inflammation of the liver.
• Between abutting hepatocytes are bile canaliculi, which
are channels 1 to 2 μm in diameter, formed by grooves
in the plasma membranes of the facing cells and
delineated from the vascular space by tight junctions.
• Numerous microvilli extend into these intercellular
spaces, which constitute the outermost reaches of the
biliary tree.
• Hepatocellular actin and myosin microfilaments
surrounding the canaliculus help propel secreted biliary
fluid along the canaliculi.
• These channels drain into the canals of Hering in the
periportal region.
• These canals are troughlike extensions of biliary
epithelium into the periportal parenchyma, abutting with
hepatocytes to form efficient channels for draining bile.
• Biliary fluid is conveyed through their lumina to bile
ductules, which traverse the portal mesenchyme to
empty into the terminal bile ducts within the portal tracts.
Pathology
• The dominant primary diseases of the liver are viral
hepatitis, alcoholic liver disease, and hepatocellular
carcinoma.
• More often, hepatic damage is secondary, to some of
the most common diseases in humans, such as cardiac
decompensation, disseminated cancer, and extrahepatic
infections.
• With the rare exception of fulminant hepatic failure, liver
disease is an insidious process in which symptoms of
hepatic decompensation may occur weeks, months, or
even years after the onset of injury.
• There is often a long time interval between disease
onset (or initiation) and detection. Conversely, the liver
may be injured and heal without clinical detection.
• Three general aspects of liver disease
(1) patterns of hepatic injury,
(2) hepatic failure and cirrhosis, and
(3) jaundice and cholestasis.
1. PATTERNS OF HEPATIC INJURY
• The liver is an inherently simple organ with a limited
repertoire of responses to injurious events.
• Regardless of cause, five general responses are seen.
a. Degeneration and Intracellular Accumulation.
- Damage from toxic or immunologic insult may cause
swelling of hepatocytes.
- Moderate cell swelling is reversible.
- With more severe damage (ballooning degeneration),
swollen hepatocytes have irregularly clumped
cytoplasmic organelles and large clear spaces.
- In cholestatic liver injury, retained biliary material may
impart a diffuse, foamy appearance to the swollen
hepatocyte (feathery degeneration).
- This lesion can be difficult to distinguish from ballooning
degeneration, except for the variable yellow
discoloration of the cytoplasm.
- Substances may accumulate in viable hepatocytes,
including iron and copper.
- Accumulation of triglyceride fat droplets within
hepatocytes is known as steatosis
- Multiple tiny droplets that do not displace the nucleus
are known as microvesicular steatosis, and appear in
such conditions as acute fatty liver of pregnancy and
valproic acid toxicity.
- A single large droplet that displaces the nucleus,
macrovesicular steatosis, may be seen in hepatocytes
throughout the livers of obese or diabetic individuals
and, interestingly, in scattered hepatocytes in patients
with hepatitis C viral infection.
b. Necrosis and Apoptosis.
- Any significant insult to the liver can cause hepatocyte
necrosis.
- In ischemic coagulative necrosis, the liver cells are
poorly stained and "mummified" and often have lysed
nuclei.
- In apoptotic cell death, isolated hepatocytes round up
to form shrunken, pyknotic, and intensely eosinophilic
cellscontaining fragmented nuclei.
- Hepatocytes may also osmotically swell and rupture, so-
called lytic necrosis, the outcome of ballooning
degeneration.
- Lytic necrosis leaves neither mummified hepatocytes nor
pyknotic cells but rather shards of cellular debris.
- Necrosis frequently exhibits a zonal distribution.
- The most obvious is necrosis of hepatocytes
immediately around the terminal hepatic vein (so-called
centrilobular necrosis, using the historical
terminology), an injury that is characteristic of ischemic
injury and a number of drug and toxic reactions.
- Pure midzonal and periportal necrosis are rare; the
latter may be seen in eclampsia.
- With most other causes of hepatic injury, a variable
mixture of hepatocellular death through the parenchyma
is encountered.
- The hepatocyte necrosis may be limited to scattered
cells within hepatic lobules (focal or spotty necrosis) or
to the interface between the periportal parenchyma and
inflamed portal tracts (interface hepatitis).
- With more severe inflammatory injury, necrosis of
contiguous hepatocytes may span adjacent lobules in a
portal-to-portal, portal-to-central, or central-to-central
fashion (bridging necrosis).
- Necrosis of entire lobules (submassive necrosis) or of
most of the liver (massive necrosis) is usually
accompanied by hepatic failure.
- With disseminated candidal or bacterial infection,
macroscopic abscesses may occur.
c. Inflammation.
- Injury to the liver associated with an influx of acute or
chronic inflammatory cells is termed hepatitis.
- Direct toxic or ischemic hepatocyte necrosis incites an
inflammatory reaction.
- With toxic damage, inflammation may also precede the
onset of inflammation.
- Destruction of antigen-expressing liver cells by cytotoxic
lymphocytes is a common mechanism of liver damage,
especially during viral infection.
- In viral hepatitis, quiescent lymphocytes may collect in
the portal tracts as a reflection of mild smoldering
inflammation, spill over into the periportal parenchyma
as activated lymphocytes (interface hepatitis) causing
a moderately active hepatitis, or suffuse the entire
parenchyma in severe hepatitis.
- Once killed, apoptotic hepatocytes do not incite an
inflammatory reaction per se.
- However, scavenger macrophages (Kupffer cells and
circulating monocytes recruited to the liver) engulf the
apoptotic cell fragments within a few hours, generating
clumps of inflammatory cells.
- Hence, identification of apoptotic hepatocytes is a sign
of very recent hepatocyte destruction.
- Foreign bodies, organisms, and a variety of drugs may
incite a granulomatous reaction.
d. Regeneration.
- Hepatocytes have long life spans, and they proliferate in
response to tissue resection or cell death
- Regeneration occurs in all but the most fulminant
hepatic diseases.
- Hepatocellular proliferation is marked by mitoses,
thickening of the hepatocyte cords, and some
disorganization of the parenchymal structure.
- The canal of Hering-bile ductule unit constitutes a
reserve compartment for restitution of severe
parenchymal injury; when it is activated, innumerable
serpentine profiles resembling bile ductules appear-so-
called ductular reaction.
- This compartment also proliferates during large bile duct
obstruction.
- When hepatocellular necrosis occurs and leaves the
connective tissue framework intact, almost perfect
restitution of liver structure can occur, even when the
necrosis is submassive or massive.
e. Fibrosis.
- Fibrous tissue is formed in response to inflammation or
direct toxic insult to the liver.
- Unlike other responses, which are reversible, fibrosis
points toward generally irreversible hepatic damage.
- However, there is now considerable debate about the
irreversibility of liver fibrosis and even cirrhosis
- Deposition of collagen has lasting consequences on
patterns of hepatic blood flow and perfusion of
hepatocytes.
- In the initial stages, fibrosis may develop around portal
tracts or the terminal hepatic vein or may be deposited
directly within the space of Disse.
- With continuing fibrosis, the liver is subdivided into
nodules of proliferating hepatocytes surrounded by
scar tissue, termed "cirrhosis."
- This end-stage form of liver disease is discussed later in
this section.
2.A HEPATIC FAILURE
• The most severe clinical consequence of liver disease is
hepatic failure.
• More often, it is the end point of progressive damage to
the liver as part of chronic liver disease, either by
insidious destruction of hepatocytes or by repetitive
discrete waves of parenchymal damage.
• These include gastrointestinal bleeding, systemic
infection, electrolyte disturbances, and severe stress
such as major surgery or heart failure.
• In most cases of severe hepatic dysfunction, liver
transplantation is the only hope for survival
• The morphologic alterations that cause liver failure fall
into three categories:
a. Massive hepatic necrosis.
- This is most often drug- or toxin-induced, as
from acetaminophen (38% of massive hepatic
necrosis cases in the United States),
halothane, antituberculosis drugs (rifampin,
isoniazid), antidepressant monoamine oxidase
inhibitors, industrial chemicals such as carbon
tetrachloride, and mushroom poisoning
(Amanita phalloides), collectively accounting for
an additional 14% of cases.
- The mechanism may be direct toxic damage to
hepatocytes (e.g., acetaminophen, carbon
tetrachloride, mushroom toxins) but more often
is a variable combination of toxicity and
inflammation with immune-mediated
hepatocyte destruction.
- Hepatitis A infection accounts for 4% of cases,
hepatitis B infection accounts for 8%, and other
causes (including unknown) account for 37%.
Hepatitis C infection does not cause massive
hepatic necrosis.
b. Chronic liver disease.
- This is the most common route to hepatic
failure and is the endpoint of relentless chronic
hepatitis ending in cirrhosis.
c. Hepatic dysfunction without overt necrosis
- Hepatocytes may be viable but unable to
perform normal metabolic function, as with
Reye syndrome, tetracycline toxicity, and acute
fatty liver of pregnancy.
Clinical Features
• Regardless of cause, the clinical signs of hepatic failure
are much the same.
• Jaundice is an almost invariable finding.
Hypoalbuminemia, which predisposes to peripheral
edema, and hyperammonemia, which may play a role in
cerebral dysfunction, are extremely worrisome
developments.
• Fetor hepaticus is a characteristic body odor that is
variously described as "musty" or "sweet and sour" and
occurs occasionally.
• It is related to the formation of mercaptans by the action
of gastrointestinal bacteria on the sulfur-containing
amino acid methionine and shunting of splanchnic blood
from the portal into the systemic circulation
(portosystemic shunting).
• Impaired estrogen metabolism and consequent
hyperestrogenemia are the putative causes of palmar
erythema (a reflection of local vasodilatation) and spider
angiomas of the skin.
• Each angioma is a central, pulsating, dilated arteriole
from which small vessels radiate. In the male,
hyperestrogenemia also leads to hypogonadism and
gynecomastia.
• Hepatic failure is life-threatening because with severely
impaired liver function, patients are highly susceptible to
failure of multiple organ systems.
• A coagulopathy develops, attributable to impaired
hepatic synthesis of blood clotting factors II, VII, IX, and
X.
• The resultant bleeding tendency can lead to massive
gastrointestinal bleeding as well as petechial bleeding
elsewhere.
• Intestinal absorption of blood places a metabolic load on
the liver, which worsens the extent of hepatic failure.
• A fortunate few can endure an acute episode until
hepatocellular regeneration restores adequate hepatic
function.
• Alternatively, liver transplantation might save the patient.
• Two particular complications merit separate
consideration, as they herald the most grave stages of
hepatic failure:
a. Hepatic encephalopathy
- is manifested by a spectrum of disturbances in
consciousness, ranging from subtle behavioral
abnormalities to marked confusion and stupor
to deep coma and death.
- These changes may progress over hours or
days in fulminant hepatic failure or more
insidiously in a patient with marginal hepatic
function from chronic liver disease.
- Associated fluctuating neurologic signs include
rigidity, hyperreflexia, and particularly asterixis:
nonrhythmic, rapid extension-flexion
movements of the head and extremities, best
seen when the arms are held in extension with
dorsiflexed wrists.
- Hepatic encephalopathy is regarded as a
disorder of neurotransmission in the central
nervous system and neuromuscular system5
and appears to be associated with elevated
blood ammonia levels, which impair neuronal
function and promote generalized brain edema.
- In the great majority of instances, there are
only minor morphologic changes in the brain,
such as edema and an astrocytic reaction, and
the encephalopathy is reversible if the
underlying hepatic condition can be corrected.
b. Hepatorenal syndrome refers to the appearance of
renal failure in patients with severe chronic liver
disease, in whom there are no intrinsic morphologic
or functional causes for the renal failure.
- Sodium retention, impaired free-water
excretion, and decreased renal perfusion and
glomerular filtration rate are the main renal
functional abnormalities.
- Several factors are involved in its development,
including a decreased renal perfusion pressure
due to systemic vasodilation, activation of the
renal sympathetic nervous system with
vasoconstriction of the afferent renal arteriolae,
and increased synthesis of renal vasoactive
mediators, which further decrease glomerular
filtration.
- Onset of this syndrome is typically heralded by
a drop in urine output, associated with rising
blood urea nitrogen and creatinine.
- The ability to concentrate urine is retained,
producing a hyperosmolar urine devoid of
proteins and abnormal sediment, and
surprisingly low in sodium (unlike renal tubular
necrosis).
- Rapid development of renal failure is usually
associated with a precipitating stress factor
such as infection, gastrointestinal hemorrhage,
or a major surgical procedure.
- Insidious development of renal failure is the
result of progressive destabilization of
circulatory physiology, frequently in the setting
of severe refractory ascites.
- The prognosis is poor, with a median survival of
only 2 weeks in the rapid-onset form and 6
months with the insidious-onset form.
2.B CIRRHOSIS
• Cirrhosis is among the top 10 causes of death in the
Western world.
• The chief worldwide contributors are alcohol abuse and
viral hepatitis.
• Other causes include biliary disease, and iron overload.
• An example of the progression to cirrhosis is given
under the subsequent discussion on alcohol.
• Cirrhosis as the end-stage of chronic liver disease is
defined by three characteristics:
a. Bridging fibrous septae in the form of delicate bands
or broad scars linking portal tracts with one another
and portal tracts with terminal hepatic veins
b. Parenchymal nodules containing proliferating
hepatocytes encircled by fibrosis, with diameters
varying from very small (<3 mm, micronodules) to
large (several centimeters, macronodules)
c. Disruption of the architecture of the entire liver
• Several features of cirrhosis should be underscored:
a. The parenchymal injury and consequent fibrosis are
diffuse, extending throughout the liver.
b. Focal injury with scarring does not constitute cirrhosis,
nor does diffuse nodular transformation without
fibrosis.
c. Nodularity is part of the diagnosis and reflects the
balance between regenerative activity and constrictive
scarring.
d.Vascular architecture is reorganized by the
parenchymal damage and scarring, with the formation
of abnormal interconnections between vascular inflow
and hepatic vein outflow channels.
e. Fibrosis is the key feature of progressive damage to
the liver.
• Infrequent types of cirrhosis also include the cirrhosis
developing in infants and children with galactosemia and
tyrosinosis, and drug-induced cirrhosis, as with α-
methyldopa.
• Severe fibrosis can occur in the setting of cardiac
disease (sometimes called "cardiac cirrhosis,").
• After all the categories of cirrhosis of known causation
have been excluded, a substantial number of cases
remain.
• Referred to as cryptogenic cirrhosis, the magnitude of
this "wastebasket" category speaks eloquently to the
difficulties in discerning the many origins of cirrhosis.
• A growing concern is that many of these cases are due
to undiagnosed nonalcoholic fatty liver disease, to be
discussed.
• Once cirrhosis is established, it is usually impossible to
establish an etiologic diagnosis on morphologic grounds
alone.
Pathogenesis
• The central pathogenetic processes in cirrhosis are
progressive fibrosis and reorganization of the vascular
microarchitecture of the liver.7
• In the normal liver, interstitial collagens (types I and III)
are concentrated in portal tracts and around central
veins, with occasional bundles in the space of Disse.
• The collagen (reticulin) coursing alongside hepatocytes
is composed of delicate strands of type IV collagen in
the space of Disse.
• In cirrhosis, types I and III collagen are deposited in the
lobule, creating delicate or broad septal tracts.
• New vascular channels in the septae connect the
vascular structures in the portal region (hepatic arteries
and portal veins) and terminal hepatic veins, shunting
blood around the parenchyma.
• Continued deposition of collagen in the space of Disse
within preserved parenchyma is accompanied by the
loss of fenestrations in the sinusoidal endothelial cells.
• In the process, the sinusoidal space comes to resemble
a capillary rather than a channel for exchange of solutes
between hepatocytes and plasma.
• In particular, hepatocellular secretion of proteins (e.g.,
albumin, clotting factors, lipoproteins) is greatly
impaired.
• The major source of excess collagen in cirrhosis is the
perisinusoidal stellate cells, which lie in the space of
Disse.
• Although normally functioning as vitamin A fat-storing
cells, during the development of cirrhosis they become
activated, a process that includes:
(1) robust mitotic activity in areas developing new
parenchymal fibrosis,
(2) a shift from the resting-state lipocyte phenotype to a
transitional myofibroblast phenotype, and
(3) increased capacity for synthesis and secretion of
extracellular matrix.
• It is predominantly the cytokines secreted by activated
Kupffer cells and other inflammatory cells that stimulate
perisinusoidal stellate cells to divide and to produce
large amounts of extracellular matrix.
• Moreover, the greatest activation of stellate cells is in
areas of severe hepatocellular necrosis and
inflammation. The stimuli for stellate cell activation may
come from several sources:
a. Chronic inflammation, with production of
inflammatory cytokines such as tumor necrosis factor
(TNF), lymphotoxin, and interleukin-1 (IL-1).
b. Cytokine production by activated endogenous cells
(Kupffer cells, endothelial cells, hepatocytes, and bile
duct epithelial cells), including transforming growth
factor-β (TGF-β), platelet-derived growth factor
(PDGF), and lipid peroxidation products.
c. Disruption of the extracellular matrix, as stellate cells
are extraordinarily responsive to the status of their
substrate.
d. Direct stimulation of stellate cells by toxins.
• Acquisition of myofibers by perisinusoidal stellate cells
also increases vascular resistance within the liver
parenchyma, since tonic contraction of these
"myofibroblasts" constricts the sinusoidal vascular
channels.
Clinical Features
• All forms of cirrhosis may be clinically silent.
• When symptomatic they lead to nonspecific clinical
manifestations: anorexia, weight loss, weakness,
osteoporosis, and, in advanced disease, frank
debilitation.
• Incipient or overt hepatic failure may develop, usually
precipitated by a superimposed metabolic load on the
liver, as from systemic infection or a gastrointestinal
hemorrhage.
• Imbalances of pulmonary blood flow, which are poorly
understood, may lead to severely impaired oxygenation
(hepatopulmonary syndrome), further stressing the
patient.
• The ultimate mechanism of most cirrhotic deaths is:
(1) progressive liver failure (discussed earlier),
(2) a complication related to portal hypertension, or
(3) the development of hepatocellular carcinoma.
PORTAL HYPERTENSION
• Increased resistance to portal blood flow may develop in
a variety of circumstances, which can be divided into
prehepatic, intrahepatic, and posthepatic causes.
• The major prehepatic conditions are obstructive
thrombosis and narrowing of the portal vein before it
ramifies within the liver.
• Massive splenomegaly may also shunt excessive blood
into the splenic vein.
• The major posthepatic causes are severe right-sided
heart failure, constrictive pericarditis, and hepatic vein
outflow obstruction.
• The dominant intrahepatic cause is cirrhosis, accounting
for most cases of portal hypertension.
• Far less frequent are schistosomiasis, massive fatty
change, diffuse fibrosing granulomatous disease such
as sarcoidosis and miliary tuberculosis, and diseases
affecting the portal microcirculation, exemplified by
nodular regenerative hyperplasia.
• Portal hypertension in cirrhosis results from increased
resistance to portal flow at the level of the sinusoids, and
compression of terminal hepatic veins by perivenular
scarring and expansile parenchymal nodules.
• Anastomoses between the arterial and portal systems in
the fibrous septa also contribute to portal hypertension
by imposing arterial pressure on the low-pressure
hepatic venous system.
• The four major clinical consequences are
(1) ascites,
(2) the formation of portosystemic venous shunts,
(3) congestive splenomegaly, and
(4) hepatic encephalopathy (discussed earlier).
Ascites
• Ascites refers to the collection of excess fluid in the
peritoneal cavity.
• It usually becomes clinically detectable when at least
500 mL has accumulated, but many liters may collect
and cause massive abdominal distention.
• It is generally a serous fluid having less than 3 gm/dL of
protein (largely albumin) as well as the same
concentrations of solutes such as glucose, sodium, and
potassium as in the blood. The fluid may contain a scant
number of mesothelial cells and mononuclear
leukocytes.
• Influx of neutrophils suggests secondary infection,
whereas red cells point to possible disseminated intra-
abdominal cancer.
• With long-standing ascites, seepage of peritoneal fluid
through transdiaphragmatic lymphatics may produce
hydrothorax, more often on the right side.
• The pathogenesis of ascites is complex, involving the
following mechanisms:
a. Sinusoidal hypertension, altering Starling's forces
and driving fluid into the space of Disse, which is then
removed by hepatic lymphatics; this movement of fluid
is also promoted by hypoalbuminemia.
b. Percolation of hepatic lymph into the peritoneal
cavity: Normal thoracic duct lymph flow approximates
800 to 1000 mL/day. With cirrhosis, hepatic lymphatic
flow may approach 20 L/day, exceeding thoracic duct
capacity. Hepatic lymph is rich in proteins and low in
triglycerides, which is reflected in the protein-rich
ascitic fluid.
c. Intestinal fluid leakage: Portal hypertension also
causes increased perfusion pressure in intestinal
capillaries. The osmotic action of the protein-rich
ascitic fluid promotes movement of additional fluid out
of intestinal capillaries into the abdomen.
d. Renal retention of sodium and water due to
secondary hyperaldosteronism.
Portosystemic Shunts
• With the rise in portal system pressure, bypasses
develop wherever the systemic and portal circulation
share common capillary beds.
• Principal sites are veins around and within the rectum
(manifest as hemorrhoids), the cardioesophageal
junction (producing esophagogastric varices), the
retroperitoneum, and the falciform ligament of the liver
(involving periumbilical and abdominal wall collaterals).
• Although hemorrhoidal bleeding may occur, it is rarely
massive or life-threatening.
• Much more important are the esophagogastric varices
that appear in about 65% of patients with advanced
cirrhosis of the liver and cause massive hematemesis
and death in about half of them.
• Abdominal wall collaterals appear as dilated
subcutaneous veins extending from the umbilicus
towards the rib margins (caput medusae) and constitute
an important clinical hallmark of portal hypertension.
Splenomegaly
• Long-standing congestion may cause congestive
splenomegaly.
• The degree of enlargement varies widely up to 1000 gm
and is not necessarily correlated with other features of
portal hypertension.
• Massive splenomegaly may secondarily induce a variety
of hematologic abnormalities attributable to
hypersplenism.
3. JAUNDICE AND CHOLESTASIS
• Hepatic bile formation serves two major functions:
(1) the emulsification of dietary fat in the lumen of the
gut through the detergent action of bile salts and
(2) the elimination of systemic waste products. Bile
constitutes the primary pathway for elimination of
bilirubin, excess cholesterol, and xenobiotics that are
insufficiently water-soluble to be excreted into urine.
Because bile formation requires well-functioning
hepatocytes, it is readily disrupted. Such disruption becomes
clinically evident as yellow discoloration of the skin and
sclerae (jaundice and icterus, respectively) due to retention
of pigmented bilirubin, and as cholestasis, characterized by
systemic retention of not only bilirubin but also other solutes
eliminated in bile.
Bilirubin and Bile Formation
• Bilirubin is the end product of heme degradation.
• The majority of daily production (0.2 to 0.3 gm) is
derived from breakdown of senescent erythrocytes by
the mononuclear phagocytic system, especially in the
spleen, liver, and bone marrow.
• Most of the remainder of bilirubin is derived from the
turnover of hepatic heme or hemoproteins (e.g., the P-
450 cytochromes) and from premature destruction of
newly formed erythrocytes in the bone marrow.
• The latter pathway is important in hematologic disorders
associated with excessive intramedullary hemolysis of
defective erythrocytes (ineffective erythropoiesis.
• Whatever the source, heme oxygenase oxidizes heme
to biliverdin (which is then reduced to bilirubin by
biliverdin reductase.
• Bilirubin thus formed outside the liver is released and
bound to serum albumin.
• Albumin binding is necessary, since bilirubin is virtually
insoluble in aqueous solutions at physiologic pH.
• The very small fraction of unbound bilirubin in plasma
may increase in severe hemolytic disease or when
protein-binding drugs displace bilirubin from albumin.
• Hepatic processing of bilirubin involves carrier-mediated
uptake at the sinusoidal membrane, conjugation with
one or two molecules of glucuronic acid by bilirubin
UDP-glucuronyltransferase in the endoplasmic
reticulum, and excretion of the water-soluble, nontoxic
bilirubin glucuronides into bile.
• Most bilirubin glucuronides are deconjugated by
bacterial β-glucuronidases and degraded to colorless
urobilinogens.
• The urobilinogens and the residue of intact pigment are
largely excreted in feces. Approximately 20% of the
urobilinogens formed are reabsorbed in the ileum and
colon, returned to the liver, and promptly re-excreted into
bile. The small amount that escapes this enterohepatic
circulation is excreted in urine.
• The hepatic conjugating enzyme, UGT1A1, is a product
of the UGT1 gene located on chromosome 2q37.
• It is a member of a family of UGTs that catalyze the
glucuronidation of an array of substrates such as steroid
hormones, carcinogens, and drugs.
• The various UGTs are distributed in a wide range of
tissues, including the liver, kidney, intestine, skin, lung,
olfactory epithelium, and testis. UGT1A1 is located
primarily in the smooth and rough endoplasmic reticulum
of hepatocytes, as a single isoform that catalyzes the
glucuronidation of bilirubin to its monoglucuronidated
and diglucuronidated forms.
• The sequence of the human UGT1 gene shows that
there are 13 isoform sequences in a tandem array for
exon 1, each of which possesses a unique promoter and
undergoes differential splicing to four common exons
(exons 2 through 5).
• This differential splicing leads to the generation of
different mRNAs that encode the different UGT isoforms.
Following translation into a polypeptide, the unique
amino terminus specifies acceptor-substrate selection,
and the common carboxy terminus specifies the enzyme
interaction with the common donor substrate, UDP-
glucuronic acid.
• In humans, two members of the UGT1 family possess
the capability to glucuronidate bilirubin in vitro, but only
one isoform is physiologically relevant in vivo.
• This bilirubin glucuronidating isoform is termed UGT1A1,
as it is generated from the exon 1A of the UGT1 gene
locus.
• The brilliant yellow color of bilirubin makes it an easily
identified component of hepatic bile formation.
• However, bilirubin metabolism and excretion are but
minor cogs in the hepatic machinery that secretes
approximately 0.5 to 1.0 L of bile daily.
• Newly secreted bile is a bicarbonate-rich fluid containing
by weight about 3% organic solutes.
• Two thirds of the organic material in bile are bile salts:
bile acids conjugated with taurine or glycine to form bile
salts.
• Bile acids are the major catabolic products of cholesterol
and are a family of water-soluble sterols with
carboxylated side chains.
• The primary human bile acids are cholic acid and
chenodeoxycholic acid.
• Bile acids and their taurine- or glycine-conjugated salts
act as highly effective detergents.
• Their primary physiologic role is solubilizing water-
insoluble lipids secreted by hepatocytes into bile, and
solubilizing dietary lipids within the gut lumen.
• The principal secreted lipids (>95%) are lecithins
(phosphatidylcholine), which are very hydrophobic and
have no appreciable aqueous solubility of their own.
• However, these insoluble amphiphiles enhance the
limited cholesterol-solubilizing capacity of bile salts in
bile.
• Cholesterol is a negligibly soluble steroid molecule with
a single polar hydroxyl group, whose solubility in bile is
increased several million-fold by the presence of bile
salts and lecithin.
• Ten percent to 20% of secreted bile salts are
deconjugated in the intestines by bacterial action.
• Ninety-five percent of secreted bile acids, conjugated or
unconjugated, are reabsorbed, primarily through the
action of a sodium-bile acid cotransporter in the apical
membrane of ileal enterocytes and are returned to the
liver via portal blood for uptake, reconjugation with
taurine or glycine, and resecretion.
• The enterohepatic circulation of bile acids provides an
efficient mechanism for maintaining a large endogenous
pool of bile acids for digestive and excretory purposes.
• Fecal loss of bile acids (0.2 to 0.6 gm per day) is
matched by their daily de novo hepatic synthesis from
cholesterol.
• This obligatory fecal loss of sterols in the form of bile
salts and residual free cholesterol constitutes the only
effective mechanism for elimination of excess
cholesterol from the body.
Pathophysiology of Jaundice
• Both unconjugated bilirubin and bilirubin glucuronides
may accumulate systemically and deposit in tissues,
giving rise to the yellow discoloration of jaundice.
• This is particularly evident in the yellowing of the sclerae
(icterus).
• There are two important pathophysiologic differences
between the two forms of bilirubin.
• Unconjugated bilirubin is virtually insoluble in water at
physiologic pH and is tightly complexed to serum
albumin.
• This form cannot be excreted in the urine even when
blood levels are high.
• Normally, a very small amount of unconjugated bilirubin
is present as an albumin-free anion in plasma.
• This fraction of unbound bilirubin may diffuse into
tissues, particularly the brain in infants, and produce
toxic injury.
• The unbound plasma fraction may increase in severe
hemolytic disease or when protein-binding drugs
displace bilirubin from albumin.
• Hence, hemolytic disease of the newborn
(erythroblastosis fetalis) may lead to accumulation of
unconjugated bilirubin in the brain, which can cause
severe neurologic damage, referred to as kernicterus
• In contrast, conjugated bilirubin is water soluble,
nontoxic, and only loosely bound to albumin.
• Because of its solubility and weak association with
albumin, excess conjugated bilirubin in plasma can be
excreted in urine.
• With prolonged conjugated hyperbilirubinemia, a portion
of circulating pigment may become covalently bound to
albumin (the delta fraction).
• In the normal adult, serum bilirubin levels vary between
0.3 and 1.2 mg/dL, and the rate of systemic bilirubin
production is equal to the rates of hepatic uptake,
conjugation, and biliary excretion.
• Jaundice becomes evident when the serum bilirubin
levels rise above 2.0 to 2.5 mg/dL; levels as high as 30
to 40 mg/dL can occur with severe disease.
• Jaundice occurs when the equilibrium between bilirubin
production and clearance is disturbed by one or more of
the following mechanisms:
 (1) excessive production of bilirubin,
(2) reduced hepatocyte uptake,
(3) impaired conjugation,
(4) decreased hepatocellular excretion, and
(5) impaired bile flow (both intrahepatic and
extrahepatic).
• The first three mechanisms produce unconjugated
hyperbilirubinemia, and the latter two produce
predominantly conjugated hyperbilirubinemia.
• More than one mechanism may operate to produce
jaundice, especially hepatitis, which can produce
unconjugated and conjugated hyperbilirubinemia.
• Generally speaking, however, one mechanism
predominates, so knowledge of the major form of
plasma bilirubin is of value in evaluating possible causes
of hyperbilirubinemia.
• Of the various causes of jaundice the most common are
due to bilirubin overproduction (as from hemolytic
anemias and resorption of major hemorrhages),
hepatitis, and obstruction to the flow of bile (considered
later in this chapter).
Neonatal Jaundice
• Because the hepatic machinery for conjugating and
excreting bilirubin does not fully mature until about 2
weeks of age, almost every newborn develops transient
and mild unconjugated hyperbilirubinemia, termed
neonatal jaundice or physiologic jaundice of the
newborn.
• Breast-fed infants tend to exhibit jaundice with greater
frequency, possibly the result of β-glucuronidases
present in maternal milk.
• These enzymes deconjugate bilirubin glucuronides in
the gut, increasing intestinal reabsorption of
unconjugated bilirubin. Sustained jaundice in the
newborn is indicative of a disease condition, discussed
later under neonatal hepatitis.
Hereditary Hyperbilirubinemias
• In rare instances, there may be a genetic lack of
UGT1A1
• In Crigler-Najjar syndrome type I, the enzyme is
completely absent. Multiple genetic defects in the locus
coding for UGT1A1 may give rise to this disorder.
• The liver is incapable of synthesizing a functional
enzyme, and the colorless bile contains only trace
amounts of unconjugated bilirubin.
• The liver is morphologically normal by light and electron
microscopy.
• However, serum unconjugated bilirubin reaches very
high levels, producing severe jaundice and icterus.
• Without liver transplantation, this condition is invariably
fatal, causing death within 18 months of birth secondary
to kernicterus.
• Crigler-Najjar syndrome type II is a less severe, nonfatal
disorder in which UGT1A1 enzyme activity is greatly
reduced, and the enzyme is capable of forming only
monoglucuronidated bilirubin.
o Unlike Crigler-Najjar syndrome type I, the only
major consequence is extraordinarily yellow skin
from moderate to high levels of circulating
unconjugated bilirubin; phenobarbital treatment can
improve bilirubin glucuronidation by inducing
hypertrophy of the hepatocellular endoplasmic
reticulum.
o Mutations either reduce the affinity of UGT1A1
toward bilirubin or reduce enzyme activity.
o Almost all patients develop normally, but there is a
risk for some neurologic damage from kernicterus.
• Gilbert syndrome is a relatively common, benign,
somewhat heterogeneous inherited condition presenting
with mild, fluctuating hyperbilirubinemia.
o The primary cause is reduction in hepatic bilirubin
glucuronidating activity to about 30% of normal
levels.
o In most patients, two extra bases (TA) are found in
the TATAA element of the 5' promoter region
(creating an A(TA)7TAA element rather than the
normal A(TA)6TAA, resulting in reduced expression
of UGT1A1.
o Alternatively, patients may be heterozygous for
missense mutations in the UGT1A1 gene. Affecting
some 6% of the population, the mild
hyperbilirubinemia may go undiscovered for years
and is not associated with functional derangements.
o When detected in adolescence or adult life, it is
typically in association with stress, such as an
intercurrent illness, strenuous exercise, or fasting.
o Gilbert syndrome has no clinical consequence
except for the anxiety that a jaundiced sufferer
might justifiably experience with this otherwise
innocuous condition.
• Dubin-Johnson syndrome results from a hereditary
defect in hepatocellular excretion of bilirubin
glucuronides across the canalicular membrane.
o The defect is due to absence of the canalicular
protein, the multidrug resistance protein 2 (MRP2;
located on chromosome 10q24), that is responsible
for transport of bilirubin glucuronides and related
organic anions into bile.
o The liver is darkly pigmented owing to coarse
pigmented granules within the cytoplasm of
hepatocytes
o Electron microscopy reveals that the pigment is
located in lysosomes, and it appears to be
composed of polymers of epinephrine metabolites,
not bilirubin pigment.
o The liver is otherwise normal.
o Apart from chronic or recurrent jaundice of
fluctuating intensity, most patients are
asymptomatic and have a normal life expectancy.
• Rotor syndrome is a rare form of asymptomatic
conjugated hyperbilirubinemia with multiple defects in
hepatocellular uptake and excretion of bilirubin
pigments.
o The liver is not pigmented. As with Dubin-Johnson
syndrome, patients with Rotor syndrome exhibit
jaundice but otherwise live normal lives.
Cholestasis
• Cholestatic conditions, which result from hepatocellular
dysfunction or intrahepatic or extrahepatic biliary
obstruction, also may present with jaundice.
• Alternatively, pruritus is a presenting symptom, related
to the elevation in plasma bile acids and their deposition
in peripheral tissues, particularly skin.
• Skin xanthomas (focal accumulations of cholesterol)
sometimes appear, the result of hyperlipidemia and
impaired excretion of cholesterol.
• A characteristic laboratory finding is elevated serum
alkaline phosphatase, an enzyme present in bile duct
epithelium and in the canalicular membrane of
hepatocytes that is released into the circulation because
of the detergent action of retained bile salts on
hepatocyte membranes.
• An isozyme derived from posttranscriptional changes is
normally present in many other tissues such as bone, so
the increased levels must be verified as being hepatic in
origin.
• Another canalicular ectoenzyme, γ-glutamyl
transpeptidase, is also released into the circulation.
• The elevated levels of these enzymes in the circulation
reflects the detergent action of bile salts retained in the
luminal space of the bile canaliculus on the apical
membranes of hepatocytes and bile duct epithelial cells,
with solubilization of these membrane ectoenzymes.
• Other manifestations of reduced bile flow relate to
intestinal malabsorption, including nutritional
deficiencies of the fat-soluble vitamins A, D, or K.
• Extrahepatic biliary obstruction is frequently amenable to
surgical alleviation; correct and prompt diagnosis is
imperative.
• In contrast, cholestasis due to diseases of the
intrahepatic biliary tree or hepatocellular secretory
failure (collectively termed intrahepatic cholestasis)
cannot be benefited by surgery (short
transplantation), and the patient's condition may be
worsened by an operative procedure.
• There is thus some urgency in making a correct
diagnosis of the cause of jaundice and cholestasis.
Familial Intrahepatic Cholestasis
• Mention should be made of a striking but heterogeneous
group of autosomal-recessively inherited cholestatic
conditions.
• The encoded protein is a canalicular P-type ATPase of
uncertain function, possibly playing a role in secretion of
bile salts indirectly through maintenance of
aminophospholipid polarity in the canalicular membrane.
• Mutations in the canalicular bile salt export pump (BSEP,
encoded by the ABCB11 gene on chromosome 2q24),
are the cause of progressive familial intrahepatic
cholestasis 2 (PFIC-2).
• An autosomal-recessive cholestatic disorder with high
serum GGT is progressive familial intrahepatic
cholestasis 3 (PFIC-3), due to mutations in the ABCB4
gene on chromosome 7q21.
• The encoded protein, MDR3, is a canalicular transport
protein that is responsible for flipping
phosphatidylcholine from the internal to the external
hemileaflet of the canalicular membrane.
of • In patients with this disorder, the absence of secreted
phosphatidylcholine in bile leaves the apical surfaces of
the biliary tree epithelia subject to the full detergent
action of secreted bile salts, with resultant toxic
destruction of these epithelia and release of GGT into
the circulation.
• Children with severe cholestasis but with absence of
elevated serum GGT and absence of pruritus may also
have inherited defects in bile acid synthesis.
• The most common condition is a deficiency of 3β-
hydroxysteroid dehydrogenase, an enzyme located early
in the pathway for bile acid synthesis from cholesterol.

Viral Hepatitis INFECTIOUS DISORDERS

• However, unlike many other cholestatic conditions, the

Hepatitis A Hepatitis Hepatitis Hepatitis D Hepatitis E Hepatitis

• Any insult to the liver can kill hepatocytes and recruit
Virus B Virus C Virus Virus Virus G Virus* inflammatory cells that’s why inflammatory disorders
Agent Icosahedral Enveloped Enveloped Enveloped Unenveloped ssRNA of the liver are frequently long-term chronic
capsid, dsDNA ssRNA ssRNA ssRNA virus conditions that must be managed medically
ssRNA
• Among inflammatory disorders, infection ranks
Transmission Fecal-oral Parenteral; Parenteral; Parenteral; Waterborne Parenteral
close close close contact supreme
contact contact • The liver is inevitably involved in blood-borne
Incubation 2-6 wk 4-26 wk 2-26 wk 4-7 wk 2-8 wk Unknown infections, whether they be systemic or arise within
period the abdomen
Carrier state None 0.1-1.0% 0.2-1.0% 1-10% in drug Unknown 1-2% of • Conditions in which hepatic lesion is prominent
of blood of blood addicts and blood
donors in donors in hemophiliacs donors in include miliary tuberculosis, malaria, staphylococcal
U.S. and U.S. and U.S. bacteremia, salmonelloses, candidiasis, and
Western Western amebiasis
world world
• Foremost hepatic infections are viral in origin
Chronic None 5-10% of >50% <5% None None
hepatitis acute coinfection,
infections 80% upon
superinfection • Systemic viral infections that can involve the liver
Hepatocellula No Yes Yes No increase Unknown, None include
r carcinoma above HBV but unlikely
1) Infectious mononucleosis (Epstein-Barr virus)
virtual absence of bile salts within the canalicular lumen - may cause a mild hepatitis during the acute phase
between hepatocytes means that serum γ-glutamyl 2) Cytomegalovirus infection
transpeptidase (GGT) levels are low for the degree of - particularly in the newborn or immunosuppressed pt
hyperbilirubinemia. 3) Yellow fever
• In benign recurrent intrahepatic cholestasis (BRIC), - a major and serious cause of hepatitis in tropical
there are intermittent attacks of cholestasis over life countries
without progression to chronic liver disease. In • Not frequently in children and immunosuppressed pts,
progressive familial intrahepatic cholestasis 1 (PFIC-1), the liver is affected in the course of rubella virus,
cholestasis begins in infancy with severe pruritus due to adenovirus, herpesvirus, or enterovirus infections
high serum bile acid levels and relentlessly progresses
to liver failure before adulthood.
• Unless otherwise specified, the term “viral hepatitis” is
• The first major characterized family with the latter reserved for infection of the liver caused by a group of
viruses having a particular affinity for the liver
syndrome are descendants of Jacob Byler, an Amish
patient.
• Affected members of this particular family are
designated as having Byler syndrome; unrelated * At present, hepatitis G virus is not considered pathogenic.
individuals with different mutations have Byler disease.
• These conditions encompass a spectrum arising usually
from mutations in the ATP8B1 gene on chromosome
18q21. Hepatitis A Virus

• Long known as infectious hepatitis and the scourge of
military campaigns since antiquity
• A benign self-limited disease with an incubation period
of 2 to 6 weeks
• Does not cause chronic hepatitis or a carrier state and
only rarely causes fulminant hepatitis so the fatality rate
associated with this is about 0.1%
• Occurs throughout the world and endemic in countries
with substandard hygiene and sanitation, so that most
native populations have detectable anti-HAV by the age
of 10 y/o
• Clinical dse. tends to be mild or asymptomatic and rare
after childhood
• Overall, HAV accounts for about 25% of clinically
evident acute hepatitis worldwide
• A small, unenveloped, single-stranded RNA picornavirus
that occupies its own genus, Hepatovirus
• Ultrastructurally, it is an icosahedral capsid 27 nm in
diameter
• Spread by ingestion of contaminated water and foods
• Shed in the stool for 2 to 3 weeks before and 1 week
after the onset of jaundice
• Thus, close personal contact with an infected individual
or fecal-oral contamination during this period accounts
for most cases which explains the outbreaks in
institutional settings such as schools, nurseries, and
water-borne epidemics under overcrowded, unsanitary
conditions
• It is not shed in saliva, urine, or semen
• Among developed countries, sporadic infections may be
contracted by consumption of raw or steamed shellfish
(oysters, mussels, clams) which concentrate the virus
from seawater contaminated with human sewage
• HAV viremia is transient so blood-borne transmission of
HAV occurs only rarely and therefore donated blood is
not specifically screened for this virus
• Serologic Dx
o Specific antibody against HAV of IgM type appears
in blood at onset of symptoms which constitutes a
reliable marker of acute infection
o Fecal shedding of the virus ends as the IgM titer
rises
o IgM response usually begins to decline in a few
mos. and followed by the appearance of IgG anti-
HAV which persists fore years, perhaps for life,
providing immunity against reinfection by all strains
of HAV
• The cause of “serum hepatitis”
• Can produce:
1) Acute hepatitis
2) Nonprogressive chronic hepatitis
3) Progressive chronic hepatitis ending in cirrhosis
4) Fulminant hepatitis with massive liver necrosis
5) An asymptomatic carrier state, with or without
progressive subclinical dse
6) The backdrop for hepatitis D virus
• Also plays an important role in the development of
Hepatocellular carcinoma
• Unlike HAV, HBV remains in blood during the last stages
of a prolonged incubation period (4 to 26 weeks) and
during active episodes of acute and chronic hepatitis
• Also present in all physiologic and pathologic body fluids
with the exception of stool
• A hardy virus and can withstand extremes of
temperature and humidity
• Whereas blood and body fluids are the primary vehicles
of transmission, virus may also be spread by contact
with body secretions such as semen, saliva, sweat,
tears, breast milk, and pathologic effusions
• Primary risk categories of HBV infection:
o Transfusion
o Blood products
o Dialysis
o Needle-stick accidents among health workers
o Intravenous drug abuse
o Homosexual activity constitute the primary risk
categories for HBV infection
• The source of infection in one-third of pts is unknown
• In endemic regions such as Africa and Southeast Asia,
spread from an infected mother to a neonate during birth
(vertical transmission) is common which often lead to
the carrier state for live
• A member of the Hepadnaviridae, a family of DNA-
containing viruses that cause hepatitis in a multiple
animal species
• The mature HBV virion is a spherical double-layered
“Dane particle” that has an outer surface envelope of
protein, lipid, carbohydrate enclosing a slightly
hexagonal core
• The genome is a partially double stranded circular DNA
molecule
• The organization of HBV genome is unique in that all
regions of the viral genome encode protein sequences:
o A nucleocapsid “core” protein (Hepatitis B core
antigen, HBcAg) and a longer polypeptide transcript
with a precore and core region, designated HBeAg
(hepatitis B e antigen)
o Envelope glycoprotein (HBsAg). Infected
hepatocytes are capable of synthesizing and
secreting massive quantities of noninfective surface
protein (HBsAg)
o A DNA polymerase that exhibits reverse
transcriptase activity, and genomic replication
occurs through an intermediate RNA template
o A protein from the X region (HBX), which is
necessary for virus replication and acts as a
transcriptional transactivator of the viral genes and
a wide variety of host gene promoters. HBX is also
thought to play a key role in the causation of
hepatocellular carcinoma
• HBV infections pass through 2 phases:
1) Proliferative phase
- HBV DNA is present in episomal form, while
formation of complete virions and all associated
antigens
Hepatitis B Virus
- Cell surface expression of viral HBsAg and HBcAg
in association with the MHC class I molecules leads
to activation of cytotoxic CD8+ T lymphocytes and
hepatocytes destruction
2) Integrative phase
- Viral DNA is incorporated into the host genome,
may occur in hepatocytes not destroyed by the
immune response
- With cessation of viral replication and the
appearance of antiviral antibodies, infectivity ends
and liver damage subsides. However, the risk of
hepatocellular carcinoma persists
• Serologic Dx
o After exposure to HBV, the long asymptomatic 4 to
26 week incubation period (mean 6-8 weeks) is
followed by acute dse. lasting many wks. to mos.
o Most pts experience a self-limited illness
 HBsAg appears before the onset of symptoms,
peaks during overt dse, and then declines to
undetectable levels in 3 to 6 mos
  HBeAg, HBV DNA, and DNA polymerase
appear in the serum soon after HBsAg, and all
signifiy active viral replication
 IgM anti-HBc becomes detectable in serum
shortly before the onset of symptoms,
concurrent with the onset of elevated serum
transaminase levels. During the months, the
IgM antibody is replaced by IgG anti-HBc
 Anti-HBe is detectable shortly after the
disappearance of HBeAg, implying that the
acute infection has peaked and the dse is on
the wane
 IgG anti-HBs does not rise until the acute dse
is over and is usually not detectable for a few
wks to several mos after the disappearance of
HBsAg. Anti-HBs may persist for live,
conferring protection; this is the basis for
current vaccination strategies using
noninfectious HBsAg
o Carrier state is defined by the presence of HBsAg in
serum for 6 mos or longer after initial detection. The
presence of HBsAg alone does not necessarily
indicate replication of complete virions, and pts may
be asymptomatic and without liver damage
o In contrast, chronic replication of HBV virions is
characterized by persistence of circulating HBsAg,
HBeAg, and HBV DNA usually with anti-HBc and
occasionally with anti-HBs. Progressive liver
damage may occur in these pts
Hepatitis C Virus
• A major cause of liver dse worldwide
• Main routes of transmission are inoculations and blood
transfusions
• Believed to be the most important cause of transfusion-
associated hepatitis, being responsible for 90% to 95%
of all cases
• Sexual transmission and vertical transmission are
infrequent
• 40% of cases are accounted for sporadic hepatitis of
unknown cause
• Seroprevalence in the US pop. is less than 0.2% but is
higher in house contacts, homosexuals, hemodialysis
pts, hemophiliacs, and IV drug abusers
• Pts with unexplained cirrhosis and hepatocellular
carcinoma have anti-HCV prevalence rates exceeding
50%
• In contrast to HBV, HCV has a high rate of progression
to chronic dse or eventual cirrhosis, exceeding 50%
• Thus, HCV may in fact be the leading infectious cause
of chronic liver dse in the Western world
• HCV and closely related HGV occupy a genius in the
Flaviviridae
• A small, enveloped, single-stranded RNA virus with a
genome that codes for a single polyprotein. This peptide
is subsequently processed into functional proteins
• Inherently unstable, giving rise to multiple types and
subtypes seriously hampering efforts to develop an HCV
vaccine
• Elevated titers of anti-HCV IgG occuriing after an active
infection do not confer effective immunity
• Characteristic feature of HCV infection: repeated bouts
of hepatic damage as a result of reactivation of a
preexisting infection or emergence of an endogenous,
newly mutated strain
• Hallmarks of HCV infection despite the generally
asymptomatic nature of the acute illness:
o Progressive infection
o Chronic hepatitis
• Cirrhosis can be present at the time of dx or may
develop during a period of 5 to 10 yrs
• Serologic Dx:
o Incubation period: from 2 10 26 weeks (mean
between 6 and 12 weeks)
o HCV RNA is detectable in blood for 1 to 6 and 12
wks
o Circulating RNA persists in many pts despite the
presence of neutralizing antibodies, incldg. more
than 90% of pts with chronic dse
o Clinical course is milder than that of HBV but
individual cases may be severe and
indistinguishable from HAV or HBV hepatitis
o A characteristic clinical feature of chronic HCV
infection is episodic elevations in serum
transaminases, with intervening normal or near-
normal periods
o Alternatively, transaminases may be persistently
elevated or may remain normal
Hepatitis D Virus
• Also called the delta agent and hepatitis delta virus
• A unique RNA virus that is replication defective causing
infection only when it is encapsulated by HBsAg
• Although taxonomically distinct from HBV, HDV is
absolutely dependent on the genetic information
provided by HBV for multiplication and causes hepatitis
only in the presence of HBV
• Delta hepatitis arises in two settings:
o Acute coinfection
 Occurs after exposure to serum containing both
HDV or HBV
 HBV must become established first to provide
the HBsAg necessary for development of
complete HDV virions
o Superinfection
 a chronic carrier of HBV with a new inoculum of
HDV (and HBV) results in dse about 30-50
days later
 carrier may be previously “healthy” or may
have had underlying chronic hepatitis
• Simultaneous coinfection with HBV and HDV results in
hepatitis ranging from mild to fulminant, with fulminant
dse more likely (3-4%) than with HBV alone
• Chronicity rarely develops
• 3 possibilities may arise when HDV is superimposed on
chronic HBV infection:
1) Mild HBV hepatitis may be converted into fulminant
dse
2) Acute, severe hepatitis may erupt in a previously
healthy HBV carrier
3) Chronic, progressive dse may develop (in 80% of
pts) often culminating in cirrhosis
• Infection by delta agent is worldwide, but prevalence
varies
• 20-40% of HBsAg carriers have anti-HDV
• In the US, HDV infection is uncommon and largely
restricted to drug addicts and hemophiliacs with
prevalence rates of 1-10%
• Homosexual men and health care workers are at low
risk for HDV infection for unclear reasons
• HDV infection is uncommon in the large population of
HBsAg carriers in Southeast Asia and China
• A 35-nm, double-shelled particle that by electron
microscopy resembles the Dane particle of HBV
• The external coat antigen of HBsAg surrounds as
internal polypeptide assembly, designated delta antigen
(HDAg)
• Serologic Dx:
o HDV RNA is detectable in the blood and liver just
before and in the early days of acute symptomatic
dse
o IgM anti-HDV is the most reliable indicator of recent
HDV exposure, though appearance is late and
frequently short-lived
o Acute coinfection by HDV and HBV is best indicated
by detection of IgM against both HDAg and HBcAg
(denoting new infection with hepatitis B)
o With chronic delta hepatitis arising from HDV
superinfection, HBsAg is present in serum and IgM
anti-HDV persists for mos or longer
Hepatitis E Virus
• An enterically transmitted water-borne infection
• Occurring primarily in young to middle-aged adults
• Sporadic infection and overt illness in children are rare
• Sporadic infection seems to be uncommon and is seen
mainly in travelers
• Characteristic feature of this infection:
o High mortality rate among pregnant women
approaching 20%
• Disease is self-limited in most cases
• It is not associated with chronic liver dse or persistent
viremia
• Average incubation period after exposure is 6 wks
• An unenveloped single-stranded RNA virus structurally
similar to Calciviridae
• A specific antigen (HEV Ag) can be identified in the
cytoplasm of hepatocytes during active infection and
virions are shed in the stool during the acute illness
• Serologic Dx
o HEV RNA and HEV virions can be detected in the
stool and liver before the onset of clinical illness
o The onset of rising serum transaminases, clinical
illness, and elevated IgM anti-HEV titers are
virtually simultaneous
o Symptoms resolve in 2-4 wks, during which time
IgM is replaced with a persistent IgG anti-HEv titer
Other Hepatitis Viruses
• Some cases of hepatitis are caused by infectious agents
according to epidemiologic studies
• A viral agent bearing similiarities to HCV has been
cloned and designated hepatitis G virus (HGV)
• Transfusion related transmission has been documented
• However, HGV appears to be nonpathogenic causing
neither liver dse nor exacerbation of liver dse
• That’s why designation of HGV as a “hepatitis” virus is
may be premature
CLINOCOPATHOLOGIC SYNDROMES
• Clinical syndromes may develop after exposure to
hepatitis virus:
o Acute asymptomatic infection with recovery:
serologic evidence only
o Acute symptomatic hepatitis with recovery: anicteric
or icteric
o Chronic hepatitis: without or with progression to
cirrhosis
o Fulminant hepatitis: with massive to submassive
hepatic necrosis
• Each of the hepatotropic viruses can cause acute
asymptomatic or symptomatic infection
• A small number of HBV-infected patients develop
chronic hepatitis
• HCV is notorious for chronic infection
• HAV and HEV do not cause chronic hepatitis in rare
exceptions
• Fulminant hepatitis is unusual, and almost unheard of
with HCV
• Other infectious or noninfectious causes, particularly
drugs and toxins, can lead to essentially identical clinical
syndromes
• Thus serologic and molecular studies are essential for
the diagnosis of viral hepatitis and the distinction
between the various types.
1. Acute Asymptomatic Infection with Recovery
o Pts in this group are identified only incidentally on
the basis of minimally elevated serum
transaminases or, after the fact, by the presence of
antiviral antibodies.
o HAV and HBV infection worldwide are frequently
subclinical events in childhood, verified only in
adulthood by the presence of anti-HAV or anti-HBV
antibodies
o Though asymptomatic acute infection is most often
the case for HCV-infected patients for whom the
exposure event is not known, recovery and
eradication of the virus are not common
2. Acute Symptomatic Infection with Recovery
o Any of the hepatotropic viruses can cause
symptomatic acute viral hepatitis, although this is
uncommon for acute HCV infection
o Regardless of the agent, the disease is more or less
the same and can be divided into four phases:
(1) an incubation period,
(2) a symptomatic preicteric phase
(3) a symptomatic icteric phase
(4) convalescence
o Incubation period
 Differs in the various viruses
 Peak infectivity occurs during the last
asymptomatic days of incubation period and
early days of acute symptoms
o Preicteric phase
 Marked by nonspecific, constitutional
symptoms
 Malaise is followed in a few days by general
fatigability, nausea, and loss of appetite
 Inconstant symptoms that can also manifest
are weight loss, low-grade fever, headaches,
muscle and joint aches, and pains and diarrhea
 10% of patients with acute hepatitis, most often
those with hepatitis B, develop a serum
sickness-like syndrome (fever, rash, arthralgias
due to circulating immune complexes)
 True origin of these symptoms is suggested by
elevated serum aminotransferase levels
 PE reveals a mildly enlarged, tender liver
 In some patients, the nonspecific symptoms
are more severe, with higher fever, shaking
chills, and headache, sometimes accompanied
by right upper quadrant pain and tender liver
enlargement.
o Icteric phase
 If this appears, is caused mainly by conjugated
hyperbilirubinemia
 Usual in adults with acute HAV infection but not
in children, but is absent in about half the cases
of HBV & majority of HCV cases
 As jaundice appears, these pts enter the icteric
phase
 Other symptoms begin to abate and the pt feels
better
  The jaundice is caused predominantly by
conjugated hyperbilirubinemia and not a result
of biliary obstruction
 Accompanied by a dark-colored urine related to
the presence of conjugated bilirubin
 Stools may become lighter owing to cholestasis
 A distressing pruritus can be experienced due
to retention of bile acids
 Liver may be mildly enlarged and moderately
tender to percussion
 Lab findings
- prolonged prothrombin time
- hyperglobulinemia
- mild elevation of serum alkaline
phosphatase
 Jaundice and most of other systemic symptoms
abates in a few weeks to several mos as
convalescence begins
 Recovery is heralded by the generation of
strong T cell responses against viral antigens
expressed on infected liver cells
o Chronic Hepatitis
 Defined as symptomatic, biochemical, or
serologic evidence of continuing or relapsing
hepatic disease for more than 6 months, with
histologically documented inflammation and
necrosis
 Though hepatitis viruses (HBV, HCV, and HBV
+ HDV) are responsible for most cases of
chronic hepatitis, there are many other causes
of chronic hepatitis
 Other causes: chronic alcoholism, Wilson
disease, α1-antitrypsin deficiency, drugs (e.g.,
isoniazid, α-methyldopa, methotrexate), and
autoimmunity
 In all instances of chronic hepatitis, etiology is
the single most important indicator of likelihood
to progress to cirrhosis
 Chronic viral hepatitis constitutes a "carrier"
state wherein these individuals harbor
replicating virus and can transmit an organism
 With “carriers” of hepatotropic viruses, there
are:
1) those who harbor one or more of the viruses
but are suffering little or no adverse clinical
or histologic effects
2) those who have chronic disease by
laboratory or histologic findings but are
essentially free of symptoms or disability
3) those who have clinically symptomatic
chronic disease
 All constitute reservoirs of infection
 In HBV, early infection particularly via vertical
transmission during childbirth produces a
carrier state of 90-95% of the time
 In contrast, only 1-10% of adult HBV infections
yields a carrier state
 Individuals with impaired immunity are likely to
become HBV carriers because the protective T
cell response does not develop
 This situation is less clear with HDV, although
there is a well-defined low risk of
posttransfusion hepatitis D, indicative of a
carrier state in conjunction with HBV
 HCV can clearly induce a carrier state given its
high rate of chronicity
 Clinical features are extremely variable and are
not predictive of outcome
- some only manifest with persistent
elevations of serum transaminases
- most common symptom: fatigue
- less common symptoms: malaise, loss of
appetite, and occasional bouts of mild
jaundice
 Physical findings:
- spider angiomas
- palmar erythema
- mild hepatomegaly
- hepatic tenderness
- mild splenomegaly
 Lab studies:
- prolongation of prothrombin time
- some instances: hyperglobulinemia,
hyperbilirubinemia, and mild elevations in
alkaline phosphatase levels
 In HBV and HCV, occasionally immune
complex disease may develop secondary to the
presence of circulating antibody-antigen
complexes, in the form of vasculitis
(subcutaneous or visceral) &
glomerulonephritis
 Cryoglobulinemia is found in 35% of pts with
chronic HCV hepatitis
Key Morphologic Features of Viral Hepatitis
Acute Hepatitis
Enlarged, reddened liver; greenish if cholestatic
Parenchymal changes:
Hepatocyte injury: swelling (ballooning degeneration)
Cholestasis: canalicular bile plugs
HCV: mild focal fatty change of hepatocytes
Hepatocyte necrosis: isolated cells or clusters
Cytolysis (rupture) or apoptosis (shrinkage)
If severe: bridging necrosis (portal-portal, central-central,
portal-central)
Lobular disarray: loss of normal architecture
Regenerative changes: hepatocyte proliferation
Sinusoidal cell reactive changes:
Accumulation of phagocytosed cellular debris in Kupffer
cells
Influx of mononuclear cells into sinusoids
Portal tracts:
Inflammation: predominantly mononuclear
Inflammatory spillover into adjacent parenchyma, with
hepatocyte necrosis
Chronic Hepatitis
Changes shared with acute hepatitis:
Hepatocyte injury, necrosis, and regeneration
Sinusoidal cell reactive changes
Portal tracts:
Inflammation:
Confined to portal tracts, or
Spillover into adjacent parenchyma, with necrosis of
hepatocytes ("interface hepatitis"), or
Bridging inflammation and necrosis
Fibrosis:
Portal deposition, or
Portal and periportal deposition, or
Formation of bridging fibrous septa
HBV: "ground-glass" hepatocytes, "sanded" nuclei
HCV: bile duct epithelial cell proliferation, lymphoid
aggregate formation
Cirrhosis: The end-stage outcome
Morphology of Acute and Chronic Hepatitis
ACUTE HEPATITIS
• Hepatocyte injury takes the form of diffuse swelling
("ballooning degeneration"), so cytoplasm looks
empty and contains only scattered eosinophilic
remnants of cytoplasmic organelles
• Cholestasis, an inconstant findings, with bile plugs in
canaliculi and brown pigmentation of hepatocytes
• Canalicular bile plugs result from cessation of the
contractile activity of the hepatocyte pericanalicular actin
microfilament web
• Two patterns of hepatocyte cell death are seen
1) Rupture of cell membranes leads to cytolysis and
focal loss of hepatocytes
- sinusoidal collagen reticulin framework
collapses where the cells have disappeared,
and scavenger macrophage aggregates
mark sites of hepatocyte loss
2) Apoptosis
- more conspicuous
- caused by anti-viral cytotoxic T cells
- Apoptotic hepatocytes shrink, become
intensely eosinophilic, and have fragmented
nuclei; effector T cells may still be present in
the immediate vicinity
- Apoptotic cells also are phagocytosed within
hours by macrophages and hence might be
difficult to find despite a brisk rate of
hepatocyte injury
- In severe cases of acute hepatitis, confluent
necrosis of hepatocytes may lead to
bridging necrosis connecting portal-to-
portal, central-to-central, or portal-to-central
regions of adjacent lobules
- Hepatocyte swelling and regeneration
compress sinusoids
- the more or less radial array of the
parenchyma is lost.
• A characteristic and usually prominent feature of acute
hepatitis: Inflammation
• Kupffer cells undergo hypertrophy and hyperplasia
and are often laden with lipofuscin pigment due to
phagocytosis of hepatocellular debris
• Portal tracts are usually infiltrated with a mixture of
inflammatory cells
• Inflammatory infiltrate may spill over into the adjacent
parenchyma to cause necrosis of periportal hepatocytes;
this "interface hepatitis" can occur in both acute and
chronic hepatitis
• Finally, bile duct epithelia may become reactive and
even proliferate to form poorly defined ductular
structures (ductular reaction), particularly in cases of
HCV hepatitis.
CHRONIC HEPATITIS
• Histo features range from exceedingly mild to severe
• Mildest forms: significant inflammation is limited to portal
tracts and consists of lymphocytes, macrophages,
occasional plasma cells, and rare neutrophils or
eosinophils
• Liver architecture usually well preserved, but smoldering
hepatocyte necrosis throughout the lobule may occur in
all forms of chronic hepatitis
• Even in mild chronic hepatitis due to HCV infection,
common findings are lymphoid aggregates and bile
duct damage in the portal tracts and focally mild to
moderate macrovesicular steatosis
• In all forms of chronic hepatitis: continued interface
hepatitis and bridging necrosis are harbingers of
progressive liver damage
• The hallmark of irreversible liver damage is the
deposition of fibrous
• At first, only portal tracts exhibit increased fibrosis, but
with time, periportal septal fibrosis occurs, followed by
linking of fibrous septa between lobules (bridging
fibrosis)
• Continued loss of hepatocytes and fibrosis results
in cirrhosis, with fibrous septae and hepatocyte
regenerative nodules
• This pattern of cirrhosis characterized by irregularly
sized nodules separated by variable but mostly broad
scars
• Historically, this pattern of cirrhosis has been termed
postnecrotic cirrhosis (but it should be noted that the
this term has been applied to all forms of cirrhosis in
which the liver shows large, irregular-sized nodules with
broad scars, regardless of etiology
• Autoimmune hepatitis, hepatotoxins (carbon
tetrachloride, mushroom poisoning), pharmaceutical
drugs (acetaminophen, α-methyldopa), and even alcohol
may give rise to a cirrhotic liver with irregular-sized large
nodules
• In some cases that come to autopsy, the inciting cause
of the so-called postnecrotic cirrhosis cannot be
determined at all ("cryptogenic cirrhosis")
• Morphology of the end-stage cirrhotic liver is neither
helpful in determining the basis of the liver injury, nor
can it be easily related to any specific set of clinical
circumstances.
Clinical course of Viral hepatitis
• Unpredictable course
• Pts experience spontaneous remission or may have
indolent disease without progression for many years
• However, some have rapidly progressive disease and
develop cirrhosis within a few year
• Major causes of death:
o cirrhosis, with liver failure
o hepatic encephalopathy
o massive hematemesis from esophageal varices
o hepatocellular carcinoma in those with long-
standing HBV (particularly neonatal) or HCV
infection.
Bacterial, Parasitic, and Helminthic Infections
• Extrahepatic bacterial infections particularly sepsis can
induce mild hepatic inflammation and varying degrees of
hepatocellular cholestasis
• The latter is due to effects of proinflammatory cytokines
released by kupffer cells and endothelial cells in
response to circulating endotoxin
• Bacteria that can affect the liver directly:
o Staphylococcus aureus – in toxic shock syndrome
o Salmonella typhi – typhoid fever
o 20 or 30 syphilis
• Bacteria may also proliferate in the biliary tree
compromised by partial or complete obstruction
• Bacterial composition reflects the gut flora, and the
severe acute inflammatory response within the
intrahepatic biliary tree is called ascending cholangitis
• Major causes of morbidity worldwide wherein the liver is
frequently involved are parasitic and helminthic
infections
• Diseases include malaria, schistosomiasis,
strongyloidiasis, cryptosporidiosis, leishmaniasis, and
infections by liver flukes Fasciola hepatica, Clonorchis
sinensis and Opisthorchis viverrini
• Liver abscesses are common in developing countries
and mostly represent parasitic infections (e.g. amebic,
 echinococcal and (less commonly) other protozoal and
helminthic organisms
• Most abscesses are pyogenic, representing a
complication of a bacterial infection elsewhere
• Organisms reach the liver by:
1) the portal vein
2) arterial supply
3) ascending infection in the biliary tract (ascending
cholangitis)
4) direct invasion of the liver from a nearby source
5) a penetrating injury
• Majority of hepatic abscesses used to result from portal
spread of intra-abdominal infections (e.g., appendicitis,
diverticulitis, colitis)
• Morphology
o Pyogenic hepatic abscesses may occur as solitary
or multiple lesions, ranging in size
o Bacterimic spread thru the arterial or portal system
tends to produce multiple small abscesses,
whereas direct extension and trauma usually cause
solitary large abscesses
o Biliary abscesses, usually multiple, may contain
purulent material from adjacent bile ducts
o Gross and microscopic features are those to be
seen in any abscess
o Causative organism occasionally can be identified
in fungal or parasitic abscesses
o Rarely, abscesses located in the subdiaphragmatic
region, particulary amebic, may burrow into the
thoracic cavity producing empyema or a lung
abscess
o Rupture of subcapsular liver abscess can lead to
peritonitis or localized peritoneal abscesses
• Liver abscesses are associated with fever and in most
instances, right upper quadrant pain and tender
hepatomegaly
• Jaundice may result from extrahepatic biliary obstruction
• Surgical drainage is often necessary for larger lesions
while antibiotic therapy may control smaller lesions
• Pts may survive with early recognition and Mx
AUTOIMMUNE HEPATITIS
• A syndrome of chronic hepatitis in pts with a
heterogenous set of immunologic abnormalities
• Histo features are indistinguishable from chronic viral
hepatitis
• Dse may run an indolent or severe course and typically
responds dramatically to immunosuppressive therapy
• Salient features include:
o Female predominance (70%), particularly young to
perimenopausal women
o Absence of viral serologic markers
o Elevated serum IgG levels (>2.5 gm/dl)
o High serum titers of autoantibodies in 80% of cases,
incldg antinuclear, anti-smooth muscle, and
antimitochondrial antibodies
o An increased frequency of HLA-B8 or HLA-DRw3
• Other forms of autoimmune dses present in pts are
Rheumatoid arthritis, thyroiditis, Sjogren syndrome, &
ulcerative colitis
• A subgroup of pts exhibits antibodies either to
liver/kidney microsomes or “soluble liver antigen”
(cytokeratins 8 and 18), suggesting 3 types of
autoimmune hepatitis exist
• Clinical presentation is similar to other forms of chronic
hepatitis
• Autoimmune hepatitis may present in an atypical fashion
with associated dse involving other organ systems,
hampering diagnostic efforts
• Clinical autoimmune hepatitis exhibiting destruction of
bile ducts (“autoimmune cholangitis”) may make
distinction from primary biliary cirrhosis or primary
sclerosing cholangitis
DRUG- AND TOXIN-INDUCED LIVER DISEASE
• The liver is subject to potential damage from an array of
pharmaceutical and environmental chemicals because it
is the major drug metabolizing and detoxifying organ in
the body
• Injury may result:
1) from direct toxicity
2) by hepatic conversion of a xenobiotic to an active
toxin
3) through immune mechanisms (usually by a drug or
metabolite acting as hapten to convert a cellular
protein to an immunogen)
• Drug reactions may be classified as:
o predictable (intrinsic) reactions
 may occur in anyone who accumulates a
sufficient dose
o unpredictable (idiosyncratic) reactions
 depend on idiosyncrasies of the host,
particularly the host’s propensity to mount an
immune response to antigenic stimulus and the
rate of which the host metabolizes the agent
 major examples:
1. chlorpromazine
- agent that causes cholestasis in those pts
who are slow to metabolize it to an
innoculous by product
2. halothane
- can cause a fatal immune-mediated
hepatitis in some pts exposed to this
anesthetic on multiple occasions
• It should be noted that:
o Injury may be immediate or take weeks to mos. to
develop which may present only after severe liver
damage has developed
o Injury may take the form of hepatocytes necrosis,
cholestasis, or insidious onset of liver dysfunction
o Drug-induced chronic hepatitis is clinically and
histologically indistinguishable from chronic viral
hepatitis
o Histologic markers of viral infection are critical for
making the distinction
• Predictable rxns are ascribed to:
o Acetaminophen
o Tetracycline
o Antineoplastic agents
o Amanita phalloides toxin
o Carbon tetrachloride
o Alcohol (certain extent)
• Idiosyncratic reactions are caused by:
o Sulfonamides
o Methyldopa
o Allopurinol
• Reye syndrome
o a potentially fatal syndrome of mitochondrial dysfxn
in liver, brain and elsewhere, occurs predominantly
in children given acetylsalicylic acid (aspirin) for the
relief of virus-induced fever
o features extensive accumulation of fat droplets
within hepatocytes (microvesicular steatosis), is
rare
• Drug-induced liver dse is followed usually by recovery
on removal of drug
• Exposureto a toxin or therapeutic agent should always
be included in the diff. Dx of liver dse
 Alcoholic Liver Disease
• The leading cause of liver dse in most western countries
is excessive alcohol consumption
• Adverse effects of chronic alcohol consumption lead to
development of overlapping forms of liver dse:
1) Hepatic steatosis
2) Alcoholic hepatitis
3) Cirrhosis (collectively referred to as alcoholic liver
dse)
• Morphology
o Hepatic Steatosis (Fatty liver)
 Small (microvesicular) lipid droplets
accumulate in hepatocytes after even moderate
intake of alcohol
 With chronic intake of alcohol, lipid
accumulates to the point of creating large clear
macrovesicular globules, compressing and
displacing the nucleus to the periphery of the
hepatocytes
 Transformation is initially centrilobular, but may
involve the entire lobule in severe cases
 Macroscopic appearance of fatty liver of
chronic alcoholism:
- large (up to 4-6 kg)
- soft organ that is yellow
- greasy
- readily fractured
- though there is little or no fibrosis at the
outset, fibrous tissue develops around the
central veins & extends into the adjacent
sinusoids with continued alcohol intake
 Up to the time that fibrosis appears, fatty
change is completely reversible if there is
abstention from further intake of alcohol
o Alcoholic Hepatitis
 Characterized by:
1. Hepatocyte swelling and necrosis
- single or scattered foci of cells undergo
swelling (ballooning) and necrosis
- swelling results from accumulation of fat
and water and proteins that normally are
exported
2. Mallory bodies
- scattered hepatocytes accumulate tangled
skeins of cytokeratin intermediate
filaments and other proteins, visible as
eosinophilic cytomplasmic inclusions in
degenerating hepatocytes
- inclusions are characteristic of but not
specific feature because they are also
seen in primary biliary cirrhosis, Wilson
dse, chronic cholestatic syndromes,
hepatocellular tumors
3. Neutrophilic reaction
- neutrophils permeate the lobule and
accumulate around degenerating
hepatocytes, part. those having Mallory
bodies
- lymphocytes & macrophages also enter
portal tracts and spill into the parenchyma
4. Fibrosis
- almost always accompanied by a brisk
sinusoidal and periventricular fibrosis
- periportal fibrosis may occasionally
predominate, particulary with repeated
bouts of heavy alcohol intake
- cholestasis and mild deposition of
hemosiderin (iron) in hepatocytes and
Kupffer cells may develop in some cases
 Macroscopic appearance:
- liver is mottled red with bile-stained
areas
- liver may be of normal or increased size
- often contains visible nodules and
fibrosis indicative of evolution to
cirrhosis
o Alcoholic Cirrhosis
 Final and irreversible form of alcoholic liver dse
usually evolves slowly and insidiously
 At first, the cirrhotic liver is yellow-tan, fatty, and
enlarged, usually weighing more than 2 kg
 During the span of years, it is transformed into
a brown, shrunken, less than 1 kg in weight
 Arguably, cirrhosis may develop more rapidly in
the setting of alcoholic hepatitis within 1-2
years
 Initially, developing fibrous septa are delicate
and extend through sinusoids from central vein
to portal regions as well as from portal tract to
portal tract
 Regenerative activity of entrapped
parenchymal hepatocytes regenerates fairly
uniformly sized “micronodules”
 The nodularity becomes more prominent
 Scattered larger nodules create a “hobnail”
appearance on liver surface
 As fibrous septa dissect and surround nodules,
liver becomes more fibrotic loses fat, and
shrinks progressively in size
 Parenchymal islands are engulfed by ever
wider bands of fibrous tissue and liver is
converted to a mixed micronodular and
macronodular pattern
 Ischemic necrosis and fibrous obliteration of
nodules eventually create broad expanses of
tough, pale scar tissue (Laennec cirrhosis)
 Bile statis often develops
 Mallory bodies are rarely evident at this stage
 Thus, end-stage alcoholic cirrhosis comes to
resemble, both micro and macroscopically, the
cirrhosis developing from viral hepatitis and
other causes
• Pathogenesis
o Short-term ingestion of up to 80 gm of ethanol (8
beers or 7 oz of 80-proof liquor) generally produces
mild, reversible hepatic changes, such as fatty liver
o Daily intake of 80 gm or more of ethanol generates
significant risk of severe hepatic injury
o Daily ingestion of 160 gm or more for 10-20 years is
associated more consistently with severe injury
o Only 10-15% if alcoholics, however, develop
cirrhosis
o Reasons are:
 Decreased gastric metabolism of ethanol
 Differences in body composition
 Women are more susceptible to hepatic injury
than are men
 Genetic susceptibility may exist but no reliable
genetic markers of susceptibility have been
identified
o Relationship between hepatic steatosis and
alcoholic hepatitis as precursors to cirrhosis both
causally and temporally is not yet clear
o Cirrhosis may develop without antecedent evidence
of steatosis or alcoholic hepatitis
o In the absence of a clear understanding of the
pathogenic factors influencing liver damage, no
“safe” upper limit for alcohol consumption can be
proposed (despite the current popularity of red
wines for amelioration of CVD)
 o Detrimental effects of alcohol and its byproducts on
hepatocellular function:
 Hepatocellular steatosis results from
1) shunting of normal substrates away from
catabolism and toward lipid biosynthesis
owing to generation of excess NADH by 2
major enzymes of alcohol metabolism,
alcohol dehydrogenase
2) impaired assembly and secretion of
lipoproteins
3) increases peripheral catabolism of fat
 induction of CP450 leads to augmented
transformation of other drugs to toxic
metabolites
 free radicals, generated during microsomal
ethanol-oxidizing system oxidation of alcohol,
react with cellular membranes and proteins
 alcohol directly affects microtubular &
mitochondrial function and membrane fluidity
 acetaldehyde (major intermediate metabolite of
alcohol en route to acetate prod’n) induces lipid
peroxidation and acetaldehyde-protein adduct
formation, further disrupting cytoskeletal and
membrane fxn
 alcohol induces immunologic attack on hepatic
neoantigens, possibly the result of alcohol-
induced or acetaldehyde-induced alteration in
hepatic proteins
o alcohol is food and can become a major calorie
source in the diet of an alcoholic, displacing other
nutrients and leading to malnutrition and vitamin
deficiency (Vit.B12)
o compounded by impaired digestive fxn related to
chronic gastric and intestinal mucosal damage and
pancreatitis
o collagen deposition by perisinusoidal hepatic
stellate cells is a response to many converging
events
 Kupffer cell activation, with release of
proinflammatory cytokines (TNF-α, IL-1 and 6,
TGF-β)
 Amplication of cytokine stimuli by PAF, a
lecithin-related lipid released by endothelial
cells and kupffer cells
 Influx of neutrophils into parenchyma in
response to proinflammatory cytokines, with
release of their noxious substances
o These events are exerted by local toxic effects of
alcohol and by alcohol-induced release of bacterial
endotoxin into portal circulation form a
compromised gut
o Alcohol also induces a vasoconstricting endothelins
from sinusoidal endothelial cells
o Endothelins induce the myofibrolast-like hepatic
stellate cells to contract, decreasing sinusoidal
perfusion and causing regional hypoxia
o Net effect: chronic d/o featuring:
 Steatosis
 Hepatitis
 Progressive fibrosis
 Marked derangement of vascular perfusion
o In essence, alcoholic liver dse can be regarded as a
maladaptive state in w/c cells in liver respond in
increasingly pathologic manner to a stimulus
(alcohol) that originally was marginally harmful
• Clinical course
o Hepatic steatosis
 may become evident as hepatomegaly with
mild elevation of serum bilirubin and alkaline
phosphatase levels
 There may be no clinical or biochemical
evidence of liver dse alternatively
 Alcohol withdrawal and provision of an
adequate diet are sufficient Tx
o Alcoholic hepatitis
 Tends to appear relatively acutely, usually after
a bout of heavy drinking
 Symptoms & lab manifestations may be
minimal or those of fulminant hepatic failure
 Between these 2 extremes are nonspecific
symptoms of malaise, anorexia, weight loss,
upper abdominal discomfort, tender
hepatomegaly
 Lab findings
- hyperbilirubinemia
- elevated alkaline phosphatase levels
- neutrophilic leukocytosis
 acute cholestatic syndrome may appear,
resembling large bile duct obstxn
 may be superimposed on established cirrhosis
 with proper nutrition and total cessation of
alcohol consumption, it may clear slowly
 in some pts, hepatitis persists despite
abstinence and progresses to cirrhosis
o Alcohol cirrhosis
 Manifestations are similar to other forms of
cirrhosis
 Include those of portal Htn (with life-threatening
variceal hemorrhage), jaundice, ascites, other
stigmata (e.g., grossly distended abdomen,
wasted extremities, caput medusae)
 Lab findings reflect developing hepatic
compromise:
- Elevated serum transaminase levels
- Hyperbilirubinemia
- Variable elevation of serum alkaline
phosphatase
- Hypoproteinemia (globulins, albumin, and
clotting factors)
- anemia
 in some instances, liver biopsy may be
indicated
 cirrhosis may be clinically silent discovered
only at autopsy or when stress such as
infection or trauma tips the balance toward
hepatic insufficiency
o Long-term outlook for alcoholics with liver dse is
variable
o 5-year survival approaches to 90% in abstainers
free of jaundice, ascites, or hematemesis; drops to
50% - 60% to those who continue to imbibe
o Causes of death in end-stage alcoholic:
1) hepatic coma
2) massive GI hemorrhage
3) intercurrent infection
4) hepatorenal syndrome after a bout of
alcoholic hepatitis
5) hepatocellular carcinoma
o Nonalcoholic steatohepatitis
 An uncommon condition resembling alcoholic
hepatitis occurring in pts who do not drink
alcohol
 Features liver biopsy findings of steatosis,
mixed inflammatory infiltrate of parenchyma,
Mallory hyaline, sinusoidal fibrosis
 Pts are largely asymptomatic with
abnormalities in biochemical lab test results
 Nonspecific constitutional symptoms may be
present
  Obesity is the most important risk factor
 Type II DM and hypertriglyceridemia are less
common antecedent conditions
 Chief risk is the dev’t of cirrhosis occurring in a
minority of pts
METABOLIC LIVER DISEASE
Nonalcoholic Fatty Liver Disease and Steatohepatitis
• Nonalcoholic fatty liver disease (NAFL) – resembles
alcohol-induced liver disease; occurs in patients who are
not heavy drinkers
• Men and women equally affected
• Strong associations with obesity, dyslipidemia,
hyperinsulinemia and insulin resistane, and overt type 2
diabetes
• Elevated serum aminotransferases and/or gamma
glutamyl transpeptidase values
• Patients are largely asymptomatic; abnormalities only in
biochemical lab tests
• Most common cause of “cryptogenic” cirrhosis
Morphology
• Liver biopsy findings: steatosis, multifocal parenchymal
inflammation, Mallory hyaline, hepatocyte death,
sinusoidal fibrosis
• Large and small vesicles of fat (triglycerides)
accumulation within hepatocytes
• Clinically benign end: no appreciable hepatic
inflammation, hepatocyte death, or scarring
• STEATOHEPATITIS (aka non-alcoholic steatohepatitis)
– intermediate form of liver damage
• CIRRHOSIS – result of years of subclinical progression
of the inflammatory and fibrotic processes.
Hemachromatosis
• Excessive accumulation of body iron – most are
deposited in parenchymal organs such as liver and
pancreas
• Results from a genetic defect causing excessive iron
absorption or as a consequence of parenteral
administration of iron
• Hereditary hemochromatosis – homozygous-recessive
inherited disorder
• Secondary hemachromatosis – acquired forms of
hemochromatosis with known sources of excess iron
• Total body iron pool: 2-6gm in normal adults
o 0.5 gram stored in Liver
 98% in hepatocytes
• In HH: total iron accumulation may exceed 50 gm, over
1/3 accumulates in liver
• Ff features characterize this disease:
o Fully developed cases exhibit: (1)micronodular
cirrhosis in all patients; (2) diabetes mellitus in
75% to 80% of patients; and (3) skin pigmentation
in 75 to 80% of patients
o Iron accumulation is lifelong
 Symptoms first appear in 5th to 6th decades
of life
o Hemochromatosis gene located on the short arm
of chromosome 6 at 6p21.3 close to the HLA
gene locus
 HFE gene – encodes an HLA class I-like
molecule that regulates intestinal
absorption of dietary iron.
 Most common HFE mutation: cysteine-to-
tyrosine substitution at amino acid 282
(called C282Y), which inactivates this 343-
amino-acid-protein.
o Males predominate with slightly earlier clinical
presentation
 Because physiologic iron loss delays iron
accumulation in women
Pathogenesis
• In HH, regulation of intestinal absorption of dietary iron
is lost, leading to net iron accumulation of 0.5 to 1.0
gm/year.
• Disease manifests after 20 gm of storage iron have
accumulated
• Critical site for HFE expression is on the basolateral
surface of the small intestinal crypt epithelial cell
• (see Figure 18-27 pg 909 sa Robbins 7th edition para
mas maintindihan, although ako di ko pa din
naintindihan haha)
o HFE complexes with the transferring receptor,
TfR, enabling the binding of plasma transferring
and its bound iron
o The TfR-Tf-iron complex is endocytosed into the
crypt enterocyte
o Acidification of the endosome releases iron into
the regulatory iron pool of the crypt cell
 This is a sensing mechanism for the
systemic iron balance
o Crypt cells with mutant HFE lack the facilitating
effect on TfR-dependent iron uptake, thus
decreasing the regulatory iron pool in the crypt
cell.
 Small intestinal crypt cells are
preprogrammed to absorb dietary iron
regardless of the systemic iron overload
o Excessive iron appears to be directly toxic to host
tissues by the ff mechanisms:
 Lipid peroxidation via iron-catalyzed free
radical reactions
 Stimulation of collagen formation
 Interactions of reactive oxygen species
and of iron itself, leading to lethal injury or
predisposition to hepatocellular carcinoma
o Most common cause of secondary
hemochromatosis: haemolytic anemias
associated with ineffective erythropoeisis
 Excess iron may result not only from
transfusions, but also from increased
absorption
 Transfusions alone (aplastic anemias) lead
to systemic hemosiderosis -> parenchymal
organ injury tends to occur in extreme
cases
o Alcoholic cirrhosis – often associated with a
modest increase in stainable iron within liver cells
Morphology
• Characterized principally by:
o Deposition of hemosiderin in the following organs
(in decreasing order of severity): liver, pancreas,
myocardium, pituitary gland, adrenal gland,
thyroid and parathyroid glands, joints, and skin
o Cirrhosis
o Pancreatic fibrosis
• In the liver, iron becomes evident first as golden-yellow
hemosiderin granules in the cytoplasm of periportal
hepatocytes
o Stains blue with the Prussian blue stain
• With increasing iron load, there is progressive
involvement of the rest of the lobule, along with bile duct
epithelium and Kupffer cell pigmentation
• Iron is a direct hepatotoxin
• Inflammation is absent
• At this stage, liver is slightly larger than normal, dense,
and chocolate brown
• Fibrous septa develop slowly  leading to micronodular
pattern of cirrhosis in an intensely pigmented liver
• Biochemical determination of hepatic iron concentration
in unfixed tissue – standard for quantitating hepatic iron
content
o In normal individuals: iron content of unfixed liver
is less than 1000 ug per gram dry weight of liver
o Adults with HH: over 10,000 ug iron per gram dry
weightr
o Hepatic iron concentrations in excess of 22,000
ug per gram – associated with fibrosis and
cirrhosis
• Pancreas
o Intensely pigmented
o Diffuse interstitial fibrosis
o May exhibit some parenchymal atrophy
o Hemosiderin is found in both acinar and the islet
cells and sometimes in the interstitial fibrous
stroma
• Heart
o Often enlarged
o Has hemosiderin granules within the myocardial
fibers  producing a striking brown coloration to
the myocardium
o Delicate interstitial fibrosis may appear
• Skin pigmentation
o Attributable to hemosiderin deposition in dermal
macrophages and fibroblasts
o Most results from increased epidermal melanin
production
o Combination of these pigments imparts a
characteristic slate-gray color to the skin
• Joint synovial linings
o Acute synovitis may develop due to hemosiderin
deposition
• Excessive deposition of calcium pyrophosphate
damages the articular cartilage  produces disabling
polyarthritis referred to as PSEUDO-GOUT
• Testes
o Small and atrophic
 Atrophy secondary to a derangement in
the hypothalamic-pituitary axis
o Not usually significantly pigmented
Clinical Features
• More often a disease of males
• Rarely becomes evident before age 40
• Principal manifestations
o Hepatomegaly
o Abdominal pain
o Skin pigmentation (particularly in exposed areas)
o Deranged glucose homeostasis or frank diabetes
mellitus due to destruction of pancreatic islets
o Cardiac dysfunction (arrhythmias,
cardiomyopathy)
o Atypical arthritis
• Some patients, the presenting complaint is
hypogonadism
• Classic triad: pigment cirrhosis with hepatomegaly, skin
pigmentation, and diabetes mellitus
o May not develop until late in the course of the
disease
• Death: may result from cirrhosis or cardiac disease
o A significant cause of death is hepatocellular
carcinoma
o Treatment for iron overload does not remove the
risk for this aggressive neoplasm
• HH can be diagnosed long before irreversible tissue
damage has occurred
• Screening:
o Demonstration of very high levels of serum iron
and ferritin
o Exclusion of secondary causes of iron overload
o Liver biopsy, if indicated
• Screening of family members of probands is important
o Heterozygotes for HH also accumulate excessive
iron, but not to the degree required to cause
significant tissue damage
o Homozygotes may be identified before onset of
clinical disease
• Identification of HFE gene opens the way for genetic
screening, limited by the heterogeneity of mutations in
this disease
• Patients with HH diagnosed in the subclinical,
precirrhotic stage and treated by regular phlebotomy
have a normal life expectancy
Wilson Disease
• Autosomal-recessive
• Marked by the accumulation of toxic levels of copper in
many tissues and organs, principally in the liver, brain,
and eye
• Normal: 40% to 60% of daily ingested copper (2 to 5
mg) is absorbed in the stomach and duodenum and
transported to the liver loosely complexed with albumin
o Free copper dissociates and is taken up into
hepatocytes, where it is incorporated into an a2-
globulin synthesized in the endoplasmic reticulum
to form ceruloplasmin and resecreted into plasma
• Ceruloplasmin accounts for 90% to 95% of plasma
copper
• Circulating ceruloplasmin is desialylted as part of normal
plasma protein aging
o Desialylated ceruloplasmin is endocytosed by the
liver, degraded within lysosomes, and its copper
is excreted into bile
 This is the primary route for copper
elimation
o Estimated total body copper: 50 to 150 mg
• Gene: ATP7B, on chromosome 13, encodes a 7.5 kB
transcript for a transmembrane copper-transporting
ATPase, located on the hepatocyte canalicular
membrane
• Majority of patients are compound heterozygotes
containing different mutations of the Wilson disease
gene on each allele.
• Defective biliary excretion leads to copper accumulation
in the liver in excess of the metallothionein-binding
capacity, causing toxic liver injury through copper-
catalyzed formation of reactive oxygen species.
• Once hepatic capacity for incorporationg copper into
ceruloplasmin is exceeded  sudden onset of critical
illness.
Morphology
• Fatty change: mild to moderate, with vacuolated nuclei
and occasionally, focal hepatocyte necrosis
• Acute hepatitis can exhibit features mimicking acute viral
hepatitis, except for the fatty change
• Chronic hepatitis exhibits moderate to severe
inflammation and hepatocyte necrosis, with
macrovesicular steatosis, vacuolated hepatocellular
nuclei,
o With progression, cirrhosis will develop
• Massive liver necrosis
o Rare manifestation
 o Indistinguishable from that caused by viruses or
drugs
• Excess copper deposition – can be demonstrated by
special stains (rhodanine for copper, orcein stain for
copper-associated protein)
• Demonstration of hepatic copper content in excess of
250 ug per gram dry weight is most helpful for making a
diagnosis
• Brain
o Toxic injury primarily affects the basal ganglia (the
putamen)  atrophy and cavitation
o Develop eye lesions called Kayser-Fleishcer rings
 green to brown deposits of copper in
Descemet’s membrane in the limbus of the
cornea
Clinical Features
• Rarely manifests before 6 years of age
• Most common presentation: acute or chronic liver
disease
• Neuropsychiatric manifestations, such as mild
behavioural changes, frank psychosis, or Parkinson
disease-like syndrome, are the initial features in most of
the remaining cases.
• Biochemical diagnosis: based on a decrease in serum
ceruloplasmin, an increase in hepatic copper content,
and increased urinary excretion of copper
• Early recognition and long-term copper chelation
therapy (as with D-penicillamine) can dramatically alter
the usual progressive downhill course
• Fulminant hepatitis or unmanageable cirrhosis – liver
transplant
a1-Antitrypsin Deficiency
• Autosomal recessive disorder
• Abnormally low serum levels of a1-antitrypsin
o Major function of this protein: inhibition of
proteases, particularly elastase, cathepsin G, and
proteinase 3
• Leads to the development of pulmonary emphysema 
lack of this protein permits tissue-destructive enzymes to
run amok
• Can also cause liver disease, mainly in neonates and
young adults
• Most commonly diagnosed genetic liver disease in
infants and children
a1-Antitrypsin
• Small, 394-amino acid plasma glycoprotein synthesized
predominantly by hepatocytes
• Gene is located on human chromosome 14; very
polymorphic
• General notation: Pi for protease inhibitor and an
alphabetic letter for the position on the gel; two letters
denote the genotype of the two alleles.
o Most common genotype: PiMM (occurs in 90% of
individuals)
o Most common clinically significant mutation: PiZ
 individuals have high risk for developing
clinical disease
Pathogenesis (di ko nagets wahahaha!)
• Normal: The mRNA is translated and the protein is
synthesized and secreted
• Deficiency variants: selective defect in migration of this
secretory protein from the ER to Golgi apparatus
o Most marked for the PiZ polypeptide
o Mutant polypeptide is abnormally folded, and
polymerizes, causing its retention in the ER
• All individuals with the PiZZ genotype accumulate
a1,AT-Z in the ER of hepatocytes
• Only 10% of PiZZ individuals develop clinical liver
disease
o They exhibit lags in the ER protein degradation
pathway  designed to degrade abnormally
folded or unassembled polypeptidees
• The intense autophagocytic response stimulated within
hepatocytes: chief cause of liver injury, possibly by
autophagocytosis of mitochondria.
Morphology
• Characterized by the presence of round-to-oval
cytoplasmic globular inclusions in hepatocytes
o In routine H and E stains – acidophilic and
indistinctly demarcated from the surrounding
cytoplasm
• Globules are also present in diminished size and
number in intermediate deficiency states
• Distinctive feature: the PAS-positive globules
• Infrequently, fatty change and Mallory bodies are
present
• Diagnostic a1-antitrypsin globules may be absent in
young infant
Clinical Features
• Neonatal hepatitis with cholestatic jaundice appears in
10-20% of newborns with the deficiency
• Adolescence: presenting symptoms may be related to
hepatitis or cirrhosis
• The disease may remain silent until cirrhosis appears in
middle to later life
• Hepatocellular CA may develop in 2-3% of PiZZ adults
• Treatment and cure for severe hepatic disease:
orthotopic liver transplantation
• In patients with pulmonary disease: avoid cigarette
smoking  can accelerate the destructive lung disease
associated with a1-antitrypsin deficiency.
Neonatal Cholestasis
• Prolonged conjugated hyperbilirubinemia in neonate
• Affects approx 1 in 2500 live births
• Major conditions causing it:
o Cholangiopathies, primarily biliary atresia
o A variety of disorders causing conjugated
hyperbilirubinemia in the neonate (collectively
called neonatal hepatitis)
o Table 18-10 pg 912
• Affected infants: jaundice, dark urine, light of acholic
stools, and hepatomegaly
• Idiopathic neonatal hepatitis represents up to 50% of
cases, biliary atresia another 20%, and a1-antitrypsin
deficiency represents 15%
Morphology
• Morphologic features of neonatal hepatitis:
o Lobular disarray with focal liver cell necrosis
o Panlobular giant cell transformation of
hepatocytes and formation of hepatocyte
“rosettes”: radially arrayed hepatocytes
o Prominent hepatocellular and canalicular
cholestasis
o Mild mononuclear infiltration of the portal areas
o Reactive changes in the Kupffer cells
o Extramedullary hematopoiesis
INTRAHEPATIC BILIARY TRACT DISEASE
Secondary Biliary Cirrhosis

• Prolonged obstruction of the extrahepatic biliary tree
• Most common cause of obstruction in adults:
extrahepatic cholelithiasis, followed by malignancies of
the biliary tree or head of the pancreas and strictures
resulting from previous surgeries
• Obstructive conditions in children:
o Biliary atresia
o Cystic fibrosis
o Choledochal cysts
o Syndromes in which there are insufficient
intrahepatic blie ducts
• Secondary inflammation initiates periportal fibrosis,
which eventually leads to hepatic scarring and nodule
formation, generating secondary biliary cirrhosis
• Subtotal obstruction may promote secondary bacterial
infection of the biliary tree  aggravates the
inflammatory injury
• Enteric organisms (colifroms and enterococci) –
common culprits
Morphology
• End-stage obstructed liver: extraordinary yellow-green
pigmentation and is accompanied by marked icteric
discoloration of body tissues and fluids
• On cut surface: liver is hard, with finely granular
appearance
• Histology:
o Coarse fibrous septae that subdivide the liver in a
jigsaw-like pattern
o Embedded in the septa are distended small and
large bile ducts, contain inspissated pigmented
material
• Cholestatic feature in the parenchyma may be severe,
with extensive feathery degeneration and formation of
bile lakes
• Once regenerative nodules have formed, bile stasis may
become less conspicuous.
• Ascending bacterial infection incites a robust
neutrophilic infiltration of bile ducts
• Severe pylephlebitis and cholangitic abscesses may
develop
Primary Biliary Cirrhosis
• Chronic, progressive, often fatal cholestatic liver
disease, characterized by the destruction of intrahepatic
bile ducts, portal inflammation and scarring, and the
eventual development of cirrhosis and liver failure
• Primary feature: nonsuppurative, inflammatory
destruction of medium-sized intrahepatic bile ducts
• Primarily, a disease of middle-aged women
• Female:male predominance in excess of 6:1
• Age of onset: 20-80 years; peak incidence: 40-50 years
• Onset is insidious; presents with pruritus; jaundice
develops later
• Hepatomegaly is typical
• Xanthomas and xanthelasmas arise owing to cholesterol
retention
• Late features: stigmata of chronic liver disease
• Over a period of two or more decades: develop hepatic
decompensation, including portal hypertension with
variceal bleeding and hepatic encephalopathy
• Serum alkaline phosphatase and cholesterol: elevated
• Hyperbilirubinemia: late development; signifies incipient
hepatic decompensation
• 90% of patients: presence of circulating
“antimitochondiral antibodies”
o These antibodies are against the E2 subunit of
the pyruvate dehydrogenase complex (PDC-E2),
dihydrolipoamide acetyltransferase
o Enzyme complex is located on the inner face of
the inner mitochondrial membrane  well-
shileded from circulating antibodies in
undamaged hepatocytes
Pathogenesis
• Auto-immune etiology
o Includes aberrant expression of MHC class II
molecules on bile duct epithelial cells and
accumulation of autoreactive T cells around bile
ducts
• Antibodies against other cellular components (nuclear
pore proteins, centomeric proteins, etc) are also
produced
• Has extrahepatic manifestations of autoimmunity
o Sicca complex of dry eyes and mouth (Sjogren
syndrome; Latin sicca meaning dryness)
o Scleroderma
o Thyroiditis
o Rheumatoid arthritis
o Raynaud phenomenon
o Membranous glomerulonephritis
o Celiac disease
• Etiology and inciting triggers of primary biliary cirrhosis
are not clear
Morphology
• Prototype of conditions leading to small-duct biliary
fibrosis and cirrhosis
• Focal and variable disease
o Different degrees of severity in different portions
of the liver
• Precirrhotic Stage
o Portal tracts are infiltrated by a dense
accumulation of lymphocytes, macrophages,
plasma cells, and occasional eosinophils
o Terminal and conducting bile ducts are infiltrated
by lymphocytes; may exhibit noncaseating
granulomatous inflammation and undergo
progressive destruction
• The obstruction to intrahepatic bile flow leads to
progressive secondary hepatic damage
o Portal tracts upstream from damaged bile ducts
exhibit bile ductular proliferation, inflammation,
and necrosis of the adjacent periportal hepatic
parenchyma
o Parenchyma develops generalized cholestasis
• Relentless portal tract scarring and bridging fibrosis lead
to cirrhosis
• Macroscopically:
o As disease progresses, bile stasis stains the liver
green
o Capsule remains smooth and glistening until a
fine granularity appears  culminates in a well-
developed, uniform micronodularity
o Liver weight: first, normal to increased (due to
inflammation); ultimately, liver weight is slightly
decreased
• Most cases, end-stage picture is indistinguishable from
secondary biliary cirrhosis or the cirrhosis that follows
chronic hepatitis from other causes
Clinical Features
• Onset is extremely insidious, may be symptom free for
many years
• Pruritis, fatigue, and abdominal discomfort develop,
followed by secondary features: xanthomas and
 xanthelasmas, steatorrhea, and malabsorption-related
osteomalacia and/or osteoporosis
• Entry into end-stage of disease: general features of
jaundice and hepatic decompensation, including portal
hypertension and variceal bleeding
• Major cause of death: liver failure
o Followed by massive variceal hemorrhage and
intercurrent infection
Primary Sclerosing Cholangitis
• Characterized by inflammation and obliterative fibrosis
of intrahepatic and extrahepatic bile ducts, with dilation
of preserved segments
• There is “beading” of a barium column in radiographs of
the intrahepatic and extrahepatic biliary tree
o Due to irregular strictures and dilations of affected
bile ducts
• Commonly seen in association with inflammatory bowel
disease, particularly chronic ulcerative colitis
• Prevalence of primary sclerosing cholangitis in
ulcerative colitis patients: 4%
• Tends to occur in third through fifth decades of life
• Males predominate, 2:1
Pathogenesis
• Cause is unknown
• Key events:
o Secretion of proinflammatory cytokines by
activated hepatic macrophages
o Followed by infiltration of T cells into the stroma
immediately around bile ducts
Morphology
• Fibrosing cholangitis of bile ducts, with a lymphocytic
infiltrate, progressive atrophy of the bile duct epithelium,
and obliteration of the lumen
• Onion-skin fibrosis – concentric periductal fibrosis
around affected ducts
o Followed by solid, cordlike fibrous scar
• In between areas of progressive stricture, bile ducts
become ecstatic and inflamed
o Result of downstream obstruction
• As disease progresses, liver becomes markedly
cholestatic  culminates in biliary cirrhosis
Clinical Features
• There is persistent elevation of serum alkaline
phosphatase
• Progressive fatigue, pruritus, and jaundice may develop
• Autoantibodies are present in less than 10% of patients
• Severely afflicted patients: symptoms associated with
chronic liver disease such as weight loss, ascites,
variceal bleeding, and encephalopathy
• Has increased risk for cholangiocarcinoma
• Definitive treatment: liver transplantation
Anomalies Of The Biliary Tree (Including Liver Cysts)
• Lesions may be found during radiographic studies or at
autopsy or may become manifest as
hepatosplenomegaly and portal hypertension in the
absence of hepatic dysfunction
• Four distinct lesions have been described
Morphology
Von Meyenburg Complexes
• Close to or within portal tracts: small clusters of
modestly dilated bile ducts embedded in a fibrous,
sometimes hyalinized stroma
• Free of pigmented material
• Arise from residual embryonic bile duct remnants
• Occasionally, triangular bile duct hamartoma may lie
under Glisson’s capsule
Polycystic Liver Disease
• Liver contains multiple diffuse cystic lesions
• Cysts are lined by cuboidal or flattened biliary epithelium
and contain straw-colored fluid
• Do not contain pigmented material
• Detached from the biliary tree
• Occasionally, liver cysts of biliary origin are identified,
more commonly in women
Congenital Hepatic Fibrosis
• Portal tracts are enlarged by irregular and broad bands
of collagenous tissue, forming septa and dividing the
liver into irregular islands
• Variable numbers of abnormally shaped bile ducts are
embedded in the fibrous tissue
• Bile duct remnants are distributed along the septal
margin
o Sometimes, curved bile duct profiles are arranged
in a concentric circle around portal tracts
• The increased number of bile ducts profiles are in
continuity with the biliary tree
• Anomaly arises because of persistence of a malformed
embryonic form of the biliary tree
Caroli Disease
• Larger ducts of the intrahepatic biliary tree are
segmentally dilated and may contain insipissated bile
• Pure forms are rare
• Usually associated with portal tract fibrosis of the
congenital hepatic fibrosis type
Clinical Features
• Von Meyenburg Complexes are common and usually
without clinical significance
• Polycystic liver disease may develop abdominal
tenderness or pain in stooping
o Occasionally, requires surgical intervention
o Slight female predilection
o Presentation common during pregnancy
• Patients with congenital hepatic fibrosis rarely develop
cirrhosis
o May still face complications of portal
hypertension, particularly bleeding varices
• Caroli disease is frequently complicated by intrahepatic
cholelithiasis, cholangitis, and hepatic abscesses, also
portal hypertension
o Has an increased risk of cholangiocarcinoma
• Each of these 4 conditions appears to arise from
intrinsic anomalies in the development of the smaller to
larger portions of the intrahepatic biliary tree
• (fig 18-33 pg 916) Well-documented association of
autosomal-dominant polycystic kidney disease with
polycystic liver disease
o Liver cyst in isolation or in abundance represent
the most frequent extra-renal manifestation of
autosomal-dominant polycystic kidney disease
and occur in most patients
• Congenital hepatic fibrosis is strongly associated with
the autosomal-recessive form of polycystic kidney
disease
• Alagille syndrome – syndromatic paucity of bile ducts
o Uncommon autosomal-dominant condition
o Liver is almost normal, but portal tract bile ducts
are completely absent
o Cause by mutations in the gene Jagged1 on
chromosome 20p, a cell-surface protein that
functions as a ligand for the Notch
transmembrane receptors
 o Jagged1:Notch signalling pathway – regulates
cell fate and involved in the development of liver,
heat, skeleton, eye, face, and kidney
o Patients exhibit extrahepatic features: peculiar
facies, vertebral anomalies, and CV defects
o Can survive into adulthood; but at risk for hepatic
failure and hepatocellular CA
CIRCULATORY DISORDERS
IMPAIRED BLOOD FLOW INTO THE LIVER
Hepatic Artery Compromise
• Thrombosis or compression of an intrahepatic branch of
the hepatic artery by embolism, neoplasia, polyarteritis
nodosa, or sepsis may result in a localized infarct that is
usually anemic and pale-tan or sometimes hemorrhagic
• Hepatic artery thrombosis in a transplanted liver leads to
infarction of the major ducts of the biliary tree and loss of
the organ
Portal Vein Obstruction and Thrombosis
• Occlusive disease of the portal vein or its major radicles
produces abdominal pain, ascites, and other
manifestations of portal hypertension (principally
esophageal varices which are prone to rupture)
o Ascites is often massive and intractable
• Acute impairment of visceral blood flow leads to
profound congestion and bowel infarction
• Extrahepatic portal vein obstruction may arise from:
o Banti Syndrome – subclinical occlusion of the
portal vein presents as variceal bleeding and
ascites
o Intra-abdominal sepsis leading to pylephlebitis in
the splanchnic circulation
o Thrombogenic disorders
o Trauma
o Pancreatitis that initiates vein thrombosis which
propagates into the portal vein
• Acute thrombosis of an intrahepatic portal vein radicle
results in a sharply demarcated area of red-blue
discoloration (infarct of Zahn)
o No necrosis; with severe hepatocellular atrophy
and marked hemostasis in distended sinusoids
• Idiopathic portal hypertension is a chronic, generally
bland condition of impaired portal vein inflow and
noncirrhotic portal hypertension
o May be associated with hypercoagulability of the
blood, myeloproliferative disorders, peritonitis, or
chronic exposure to arsenicals
o Histologic manifestation: hepatoportal sclerosis
 dense fibrosis of intrahepatic portal tracts with
obliteration of portal vein channels
IMPAIRED BLOOD FLOW THROUGH THE LIVER
• Most common cause: cirrhosis
• Physical occlusion of the sinusoids occur in a small but
striking group of diseases
• Sickle cell disease: hepatic sinusoids may become
packed with sickled erythrocytes, both free within the
vascular space and phagocytosed by Kupffer cells
o Leads to panlobular parenchymal necrosis
• DIC: may occlude sinusoids
o Periportal sinusoidal occlusion and parenchymal
necrosis may arise in pregnancy as part of
eclampsia
• Metastatic tumor cells may fill the hepatic sinusoids in
the absence of a mass lesion
• The obstruction to blood flow and massive necrosis of
hepatocytes can lead to fulminant hepatic failure
Passive Congestion and Centrolobular Necrosis
• Considered together because they represent a
morphologic continuum
o Both changes are commonly seen at autopsy
because there is an element of pretermed
circulatory failure with every death
• The only clinical evidence of centrilobular necrosis or its
variants is mild to moderate transient elevation of serum
aminotransferases
• Parenchymal damage: can induce mild to moderate
jaundice
Morphology
• Right-sided cardiac decompensation leads to passive
congestion of the liver
o Liver is slightly enlarged, tense, and cyanotic with
rounded edges
o Microscopically: congestion of centrolobular
sinusoids
o With time: centrolobular hepatocytes become
atrophic  results in markedly attenuated liver
cell cords
• Left-sided cardiac failure or shock
o May lead to hepatic hypoperfusion and hypoxia
• Hepatocytes in the central region of the
lobule undergo ischemic coagulative
necrosis (centrolobular necrosis)
• Hypoperfusion + retrograde congestion = centrolobular
hemorrhagic necrosis
o Liver has mottled appearance reflecting
hemorrhage and necrosis in the centrilobular
regions  known as nutmeg liver
o Microscopically: sharp demarcation of viable
periportal and necrotic pericentral hepatocytes,
with suffusion of blood through the centrilobular
region
• Uncommon complication of severe congestive heart
failure: cardiac sclerosis
o Pattern of liver fibrosis is distinctive, mostly
centrilobular
Peliosis Hepatis
• Rare condition in which sinusoidal dilation is primary
• Most commonly associated with exposure to anabolic
steroids, and rarely, oral contraceptives and danazol
o Pathogenesis is unknown
• Clinical signs are generally absent
• Potentially fatal intra-abdominal hemorrhage or hepatic
failure may occur
• Lesions usually disappear after cessation of drug
treatment
HEPATIC VENOUS OUTFLOW OBSTRUCTION
Hepatic Vein Thrombosis and Inferior Vena Cava
Thrombosis
• Obstruction of a single main hepatic vein by thrombosis
is clinically silent
• Obstruction of 2 or more major hepatic vein produces
liver enlargement, pain, and ascites  called the Budd-
Chiari syndrome
o Caused by increased intrahepatic blood pressure
and an inability of the massive hepatic blood flow
to shunt around the blocked outflow tract
• Hepatic vein thrombosis is associated with primary
myeloproliferative disorders, inherited disorders of
coagulation, antiphospholipid syndrome, paroxysmal
nocturnal hemoglobinuria, and intra-abdominal cancers
• Occurance in pregnant women or those taking OCPs is
usually through interaction with an underlying
thrombogenic disorder
• 10% of cases: idiopathic in origin
• Separate distinction is made for inferior vena cave
thrombosis at its hepatic portion (obliterative
heptocavopathy)
o Frequently idiopathic
o Nepal: endemic
• Mortality if untreated: high
• Prompt surgical creation of a portosystemic venous
shunt: revese flow through the portal vein, improves
prognosis
• In the case of vena caval thrombosis, direct dilation of
caval obstruction may be possible during angiography
• Chronic forms are far less lethal, over 2/3 of patients are
alive after 5 years
Morphology
• Liver is swollen and red-purple and has a tense capsule
• Microscopically:
o The affected hepatic parenchyma reveals severe
centrilobular congestion and necrosis
• Centrilobular fibrosis: develops when thrombosis is
slowly developing
• Major veins may contain totally occlusive fresh thrombi,
subtotal occlusion, or in chronic cases, organized
adherent thrombi
• Thrombosis of obliterative hepatocavopathy may heal to
leave only an incomplete membranous web protruding
into the lumen of the inferior vena cava
Veno-Occlusive Disease (Sinusoidal Obstruction
Syndrome)
• Occurs primarily in the immediate weeks following bone
marrow transplantation
• Incidence: 25% in recipients of allogeneic marrow
transplants; mortality: over 30%
• Diagnosis: made on clinical grounds only (tender
hepatomegaly, ascites, weight gain, and jaundice)
o High risk of liver biopsy in these patients
• Arises from toxic injury to the sinusoidal epithelium
o Cells round up and slough off the sinusoidal wall,
embolizing downstream and obstructing
sinusoidal blood flow
o Accompanied by passage of erythrocytes into the
space of Disse and downstream accumulation of
cellular debris in the terminal hepatic vein
o It is followed by proliferatin of perisinusoidal
stellate cells and subendothelial fibroblasts in the
terminal hepatic vein, with deposition of
extracellular matrix
• Obliterative changes in the terminal hepatic vein are
secondary to sinusoidal damage  alternative name:
sinusoidal obstructive syndrome
• 70-85% of patients recover spontaneously
• Treatment: largely supportive
Morphology
• Characterized by obliteration of hepatic vein radicles by
varying amouns of subendothelial swelling and fine
reticulated collagen
• Acute disease, there is striking centrolobular congestion
with hepatocellular necrosis and accumulation o
hemosiderin-laden macrophages
• As the disease progresses, obliteration of the lumen of
the venule is easily identified by using special stains for
connective tissue
• Chronic or healed veno-occlusive disease:
o Dense perivenular fibrosis radiating out into the
parenchyma, frequently with total obliteration of
the venule
o Hemosiderin deposition is evident in the scar
tissue
o Congestion is minimal
HEPATIC DISEASE ASSOCIATED WITH PREGNANCY
• Most common cause of jaundice in pregnancy: viral
hepatitis (HAV, HBV, HCV, and HBV+HDV)
o Pregnancy does not specifically alter the course
of the liver disease, except hepatitis E viral
infection  runs a more severe course in
pregnant patients, fatality rates of 10-20%
• Unique and very small subgroup develop hepatic
complications directly attributable to pregnancy:
preeclampsia, acute fatty liver of pregnancy, and
intrahepatic cholestasis of pregnancy
o Extreme cases of the first 2 conditions is fatal
Preeclampsia and Eclampsia
• Preeclampsia
o Affects 7-10% of pregnancies
o Characterized by maternal hypertension,
proteinuria, peripheral edema, coagulation
abnormalities, and varying degrees of DIC
• Eclampsia
o When hyperreflexia and convulsions occur
o May be life threatening
• Subclinical hepatic disease may be the primary
manifestation of preeclampsia, as part of a syndrome of
hemolysis, elevated liver enzymes, and low platelets 
HELLP syndrome
• Patients with hepatic involvement in preeclampsia may
exhibit modest to severe elevation of serum
aminotrasnferases and mild elevation of serum bilirubin
• Definitive treatment in severe cases: termination of
pregnancy
o Mild cases: managed conservatively
• Those who survived severe preeclampsia recover
without sequelae
Morphology
• Affected liver in preeclampsia is normal in size, firm, and
pale, with small red patches due to hemorrhage
• Occasionally, yellow or white patches of ischemic
infarction can be seen
• Microscopically:
o Periportal sinusoids contain fibrin deposits with
hemorrhage into the space of Disse  leads to
periportal hepatocellular coagulative nerosis
• Blood under pressure may coalesce and expand to form
a hepatic hematoma
o Dissection of blood under Glisson’s capsule: may
lead to hepatic rupture
Acute Fatty Liver of Pregnancy
• Present in later half of pregnancy, usually in the 3rd
trimester
• Symptoms are directly attributable to incipient hepatic
failure, including bleeding, nausea and vomiting,
jaundice, and coma
• Can progress within days to hepatic failure and death
• Primary treatment: termination of pregnancy

Morphology
• Diagnosis rests on biopsy identification of the
characteristic microvesicular fatty transformation of
hepatocytes
• In severe cases: lobular disarray with hepatocyte
dropout, reticulin collapse, and portal tract inflammation
• Diagnosis depends on:
o High index of suspicion
o Confirmation of microvesicular steatosis using
special stains for fat (oil-red-O or Sudan black) on
frozen tissue sections
 Electron microscopy can ale be used for
steatosis
Intrahepatic Cholestasis of Pregnancy
• Onset of pruritus in the 3rd trimester, followed by
darkening of urine and occasionally light stools and
jaundice heralds the development of this syndrome
• Serum bilirubin (conjugated mostly) rarely exceeds
5mg/dl
• Alkaline phosphatase may be slightly elevated
• Liver biopsy: mild cholestasis without necrosis
o Altered hormonal state of pregnancy appears to
combine with biliary secretion defects to
engender cholestasis
• Generally a benign condition
o But mother is at risk for gallstones and
malabsorption
o Incidence of fetal distress, stillbirth, and
prematurity is modestly increased
HEPATIC COMPLICATIONS OF ORGAN OR BONE
MARROW TRANSPLANTATION
Drug Toxicity After Bone Marrow Transplantation
• Describes a syndrome of hepatic dysfunction following
the cytotoxic therapy administered to patients just prior
to bone marrow transplantation
• Affects up to one half of patients
• Characterized by weight gain, tender hepatomegaly,
edema, ascites, hyperbilirubinemia, and a fall in urinary
sodium excretion
• Onset: days immediately following the transplantation
• A spectrum of centrolobular necrosis and inflammatory
changes is encountered  culminates in veno-occlusive
disease
• Clinical outcome is directly related to the severity of liver
toxicity
• Persistent severe liver dysfunction: fatal outcome,
succumbs to septicemia, pneumonia, bleeding, and/or
multiorgan failure
Graft-Versus-Host Disease and Liver Rejection
• Liver transplants are reasonable tolerated by recipients
o This is because the transplanted liver carries
many donor lymphocytes, establishing a state of
chimerism in the recipient
 Prevents the recipient’s immune system
from reacting against donor alloantigens
Morphology
• Acute graft-versus-host disease (10-50 days after
transplant)
o Liver damage is dominated by direct attack of
donor lymphocytes on epithelial cells and
inflammation of the parenchyma and portal tracts
• Chronic graft-versus-host disease (more than 100 days
after)
o Portal tract inflammation
o Selective bile duct destruction
o Eventual fibrosis
• Portal vein and hepatic vein radicles may exhibit
endothelitis  subendothelial lympocytic infiltrate lifts
the endothelium from its basement membrane
• Cholestasis seen in both acute and chronic
• Acute cellular rejection
o Characterized by infiltration of a mixed population
of inflammatory cells into portal tracts, bile duct
and hepatocyte injury, and endothelitis
• Chronic rejection
o Severe obliterative arteritis of small and large
arterial vessels results in ischemic changes in the
liver parenchyma
o Bile ducts are progressively occluded  due to
direct attack or obliteration of their arterial supply
• Both may lead to loss of the graft
Nonimmunologic Damage to Liver Allografts
• Revascularization and prefusion of the donor liver may
result in preservation injury
o Attributable to generation of oxygen radicals in a
hypoxic organ with insufficient reserves of oxygen
scavengers to prevent damage
o Leads to sinusoidal endothelial injury and Kuppfer
cell activation, neutrophil adhesion, platelet
aggregation, and local cytokine release
• Hepatocyte ballooning and cholestasis follow, with
variable degrees of centrilobular necrosis
• Severe injury: portal tracts are damaged  cause
inflammation, bile duct proliferation, and fibrosis
• Hepatic artery thrombosis – sufficiently severe vascular
insult to cause severe compromise in the transplanted
liver
• Portal vein thrombosis may be insidious and present
only as variceal hemorrhage weeks to months later
• Bile duct obstruction – from stricture at the anastomosis
with the native common bile duct
TUMORS AND TUMOR-LIKE CONDITIONS
• The most common hepatic neoplasms are metastatic
carcinomas
• Important in the differential diagnosis of hepatic masses
are
1. whether there is underlying liver disease, especially
cirrhosis, in which there is a greater risk for primary
hepatocellular carcinoma
2. whether the mass is solitary or multiple
Benign Tumors
• The most common benign lesions are cavernous
hemangiomas
- These well-circumscribed lesions consist of
endothelial cell-lined vascular channels and
intervening stroma
- They appear as discrete red-blue, soft nodules,
usually less than 2 cm in diameter, often, directly
beneath the capsule
• Focal nodular hyperplasia – a well-demarcated but
poorly encapsulated nodule with a central fibrous scar
ranging up to many cm. in diameter
 - Believed to represent nodular regeneration in
response to local vascular injury and is not a
neoplasm per se
• Liver cell adenoma – occur in women of childbearing
age who have used OCPs
- These tumors may be pale, yellow-tan or bile-
stained, well-demarcated nodules found anywhere
in the hepatic substance but often beneath the
capsule
- Composed of sheets and cords of cells that may
resemble normal hepatocytes or have some
variation in cell and nuclear size
- Portal tract are absent, instead, prominent arterial
vessels and draining veins are distributed through
the substance of the tumor
- Significant for 2 reasons:
1. when they present as an intrahepatic mass
2. subcapsular adenomas are at risk for rupture,
particularly during pregnancy (under estrogenic
stimulation), causing life-threatening
intraabdominal hemorrhage
Primary Carcinoma of the Liver
• Most arise from hepatocytes and are termed
hepatocellular carcinoma (HCC)
• Much less common are carcinomas of bile duct origin
(cholangiocarcinomas) or tumors that are a mixture of
the 2 cell types
• Two rare forms are:
1. Hepatoblastoma - an aggressive hepatocellular
tumor of childhood
2. Liver angiosarcoma – associated with exposure to
vinyl chloride, arsenic, or Thorotrast
Pathogenesis
• Three major etiologic associations have been
established:
1. infection with HBV
2. chronic liver disease (including HCV and alcohol)
3. hepatocarcinogens in food (aflatoxin)
• Many factors including age, sex, chemicals, viruses,
hormones, alcohol, and nutrition, interact in the
development of HCC.
• Rare hereditary tyrosinemia most likely give rise to HCC
• Cirrhosis appears to be an important but not requisite
contributor to HCC
• Extensive epidemiologic evidence links chronic HBV
infection with liver cancer, and there is a strong evidence
implicating HCV infection
- Repeated cycles of cell death and regeneration, as
occurs in chronic hepatitis from any cause, are
important in the pathogenesis of liver cancers
- The accumulation of mutations during continuous
cycles of cell division may eventually transform
some hepatocytes. Genomic instability is more
likely in the presence of integrated HBV DNA,
giving rise to chromosomal aberrations such as
deletions, translocations, and duplications
- Molecular analysis of tumor cells in HBV-infected
individuals reveals that each case is clonal with
respect to HBV DNA integration pattern suggesting
that viral integration precedes or accompanies a
transforming event
- The HBV genome encodes a regulatory element,
the HBV X-protein that is a transacting
transcriptional activator of many genes and is
present in most tumors with integrated HBV DNA. It
appears that in liver cells infected with HBV, the
HBV X-protein disrupts normal growth control by
activation of host cell protooncogenes and
disruption of cell cycle control. It also exerts anti
apoptotic effects.
- As with human papillomaviruses, some studies
suggest that certain HBV proteins bind to and
inactivate the tumor suppressor gene TP53
• Aflatoxins – derived from the fungus Aspergillus flavus
found in “moldy” grains and peanuts
- Bind covalently with cellular DNA and cause
mutations in protooncogenes or tumor suppressor
genes, particularly TP53
• Cholangiocarcinoma – only recognizes causal
influences are primary sclerosing cholangitis, chronic
infection of the biliary tract by the liver fluke Opisthorchis
sinensis and previous exposure to Thorotrast
Morphology
• Primary liver carcinomas appear grossly as:
1. unifocal – massive tumor
2. multifocal – widely distributed nodules of variable
size
3. diffusely infiltrative – permeating widely and
sometimes involving the entire liver
• Discrete tumor masses are usually yellow-white,
punctuated sometimes by bile staining and areas of
hemorrhage or necrosis
• All patterns of HCC have a strong propensity for
invasion of vascular channels
• Snakelike masses of tumor invade the portal vein (with
occlusion of the portal circulation) or inferior vena cava
extending to the right side of the heart
• Histologically, HCCs range from well-differentiated
lesions with hepatocytes arranged in cords or small
nests to poorly differentiated lesions made up of large
multinucleated anaplastic tumor giant cells
• Globules of bile may be found within the cytoplasm of
cells and pseudocanaliculi between cells
• Acidophilic hyaline inclusions may be present
resembling Mallory bodies
• Fibrolamellar carcinoma – single, large, hard “scirrhous”
tumor with fibrous bands coursing through it
- Well-differentiated polygonal cells in nests or cords
separated by parallel lamellae of dense collagen
bundles
• Cholangiocarcinomas – well-differentiated
adenocarcinomas with abundant fibrous stroma
(desmoplasia) explaining their firm, gritty consistency
- Clearly defined glandular and tubular structures
lined by somewhat anaplastic cuboidal-to-low
columnar epithelial cells
- Bile pigment and hyaline inclusions not found within
the cells
Clinical Features
• Rapid increase in liver size
• Sudden worsening of ascites or appearance of bloody
ascites
• Fever
• Pain
• Elevated serum levels of a-fetoprotein = lacks specificity
• Complications:
o Profound cachexia
o GI or esophageal variceal bleeding
o Liver failure with hepatic coma
o Rupture of the tumor with fatal hemorrhage