HEPATIC PATHOLOGY

Normal
 Normal liver in situ

This is an in-situ photograph of the chest and abdominal

contents. As can be seen, the liver is the largest
parenchymal organ, lying just below the diaphragm. The
right lobe (at the left in the photograph) is larger than the
left lobe. The falciform ligament is the rough dividing line
between the two lobes.
Normal liver – find hepatic artery

BD
PV
HV

The color is brown and the surface is smooth. A normal liver is about
1200 to 1600 grams. The cut surface of a normal liver has a brown
color. Near the hilum here, note the portal vein (PV) carrying blood
to the liver, which branches at center left, with accompanying
hepatic artery and bile ducts (BD). At the lower right is a branch of
hepatic vein (HV) draining blood from the liver to the inferior vena
cava.
 Normal liver zones

Liver is divided histologically into lobules. The center of

the lobule is the central vein (black arrow). At the
periphery of the lobule are portal triads (red arrow).
Functionally, the liver can be divided into three zones,
based upon oxygen supply. Zone 1 encircles the portal
tracts where the oxygenated blood from hepatic arteries
enters. Zone 3 is located around central veins, where
oxygenation is poor. Zone 2 is located in between.
Steatosis
 Fatty metamorphosis of liver
(a) This liver is slightly enlarged and has a
pale yellow appearance, seen both on the
(a) capsule and cut surface. This uniform
change is consistent with fatty
metamorphosis (fatty change).
(b) The lipid accumulates in the hepatocytes
as vacuoles. These vacuoles have a clear
appearance with H&E staining. The most
common cause of fatty change in
developed nations is alcoholism. In
(b) developing nations, kwashiorkor in
children is another cause. Diabetes
mellitus, obesity, and severe
gastrointestinal malabsorption are
additional causes.
(c) Here are seen the lipid vacuoles within
hepatocytes. The lipid accumulates when
lipoprotein transport is disrupted and/or
(c) when fatty acids accumulate. Alcohol, the
most common cause, is a hepatotoxin that
interferes with mitochondrial and
microsomal function in hepatocytes,
leading to an accumulation of lipid.
Cirrhosis
 Cirrhosis of liver

Microscopically with cirrhosis, the regenerative nodules

of hepatocytes are surrounded by fibrous connective
tissue that bridges between portal tracts. Within this
collagenous tissue are scattered lymphocytes as well as
a proliferation of bile ducts.
 Macronodular cirrhosis of liver

• LEFT: Ongoing liver damage with liver cell necrosis followed by

fibrosis and hepatocyte regeneration results in cirrhosis. This
produces a nodular, firm liver. The nodules seen here are
larger than 3 mm and, hence, this is an example of
"macronodular" cirrhosis.
• RIGHT: Here is another example of macronodular cirrhosis. Viral
hepatitis (B or C) is the most common cause for macronodular
cirrhosis. Wilson's disease and alpha-1-antitrypsin deficiency
also can produce a macronodular cirrhosis.
 Micronodular cirrhosis of liver

• LEFT: The regenerative nodules are quite small, averaging

less than 3 mm in size. The most common cause for this is
chronic alcoholism. The process of cirrhosis develops over
many years.
• RIGHT: This magnetic resonance imaging (MRI) scan of the
abdomen in transverse view demonstrates a small, nodular
liver with cirrhosis (L). The spleen (S) is enlarged from portal
hypertension.
 Micronodular cirrhosis and fatty
change of liver
(a) (b)

(a) The regenerative nodules are quite small,

averaging less than 3 mm in size. The most
common cause for this is chronic alcoholism. The
(c) process of cirrhosis develops over many years.
(b) Here is another example of micronodular
L cirrhosis. Note that the liver also has a yellowish
hue, indicating that fatty change (also caused by
S alcoholism) is present.
(c) This magnetic resonance imaging (MRI) scan of
the abdomen in transverse view demonstrates a
small, nodular liver (L) with cirrhosis. The spleen
(S) is enlarged from portal hypertension.
Micronodular cirrhosis and fatty
change of liver

Micronodular cirrhosis is seen along with

moderate fatty change. Note the regenerative
nodule surrounded by fibrous connective tissue
extending between portal regions.
 Mallory's hyaline, liver

At high magnification can be seen globular red hyaline

(arrow) material within hepatocytes. This is Mallory's
hyaline, also known as "alcoholic" hyaline because it is
most often seen in conjunction with chronic alcoholism.
The globules are aggregates of intermediate filaments in
the cytoplasm resulting from hepatocyte injury.
 Alcoholic hepatitis

Mallory's hyaline is seen here, but there are also neutrophils,

necrosis of hepatocytes, collagen deposition, and fatty
change. These findings are typical for acute alcoholic
hepatitis. Such inflammation can occur in a person with a
history of alcoholism who goes on a drinking "binge" and
consumes large quantities of alcohol over a short time.
 Caput medusae of skin with
portal hypertension

Portal hypertension results from the abnormal blood flow

pattern in liver created by cirrhosis. The increased
pressure is transmitted to collateral venous channels.
Sometimes these venous collaterals are dilated. Seen
here is "caput medusae" which consists of dilated veins
seen on the abdomen of a patient with cirrhosis of the
liver.
Esophageal varices with portal
hypertension

A much more serious problem produced by portal

hypertension results when submucosal veins in the
esophagus become dilated. These are known as
esophageal varices. Varices are seen here in the lower
esophagus as linear blue dilated veins. There is
hemorrhage around one of them. Such varices are easily
eroded, leading to massive gastrointestinal hemorrhage.
Splenomegaly with portal hypertension

One of the most common findings with portal

hypertension is splenomegaly, as seen here. The spleen
is enlarged from the normal 300 grams or less to
between 500 and 1000 gm. Another finding here is the
irregular pale tan plaques of collagen over the purple
capsule known as "sugar icing" or "hyaline perisplenitis"
which follows the splenomegaly and/or multiple episodes
of peritonitis that are a common accompaniment to
cirrhosis of the liver.
Pigmentary Disorders
 Hemosiderosis of liver
The hepatocytes and Kupffer
cells here are full of granular
brown deposits of
hemosiderin from
accumulation of excess iron
in the liver. The term
"hemosiderosis" is used to
denote a relatively benign
accumulation of iron. The
term "hemochromatosis" is
used when organ dysfunction
occurs. The iron
accumulation may lead to a
micronodular cirrhosis (so
called "pigment" cirrhosis).
A Prussian blue iron stain demonstrates
the blue granules of hemosiderin in
hepatocytes and Kupffer cells.
Hemochromatosis can be primary
(the cause is probably an autosomal
recessive genetic disease) or
secondary (excess iron intake or
absorption, liver disease, or
numerous transfusions).
Hemochromatosis leads to bronze
pigmentation of skin, diabetes
mellitus (from pancreatic
involvement), and cardiac
arrhythmias (from myocardial
involvement).
 Hemochromatosis of liver

LPO

The dark brown color of the liver, as The Prussian blue iron stain reveals
well as the pancreas (bottom center)
and lymph nodes (bottom right) on
sectioning is due to extensive iron
deposition in a middle-aged man with
hereditary hemochromatosis (HHC).
HHC results from a mutation
involving the hemochromatosis gene
(HFE) that leads to increased iron
absorption from the gut.
extensive hepatic hemosiderin
deposition microscopically in this
case of hereditary
hemochromatosis (HH). Note that
there is also cirrhosis. Excessive
iron deposition in persons with HH
can affect many organs, but heart
(congestive failure), pancreas
(diabetes mellitus), liver (cirrhosis
and hepatic failure), and joints
(arthritis) are the most severely
affected.
Lipochrome (lipofuscin) pigment
in liver

The pale golden brown finely granular pigment seen

here in nearly all hepatocytes is lipchrome (lipofuscin).
One such deposit within a hepatocyte is marked by the
arrow. This is a "wear and tear" pigment from the
accumulation of autophagolysosomes over time. This
pigment is of no real pathologic importance.
 Cholestasis of liver

The yellowish-green accumulations of pigment seen

here are bile. Most often this is due to extrahepatic
biliary tract obstruction. However, bile may also
accumulate in liver (called cholestasis) when there is
hepatocyte injury.
Intrahepatic lithiasis, liver

Here is an example of intrahepatic obstruction with a

small stone in an intrahepatic bile duct. This could
produce a localized cholestasis, but the serum bilirubin
would not be increased, because there is plenty of non-
obstructed liver to clear the bilirubin from the blood.
However, the serum alkaline phosphatase is increased
with biliary tract obstruction at any level.
Neoplasms
Hepatic adenoma

(a) At the upper right is a well-circumscribed

neoplasm that is arising in liver.
(b) The cut surface of the liver reveals the
hepatic adenoma. Note how well
circumscribed it is. The remaining liver is
a pale yellow brown because of fatty
change from chronic alcoholism.
(c) Normal liver tissue with a portal tract is
seen on the left. The hepatic adenoma is
on the right and is composed of cells that
closely resemble normal hepatocytes, but
the neoplastic liver tissue is disorganized
hepatocyte cords and does not contain a
normal lobular architecture.
Hepatocellular carcinoma
The neoplasm is large and bulky and has a greenish cast
because it contains bile. To the right of the main mass are
smaller satellite nodules.

Here is another hepatocellular carcinoma with a greenish

yellow hue. One clue to the presence of such a neoplasm is
an elevated serum alpha-fetoprotein. Such masses may also
focally obstruct the biliary tract and lead to an elevated
alkaline phosphatase.

The malignant cells of this hepatocellular carcinoma (seen

mostly on the right) are well differentiated and interdigitate
with normal, larger hepatocytes (seen mostly at the left).

Note that this hepatocellular carcinoma is composed of liver

cords that are much wider than the normal liver plate that is
two cells thick. There is no discernable normal lobular
architecture, though vascular structures are present.
Hepatocellular carcinoma with
satellite nodules

The satellite nodules of this hepatocellular

carcinoma represent either intrahepatic spread
of the tumor or multicentric origin of the tumor.
Cholangiocarcinoma, liver

The carcinoma at the left has a glandular appearance

that is most consistent with a cholangiocarcinoma. A
liver cancer may have both hepatocellular as well as
cholangiolar differentiation. Cholangiocarcinomas do not
make bile, but the cells do make mucin, and they can be
almost impossible to distinguish from metastatic
adenocarcinoma on biopsy or fine needle aspirate.
 Metastatic adenocarcinoma, liver

• LEFT: Note the numerous mass lesions that are of variable size. Some of
the larger ones demonstrate central necrosis. The masses are
metastases to the liver. The obstruction from such masses generally
elevates alkaline phosphatase, but not all bile ducts are obstructed, so
hyperbilirubinemia is typically not present. Also, the transaminases are
usually not greatly elevated.
• RIGHT: This computed tomographic (CT) scan without contrast of the
abdomen in transverse view demonstrates multiple mass lesions resulting
in a markedly enlarged liver extending from right to nearly the left side of
the upper abdomen. These are metastases from a colonic
adenocarcinoma. A normal sized spleen is seen at the lower left.
Metastatic adenocarcinoma, liver

• LEFT: Here are liver metastases from an

adenocarcinoma primary in the colon, one of the most
common primary sites for metastatic adenocarcinoma to
the liver.
• RIGHT: This computed tomographic (CT) scan with
contrast of the abdomen in transverse view
demonstrates multiple mass lesions representing
metastases from a colonic adenocarcinoma. A
normal spleen appears at the lower right in the image
(on the patient's left).
Metastatic adenocarcinoma, liver

Microscopically, metastatic infiltrating ductal

carcinoma from breast is seen on the right, with
normal liver parenchyma on the left.
Viral Hepatitis
 Viral hepatitis, liver

• LEFT: Grossly, there are areas of necrosis and

collapse of liver lobules seen here as ill-defined
areas that are pale yellow. Such necrosis occurs
with hepatitis.
• RIGHT: The necrosis and lobular collapse is
seen here as areas of hemorrhage and irregular
furrows and granularity on the cut surface of the
liver.
 Viral hepatitis B

LPO HPO

• LPO: Viral hepatitis leads to liver cell destruction. A mononuclear

inflammatory cell infiltrate extends from portal areas and disrupts
the limiting plate of hepatocytes which are undergoing necrosis,
the so-called "piecemeal" necrosis of chronic active hepatitis. In this
case, the hepatitis B surface antigen (HbsAg) and hepatitis B
core antibody (HbcAb) were positive.
• HPO: Individual hepatocytes are affected by viral hepatitis. Viral
hepatitis A rarely leads to signficant necrosis, but hepatitis B can
result in a fulminant hepatitis with extensive necrosis. A large pink
cell undergoing "ballooning degeneration" is seen below the right
arrow. At a later stage, a dying hepatocyte is seen shrinking
down to form an eosinophilic "councilman body" below the arrow on
the left.
 Viral hepatitis C
HPO
LPO

• LPO: This is a case of viral hepatitis C which is at a high stage with

extensive fibrosis and progression to macronodular cirrhosis, as evidenced
by the large regenerative nodule at the center right. At present, the
sole laboratory test for identification of this form of viral hepatitis is the
hepatitis C antibody test. Hepatitis C accounts for most (but not all) cases
formerly called "non-A, non-B hepatitis".
• HPO: This is a case of viral hepatitis C, which in half of cases leads to
chronic liver disease. The extent of chronic hepatitis can be graded
by the degree of activity (necrosis and inflammation) and staged by the
degree of fibrosis. In this case, necrosis and inflammation are prominent,
and there is some steatosis as well. Regardless of the grade or stage, the
etiology of the hepatitis must be sought, for the treatment may depend
upon knowing the cause, and chronic liver diseases of different
etiologies may appear microscopically and grossly similar.
Viral hepatitis with collapse, liver

This trichrome stain demonstrates the collapse

of the liver parenchyma with viral hepatitis. The
blue-staining areas are the connective tissue of
many portal tracts that have collapsed together.
Miscellaneous Parenchymal
Diseases
 Chronic passive congestion
(nutmeg liver)

Note the dark red Microscopically, the

congested regions that nutmeg pattern results
represent accumulation of from congestion around
RBC's in centrilobular the central veins, as seen
regions.
here. This is usually due to
a "right sided" heart
failure.
Centrilobular necrosis, liver

If the passive congestion is pronounced, then there can

be centrilobular necrosis, because the oxygenation in
zone 3 of the hepatic lobule is not great. The light brown
pigment seen here in the necrotic hepatocytes around
the central vein is lipochrome.
Chronic passive congestion with
"cardiac cirrhosis", liver

If chronic hepatic passive congestion continues for a long

time, a condition called "cardiac cirrhosis" may develop in
which there is fibrosis bridging between central zonal regions,
as shown below, so that the portal tracts appear to be in the
center of the reorganized lobule. This process is best termed
"cardiac sclerosis" because, unlike a true cirrhosis, there is
minimal nodular regeneration.
 Infarction, liver

At the right are seen several infarcts of the liver. Infarcts

are uncommon because the liver has two blood supplies-
portal venous system and hepatic arterial system. The
infarcts seen here are yellow, with geographic borders
and surrounding hyperemia. About half of liver infarcts
occur with arteritis, and the remaining half are due to a
variety of causes.
Necrosis with acetaminophen
overdose, liver

There is extensive hepatocyte necrosis seen here in a

case of acetaminophen overdose. The hepatocytes at
the right are dead, and those at the left are dying. This
pattern can be seen with a variety of hepatotoxins. Acute
liver failure leads to hepatic encephalopathy.
 Dominant polycystic kidney
disease with polycystic liver

• LEFT: Numerous cysts appear in this liver from a patient with dominant
polycystic kidney disease (DPKD). Such cases occur in adults and
manifest with renal failure beginning in middle age. Sometimes the
liver (as seen here) can be affected as well by polycystic change. Less
commonly the pancreas is involved. These patients with DPKD can also
have berry aneurysms in the cerebral arteries.
• RIGHT: This transverse CT scan of the liver demonstrates multiple large
cysts in the parenchyma, consistent with polycystic change in the liver of
a patient with dominant polycystic kidney disease.
 Primary biliary cirrhosis

This is a case of primary biliary cirrhosis, a rare

autoimmune disease (mostly of middle-aged women)
that is characterized by destruction of bile ductules within
the triads of the liver. Antimitochondrial antibody can be
detected in serum. Seen here in a portal tract is an
intense chronic inflammatory infiltrate with loss of bile
ductules. Micronodular cirrhosis ensues.
 Anti-mitochondrial antibody,
immunofluorescence microscopy

This immunofluorescence pattern is positive for anti-

mitochondrial antibody (AMA) which has an association
with primary biliary cirrhosis. The tissue substrate for this
test is renal parenchyma, and the tubule cells have lots
of mitochondria, which stain bright green.
 Extrahepatic biliary atresia, liver

This 3 month old child died with

extrahepatic biliary atresia, a disease in Microscopically, extrahepatic biliary
which there is inflammation with atresia leads to this appearance in
stricture of hepatic or common bile the liver, with numerous brown-green
ducts. This leads to marked cholestasis bile plugs, bile duct proliferation (seen
with intrahepatic bile duct proliferation, at lower center), and extensive
fibrosis, and cirrhosis. This liver was fibrosis. If a large enough bile duct
rock hard. The dark green color comes can be found to anastomose and
from formalin acting on bile pigments in provide bile drainage, then surgery
the liver from marked cholestasis, can be curative.
turning bilrubin to biliverdin.
Neonatal giant cell hepatitis

Seen here is the major differential diagnosis of biliary

atresia: this is neonatal giant cell hepatitis. There is
lobular disarray with focal hepatocyte necrosis, giant cell
transformation, lymphocytic infiltration, Kupffer cell
hyperplasia, and cholestasis (not seen here). Neonatal
hepatitis may be idiopathic or of viral origin. Many
neonates recover in a couple of months.
Alpha-1-antitrypsin deficiency,
liver, PAS stain

The periportal red hyaline globules seen here with periodic

acid-Schiff (PAS) stain are characteristic for alpha-1-
antitrypsin deficiency (a person with homozygous pi-ZZ
genotype) The globules are intrahepatic collections of
alpha-1-antitrypsin that is not being excreted from the
hepatocytes. This may eventually lead to a macronodular
cirrhosis. These patients are also prone to develop
panlobular emphysema of lungs.
 Sclerosing cholangitis, liver

• LEFT: This trichrome stain of the liver demonstrates

extensive portal tract fibrosis with sclerosing
cholangitis. The hepatocytes are normal.
• RIGHT: Microscopically, this bile duct in a case of
sclerosing cholangitis is surrounded by marked
collagenous connective tissue deposition. Gigi  - sec D – ustmed2007