PATHOLOGY

LIVER PATHOLOGY
Dr. Janet L. Dy
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November 29, 2011

General Features of hepatic Disease

Infectious Diseases
Autoimmune Disorders
Toxic Liver Disease
Metabolic Liver Disease
Vascular Diseases of the Liver
Hepatic Tumors

Liver Necrosis Types:

1. Focal: Groups of hepatocytes in few areas

Note:
This first section was not discussed in the lecture but was
included in last years trans. Its good supplementary information
if you have time to read it. It will discuss you some basic
histopathology description before we go in each diseases.

GENERAL FEATURES OF HEPATIC DISEASES

Patterns of Hepatic Injury
Degeneration and intracellular accumulation
1. Necrosis and apoptosis
2. Inflammation
3. Regeneration
4. Fibrosis

Fig. 2. Few necrotic hepatocytes. Small area/group of necrotic cells replaced by

inflammatory cells

2. Multifocal: Necrosis in multiple areas

3. Zonal: Affects any of 3 zones of the lobule (ex. centrilobular)
4. Confluent (bridging): Necrosis of contiguous liver
cells connect to adjacent lobules (portal to portal field,
portal to central vein and central vein to central vein)

Liver Degeneration and Intracellular accumulation

Ballooning degeneration
o Marked cell enlargement
o Clear spaces & irregularly clumped cytoplasm
o Ballooning- severe swelling
Swollen cells Cells are only enlarged with granularity in
cytoplasm
Change in the cell without death, if injurious agent removed
Return to normal
Feathery degeneration: Foamy appearance of the
hepatocytes due to retained biliary material

Fig. 3. Continuity or bridging of one area of necrosis to another area

5. Piecemeal Necrosis (interface): Death of hepatocytes

about periphery of the portal tract.

Fig. 4. Usually seen in chronic hepatitis. Between periphery of portal tract/ periportal
area and limiting plate. Occurs near portal tract (made up of bile duct, portal vein,
hepatic artery). Seen in the picture are inflammatory cells around the portal tract.
Hepatocytes show some degree of swelling (accumulation of fluid in cytoplasm)

6. Panacinar Submassive: Involves all 3 zones

7. Panacinar Massive: Involvement of most of the liver
parenchyma It is fatal (seen in fulminant hepatits)
Review:
Fig. 1. Cell on the left shows swelling, while cell on the right of the picture exhibits
cellular ballooning.

Accumulations:
o Iron (Siderosis)
o Copper (Wilsons disease)
o Fat (Steatosis)
Microvesicular
Smaller accumulation of fat (Reyes syndrome)
AFL (Acute Fatty Liver) of pregnancy
Macrovesicular
Larger fat accumulation such that nuclei of
hepatocytes displaced to the periphery
Fat in cytoplasm (Alcoholic liver disease, obesity
and DM)

Apoptosis and Necrosis

Apoptosis is a form of programmed cell death, organelles are
retained
Cells condense,become round separate from other cells
fragment and phagocytized by histiocytes.
In the liver the apoptotic cells are called Councilmann
bodies (highly acidophilic cells; dead cells that underwent
shrinkage and condensation)

SECTION B

Fig. 5. Hepatic Lobule

- Hepatic Lobule:
Liver is divided into hexagonal structures called hepatic
lobules made up of:
Portal tract
Central vein
Liver parenchyma
This division is oriented in terms of blood supply, divides
the parenchyma into 3 zones:
a. Zone 1 Periportal zone: Near the blood supply
b. Zone 2 Mid-zonal
c. Zone 3 Centrilobular zone: Near the central
vein, farthest from blood supply
During hypoxic states, cells in zone 3 will undergo
necrosis first (centrilobular necrosis)
During toxin mediated insults, cells in zone 1 will be
affected first (periportal necrosis)

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Liver Inflammation
Around liver cell necrosis (injury to hepatocytes + influx of
acute or chronic inflammatory cells)
Follow or precedes necrosis
Type and distribution of inflammation vary according to the
etiological agent:
o Viral hepatitis Lymphocytes
o Alcoholic Liver Disease (ALD) Neutrophils
Acute, chronic granulomatous

Liver Regeneration
Ability to regenerate is great
Evidences of Liver regeneration: Mitosis, Multi-nucleation
(increase in number of nucleus but N:C ratio should be
maintained ) and Parenchymal disorganization
o Which may exist in two forms:
a. Repair: By complete restitution
b. Scarring: If damage affects the reticular framework
Repair by scarring Circulatory re-arrangement
Cirrhosis (end result)

Elevated alkaline phosphatase (injury to bile ducts)

o It confirms liver injury if it is added to elevated GGT
o Alakaline phosphatase are stored in bile duct and
canalicular cells
Bilirubin: Hyperbilirubinemia Jaundice
Note:
Test on aminotransferases/ cytosolic hepatocellular
enzymes Test the hepatocyte integrity
Protein synthesis/ proteins secreted into the bloodhepatocyte function/ functional state
Both ALP and GGT are elevated in diseases of the bile duct

Manifestations of Liver Disease

Jaundice/Icteresia
Yellow discoloration of skin & sclera (and mucus membranes)
respectively
Hyperbilirubinemia Due to retained bilirubin in systemic
circulation
Normal value 1.2 mg/dL (8-24 umol/L)
>2.0 mg/dL (30-40 umol/L) Jaundice
Notes: (Robbins)
Common causes of jaundice are bilirubin overproduction,
hepatitis, and obstruction of bile flow
Hepatic bile: (1) Emulsifies dietary fat in lumen of Gut
through detergent properties of bile salts; (2) Elimination of
bilirubin, excess cholesterol, xenobiotics, and other waste
products

Fig. 6. Liver Cell Regeneration There is mitosis, mild to moderate enlargement

of cells, no atypical mitosis, and binucleation

Liver Fibrosis
Consequence of chronic liver injury
Associated with derangement of the architecture, circulation
remodeling, cirrhosis, and portal hypertension
Irreversible change (once it has started)

Fig. 7. Bridging Fibrosis: Fibrosis of sinusoidal spaces and in between central

vein, individual liver cells are also surrounded by collagen/fibrous tissue. Thickening
of fibrosis will eventually lead to obstruction Decrease in liver cell perfusion.

Functional Changes due to Liver Injury

Decrease protein: Leading to hypoalbuminemia and edema
o Liver is the only organ that synthesizes proteins
o It synthesizes all proteins except the von Willebrand
Factor
o Synthesizes clotting factors especially factors V, VII, XI,
XII and albumin
Prolonged prothrombin time: Due to decrease in coagulative
factors Bleeding (bruise, petechiae, hematomas easily)
Alanine aminotransferase ALT (or serum glutamic pyruvic
transferase sGPT)
o More specific for liver diseases
Aspartate aminotransferase AST (or serum glutamic
oxaloacetate Transferase sGOT)
o AST may also be elevated in diseases affecting other
organs, such as the heart or muscles
Gamma glutamyltransferase gamma-GT (GGT) these 3
enzymes are elevated due to hepatocellular necrosis
o Can be used to screen chronic alcohol abuse
o Is not helpful in distinguishing different causes of liver
damage

SECTION B

Fig. 8. Bilirubin Metabolism (Site: RES/Spleen). In intestines, B2 is deconjugated,

into urobilinogen. Urobilinogen Stercobilinogen (reduced). Stercobilinogen
reduced to stercobilin (yellow brown color of feces. Some urobilinogen is
reabsorbed back to liver excreted in urine. Bilirubin is formed in the spleen;
Conjugation takes place in the liver

Unconjugated bilirubin ( B1) vs. Conjugated bilirubin (B2)

- B1 non water soluble; highly bound to albumin; not seen in
urine
B1 is lipid soluble and is thus very toxic
Small amounts may cross BBB, diffuse into brain of
infants Kernicterus (brain is yellow in color)
Erythroblastosis fetalis (hemolytic disease of newborn)
lead to accumulation of unconjugated bilirubin in the
brain Kernicterus
B1 increases in hemolytic diseases
- B2 Water soluble
increase in B2 is reflected in urine
Dark amber/coca-cola/tea color
Non toxic
Notes (Robbins):
With prolonged conjugated hyperbilirubinemia, a portion of
circulating pigment become covalently bound to albumin
referred to as bilirubin delta fraction

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Pathophysiology of jaundice
A. Predominantly Unconjugated Hyperblirubinemia
-

Total bilirubin: Increased

B2: Normal
B1: Increased
Urine will be normal in color because only conjugated
bilirubin is seen in urine

1. Excessive production of bilirubin

a. Hemolytic anemias
b. Ineffective erythropoesis
2. Decreased hepatic uptake
a. Drug interference with membrane carrier system
3. Impaired bilirubin conjugation - Deficiency of
glucoronyl transferase
a. Physiologic neonatal jaundice (transient) 10
days normal. More than 10 days Pathologic
- Hepatic machinery of conjugating and
excreting bilirubin does not fully mature until
about 2 weeks of age Newborns develop
transient miled unconjugated
hyperbilirubinemia
- Can be exacerbated by breastfeeding
Presence of bilirubin deconjugating enzymes in
breast milk
b. Crigler Najjar Syndrome types I and II
- Type 1 Hepatic UGT1A1 is completely
absent Colorless bile contains only trace
amounts of unconjugated bilirubin
Liver is morphologically normal
Without immediate liver transplantation
causes death within 18 months of birth
- Type 2 Less severe, non fatal
Hepatic UGT1A1 enzyme is greatly
reduced
Capable of forming monoglucoronidated
bilirubin
Only consequence is yellow skin;
Phenobarbital treatment may improve
glucoronidation by inducing hypertrophy of
hepatocellular ER
c. Gilberts Syndrome (mild,fluctating
hyperbilirubinemia)
- Benign inherited syndrome
- Absence of hemolysis of liver
- Jaundice related to stress (exercise/ fasting)
- Usually detected in adult life
- Homozygous insertion of two extra bases in
the 5 promoter region of UGT1 gene leading to
reduced transcription
B. Predominantly Conjugated Hyperbilirubinemia
- Urine with tea/coca-cola color and stool is pale
1. Decreased hepatocellular excretion Liver cell
necrosis (ex. Hepatitis)
Total bilirubin: Increased
B2: Increased
B1: Normal (if there are still viable liver cells and injury
is not extensive) or increased (severe liver damage

a. Dubin Johnson Syndrome: Deficiency in

canalicular membrane transport. Autosomal
recessive disorder.
- Chronic conjugated hyperbilirubinemia caused by
defect in hepatocellular excretion of bilirubin
glucoronidase across canalicular membrane
(absence of multidrug resistance protein 2)
- Liver: Hepatomegaly and has a brown to black
color (polymerized epinephrine and not bilirubin)
- Total biliribin: Increased
- B2: Increased
- B1: Normal

SECTION B

b. Rotor syndrome: Defect hepatocellular uptake &

excretion
- Rare form of asymptomatic conjugated
hyperbilirubinemia
- Multiple defects in hepatocellular uptake and
excretion of bilirubin pigments
- Aside from jaundice, patient lives a normal life
2. Impaired bile flow
- Extrahepatic biliary obstruction
- ex. Stone,tumor
- TB: Increased
- B2: Increased
- B1: Normal
Gross Morphology (Icteretic liver)
- Normal liver is mahogany colored
- Liver with jaundice has a greenish/ green-yelllow color
because biliverdin is green

Fig. 9. Liver with jaundice

Cholestasis
Stagnation of bile due to impairment of bile flow along its
outflow tract leading to accumulation of bile components in
the blood
Major components of bile
o Bilirubin
o Bile acids
o Cholesterol
Morphologic Features of Cholestasis
- Depends on the severity, duration and underlying cause
- Common in both obstructive and non-obstructive
cholestasis: Accumulation of bile pigment within hepatic
parenchyma
- Histologic findings: Portal duct edema, periductural infiltrates
of neurophils, bile lakes
a. Extrahepatic cholestasis Surgical case
- Bile plugs
- Bile lakes: Bile accumulation in surrounding stroma
- Bile is toxic due to its soap/detergent effect (irritant)
- This may injure cell lining of bile duct
- Inflammation can cause rupture Zccumulation of
bilie outside the ducts
- Ductal proliferation: Compensatory mechanism
- Foamy degeneration: Droplets of bile can
accumulate within hepatocytes which can take fine,
foamy appearance (feathery degeneration)
This is different from ballooning degeneration
- Biliary cirrhosis
b. Intrahepatic cholestasis Medical case
- Patients condition may be worsened by surgery
- Bile plug
Types based on Morphology
a. Cytoplasmic cholestasis Presence of bile throughout the
cytoplasm of hepatocytes
b. Canalicular Cholestasis Presence of bile thrombi in bile
canaliculi
c. Ductular Cholestasis Stagnation of bile in periportal bile
ductules (ducts of Hering). Seen in:
- Severe biliary obstruction
- Severe necrotizing hepatitis
- Septicemia
d. Ductal Cholestasis Presence of bile casts in portal bile
ducts and is rarely seen

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Fig. 10. Left: Canalicular cholestasis with foamy appearance of the hepatocytes
due to retained biliary material (feathery degeneration). Right: Ductal cholestasis.

Clinical Manifestations of Cholestasis

- Pruritus( increase bile acids): Due to deposition of bile
pigments in skin and subcutaneous tissue
- Cuteneous xanthomas (focal accumulation of cholesterols)
- Jaundice
- Dark urine: Increased B2
- Stool color
- Pale due to obstruction (no stercobilin)
- Increased alkaline phosphatase (canalicular membrane,bile
duct epithelium)
- Biliary obstruction
- Increased gamma glutamyl transpeptidase (GGT)
- Symptoms related to intestinal malabsorption Nutritional
deficiencies of fat soluble vitamins (A,D,K)
Note:
Increase in Alkaline phosphatase and GGT are characteristic
of Cholestasis. Why there is nutritional deficiency? Because it is
absorbed with bile, but since there is stasis of bile then no
absorption happen for these fat soluble vitamins. Again, since
there is obstruction, B2 is increased plus it is water soluble, then
it will be detected in urine.

8. Increased liver enzymes (ALT > AST)

9. Hepatorenal syndrome: Appearance of acute renal failure
in the absence of a kidney pathology leads to sodium
retention, impaired free water excretion, decreased renal
perfusion and GFR
- Onset of anuria and azotemia (BUN, creatinin , Na,
decreased GFR)
- Poor prognosis
10. Hepatic encephalopathy: Disorder of neurotransmission in
the CNS and neuromuscular system
- Clinical features: Disturbed consciousness Confusion
Stupor Coma Death
- Fluctuating neurologic signs (rigidity, asterexis nonrhythmic, rapid extension flexion movements of the
head and extremities)
- Increased NH3 promotes generalized brain edema, &
impair neuronal function (underlying pathology is brain
edema)
- Reversible
11. Hepatopulmonary Syndrome (HPS)
- Intrapulmonary vascular dilatation
- Hypoxemia/Impaired oxygenation, due to diffusionperfusion defect, lack of uniform bloodflow, shunting of
blood.
Note:
There are 3 severe complications in Hepatic Failure:
1. Hepatorenal
2. Hepatoencephalopathy
3. Hepatopulmonary
So it just mean, when the liver is problematic, the kidney, brain
and lungs will follow.

Hepatic Failure
Most severe clinical consequence of liver disease
Final pathway of progressive liver injury
Loss 80 90% of hepatic functional capacity
70 95% MR
Acute: Massive necrosis secondary to cirrhosis
Chronic: Common cause of liver failure
Transplantation is the remedy
Causes of Hepatic Failure
1. Massive hepatic necrosis
- Fulminant viral hepatitis
- Drugs ex. CCl4 halothane, INH
2. Chronic Liver Disease
- Cirrhosis (most common route to Hepatic Failure)
3. Hepatic dysfunction without overt necrosis
- Ex. Reyes Syndrome, acute fatty liver of pregnancy and
tetracycline toxicity
- Liver is viable but not functional
Major Clinical Features of Hepatic Failure (reflection of
metabolic function of liver)
1. Jaundice Due to less bile production
2. Hypoalbuminemia: Edema due to decreased synthesis of
albumin
3. Coagulopathy (F2, 7, 9 & 10): Bleeding can lead to massive
GI bleeding and further metabolic load on the liver can
worsen hepatic failure
4. Hyperammonemia (defective urea cycle) increase NH4
Cerebral dysfunction
5. Fetor hepaticus due to mercaptan accumulation
(musty/sweet and sour odor) and porto-systemic shunting
6. Increased estrogen secretion, palmar erythema,
amenorrhea, gynecomastia, testicular atrophy
(hyperestrogenemia in males)
7. Spider nevi/ Spider angioma
- Due to increased estrogen in blood
- Central pulsating dilated arteriole with radiating small
vessels
- Seen in anterior chest wall and face

SECTION B

Cirrhosis
Irreversible
Chronic, progressive liver disease
Multiple causes: Chronic alcoholism, Hep B/ Hep C infection,
biliary disease, autoimmune,hemochromatosis, NASH
3 Main Morphologic features
a. Widespread fibrosis
- Broad scars linking portal tracts and terminal hepatic
veins
- Fibrosis is the key feature of progressive damage to
the liver
- Presence of bridging fibrous septa between lobules
b. Regenerative parenchymal nodules
- Containing hepatocytes encircled by fibrosis
- Nodularity results from cycles of hepatocyte
regeneration and scarring
c. Disorganization of Parenchymal / vascular
architecture
- Additional features: Inflammation & ductal proliferation
Note:
If the liver is compensated; there is no necrosis, but is it is
uncompensated then necrosis is present
WHO Classification of Cirrhosis
- Based on Etiology
Alcohol Liver disease 60-70%
Viral Hepatitis 10%
Biliary diseases 5-10%
o
1 Hemochromatosis 5%
Wilsons Disease Rare
Alpha1 Antitrypsin def Rare
Cryptogenic 10-15%
- Based on the morphology (size) of the nodule
a. Macronodular >3mm, thick fibrous bands CT
b. Micronodular<3mm, thin fibrous

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Pathogenesis of Cirrhosis
1. Injury (insult) of liver Liberating inflammatory cytokines
(TNF, IL-, lymphokines)
2. Disruption of extracellular matrix by cytokines, stimulating
LTO cell metaplasia.
Note:
Hepatic stellate cells/ LTO cells: Normally acting as fat storing
cells
3. LTO cells change to myofibroblastic cells which produce
collagen
4. Collagen deposition (fibrosis) in the wall of sinusoid
Closure of fenestrations.
5. Capillarization of sinusoids with no fenestration and walls
become thick
6. Reduced hepatocytes perfusion
7. More injury (death of cells) with some viable cells that
compensate by regeneration
8. Regenerating nodules (pseudonodules)
9. Loss of lobular morphology.
Note:
3 things very important in pathogenesis: (1) Death of
hepatocytes, (2) Extracellular matrix deposition, and (3) Vascular
reorganization producing cirrhosis.

Fig. 11. Micronodular cirrhosis. Left: Gross The regenerative nodules are quite
small, averaging less than 3 mm in size. Presence of bumpy, fine nodules which
are firm and hard due to fibrosis. The most common cause for this is chronic
alcoholism ( AKA-Laennec/Hobnail). Right: Histology Here, the central vein is
obliterated and portal vessels are difficult to appreciate Lobules are separated by
thick fibrous CT. Presence of pseudolobules, which are lobes formed by viable
hepatocytes that proliferate.

Fig. 12. Micronodular with fatty change. Left: Gross Micronodular cirrhosis may
also be seen with Wilson's disease, primary biliary cirrhosis, and hemochromatosis.
There is a thin band of fibrous connective tissue. Normally green/yellow due to fatty
change and retention of bilirubin. Right: Histology Fat vacuoles are seen in the
cytoplasm of the cells. A thin band of fibrous CT separates each nodule. This liver is
compensated because no presence of necrosis and inflammatory cells.

Fig. 13. Macronodular cirrhosis. The nodules seen here are larger than 3 mm.,
hence, this is an example of "macronodular" cirrhosis. This is commonly caused by
viral hepatitis B and C. Fibrous CT are wider and thickened.

Note:
Viral hepatitis (B or C) is the most common cause for
macronodular cirrhosis. Wilson's disease and alpha-1-antitrypsin
deficiency can also produce a macronodular cirrhosis.
Clinical manifestation of Cirrhosis:
- 40% asymptomatic in early stage
- Nonspecific manifestations: weakness, anorexia and wt. loss
- Advanced disease: Jaundice, chronic liver failure, portal
hypertension
- Liver failure is the most feared complication of cirrhosis due
to infection and GIT bleeding.
Leading causes of death in Cirrhosis
1. Liver failure
2. Portal hypertension
3. Hepatocellular carcinoma
- Why? Because it stimulate the remaining viable cells to
proliferate
- Too much proliferate cause mutation and become
cancer cell

Portal Hypertension
Caused by increased resistance to portal venous flow leading
to abnormal increase in pressure in the portal venous system
Causes of portal hypertension
1. Prehepatic
2. Intrahepatic
3. Posthepatic
1. Pre-hepatic: Caused by obstruction to blood flow at
the level of portal vein
- Thrombosis of portal vessels
- Obstruction of portal vessels
- Massive splenomegaly with increased splenic vein
outflow
2. Intrahepatic
- Cirrhosis: Most important and most common cause
of portal HTN
- Schistosomiasis
3. Post hepatic obstruction to blood flow at the level of
hepatic vein:
- Severe right sided heart failure
- Constrictive pericarditis
- Hepatic vein outflow obstruction (Budd-Chiari
syndrome)
Mechanism of Portal Hypertension in Cirrhosis (intrahepatic
level)
1. Decreases oncotic pressure secondary to hypoalbuminemia
2. Increased hydrostatic pressure / portal pressure
3. Compression of sinusoids & central veins by fibrosis &
expansile nodules in liver parenchyma
4. Obstructed vessels and lymphatic flow
5. A-V anastomoses within scars
Clinical Manifestation of Portal HTN
1. Ascites
- Mechanism: Increased hydrostatic pressure (Starlings)
- Accumulation of excess fluid in the peritoneal cavity (at
least 500 ml to be detected)
- Decreased plasma oncotic pressure: Main mechanism of
ascites due to sinusoidal hypertension
- Renal retention of sodium & water
- Increased formation of hepatic lymph
2. Congestive Splenomegaly causing pancytopenia due to
hypersplenism
3. Portosystemic venous shunts Varices shunt flow where

the portal and systemic share common circulation

Fig. 14. Post Necrotic Cirrhosis. Often end result of viral hepatitis, post hepatitis,
macronodula, and leads to HCC

SECTION B

- Cardioesophageal junction esophageal varices (most

common site)
- Inferior mesenteric vein (rectal branches hemorrhoids)
- periumblical & abdominal wall Caput medusae
4. Hepatic Encephalopathy

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Fig. 15. Left: Esophageal Varices with portal HTN is seen here in the lower
esophagus as linear blue dilated vein. There is subserosal dilatation with
hemorrhage. Such varices are easily eroded, leading to massive hematemesis.
Asymptomatic > of patients die from the 1st bleeding episode. Right: Caput
medusae" which consists of dilated veins on the abdomen; plus the patient also
presented gynecomastia and spider angioma due to cirrhosis.

Fig. 16. Splenomegaly. The spleen is enlarged from the normal 150-200 grams to
between 500 and 1000g. Increased function of the spleen leads to increased
destruction of RBC, WBC and platelets. Which may result to anemia, infection and
bleeding tendencies. May lead to pancytopenia.

INFECTIOUS DISORDERS
Viral Hepatitis
Viral hepatitis caused by the hepatotropic viruses
- Other viruses:
- Yellow fever
- Herpes viruses
- Epstein Barr
- Coxsackie A & B
- Lassa fever
- CMV
Types of viral hepatitis (Hepatotropic viruses)
- A (HAV) Picornavirus
- B (HBV) Hepadnavirus
- C (HCV) Flavivirus
- D (HDV) Variate B
- E (HEV) Calicivirus
- F (HFV) Togavirus**
- G (HGV) Flavivirus
Note:
HFV is technically a non-existant virus. However, an
infection common in the Far East has shown that a new
virus, which is neither hepatitis A, B, C, D, nor E has
emerged. In some circles, this virus is being recognized as
the hepatitis F virus. (Deka et al.)
In viral hepatitis, only the liver is involved.

Hepatitis A Viral Infection

Also known as Infectious hepatitis

Transmission is by oral fecal route
Close personal contact
Short incubation period (2-4wks)
Cllinical Asymptomatic 90%, jaundice 10%
Does not produce chronic hepatitis either cirrhosis nor a carrier
No risk of development of HCC
Very low risk of fulminant hepatitis
MR is low (0.1%)
Serologic markers antiIgMHAV & antiIgGHAV
Route of entry and clinical course:
o Transmission by ingestion of raw shellfish
o Multiplies in the intestine and invades the blood, liver and
saliva before any clinical manifestation of the disease
appears
o Transient viremia
o Not transmissible by blood
o vVrus disappears soon after the peak of serum
transaminase
o Self limited Disease

SECTION B

Fig. 17. Clinical course of HAV

Hepatitis B Viral Infection

Also known as Serum hepatitis
Long incubation (1-4 months)
3 routes of transmission:
o Parenteral
o Sexual intercourse
o Vertical transmission: Carrier state for life
Most serious cause of Hepatocellular Carcinoma (HCC) in the
Philippines
Remains in blood until active episodes of acute and chronic
hepatitis
Can cause:
i. Acute hepa with recovery
ii. Non-progressive chronic hepa
iii. Progressive chronic disease ending in cirrhosis
iv. Fulminant hepa with massive liver necrosis
v. Asymptomatic carrier state
Serologic markers:
o HbsAg, HbeAg, HBcAg, Anti-HBcAg, Anti-HbsAg & Anti-HbeAg

Mechanism of injury :
o Does not produce a direct hepatotoxic damage
o Injury is a result of immune mediated response to viral
antigens expressed by infected hepatocytes
Serologic Diagnosis
o The antigens are: HBsAg Appear before onset of
symptoms, peaks during disease and declines in 3-6
months
o HBeAg Indicator of continued viral replication, infectivity
and probable progression to chronic hepatitis, with high
infectivity
o HBV-DNA, DNA polymerase Appear after HBsAg and
signify active viral replication
o HBcAg Detectable in serum shortly before onset of
symptoms, with onset of elevated serum
aminotransferrase
o Serologic diagnosis depends on the presence of these
antigens and their antibodies in the serum of the patient
(hepatitis profile) which tell as about the patient status,
whether acute, chronic, carrier
o IgM indicate acute state.
o Anti-Hbe Ag- resolution of disease

Fig. 18. Clinical course of HBV

Note:
There is a period where both HBsAg and Anti-HBsAg are
absent or cannot be detected in the serum, this is called window
period. This period can give wrong notion since it can interpret
false negative for a patient with infection. Only Anti-HBc Ag is
detected in that period

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Hepatitis E Viral Infection

HBsAg

AntiHBsAg

AntiHBcAg
(IgG)

AntiHBcAg
(IgM)

Susceptible

+/-

Immune from previous

infection
Immune from HBV vaccine

Interpretation

Similar to hepatitis A in many respects

o Enterically transmitted, water borne infection
o High mortality rate among pregnant
o Not associated with HCC
o Does not lead to chronic liver diseases
o PCR detects HEV RNA and HEV virions before onset of
illness in stool and serum

Acute infection

Hepatitis G Viral Infection

Chronic infection

+/-

Recovering from acute

infection

Similar to HCV
o Not hepatotropic virus, no increase in liver enzymes
o Replicate in bone marrow and spleen
o Has protective effect in patient co-infected with HIV (inhibit
HIV replication).
o Asymptomatic, confirmed by serological testing

Note:
Try to analyze this table since Dr. Dy mentioned that she might
give this type of question and you need to interpret (again) what
is the status of the given patient.

Fig. 19. Potential outcomes of HBV infection

Hepatitis C Viral Infection

Responsible for >90% of post transfussion hepatitis

Spread is by inoculation & blood transfusion
Transmission by sexual contact is extremely low
Parenteral is the common route
Incubation Period: 2-26 wks
Clinical 95% asymptomatic, 5% jaundice
Hallmarks: Persistent infection and chronic hepatitis
May lead to chronic hepatitis & cirrhosis
Fulminant hepatitis is rare
Serologic markers: antiHCV IgG After an active infection do
not consistently confer effective immunity and anti HCV IgM
Characteristic feature of HCV: Repeated episodes of hepatic
damage, result of reactivation of preexisting infection or newly
mutated strain

Hepatitis D Viral Infection

Replicatively defective
Transmission: Same as HBV
Infection occurs when encapsulated by HBsAg
Usually causes illness more severe than HBV
Detectable in blood and liver
Can be acquired as:
o Coinfection: Infects patient together with HBV
o Superinfection: May present as severe acute hepa or as
an exacerbation of preexisting chronic hepaB
Serologic markers:
1. HDV-RNA
2. IgM Anti-HDV: Most reliable indicator of recent HDV
exposure
3. IgM Anti-HDV + IgM Anti-HBcAg: Indicates acute
coinfection
4. HbsAg + Anti-HDV: Iindicates superinfection
5. PCR

SECTION B

5 Clinicopathologic Syndrome in Viral Hepatitis

1. Carriers
a. Healthy carriers
i. (-) HBeAg but (+) anti-HBe
b. Carriers with chronic disease: Patients with no clinical
manifestations and yet have progressive destruction of
the liver
- Morphology:
Ground glass appearance HBsAg
Sanded nuclei HbcAg
- Diagnostic tools: in situ hybridization and DNA
probes
2. Acute asymptomatic with recovery
- Serologic evidence only (no pathologic/clinical)
(-) Clinical manifestations
(-) Abnormality in liver biopsy
Blood exam: (+) Ab against the virus
3. Acute symptomatic infection with recovery (acute viral
hepatitis)
- Patient manifests the disease
- Subdivided into 4 stages:
1. Incubation period
Depends on etiologic agent
2. Preicteric phase
Manifests as nonspecific symptoms: Flu-like
symptoms
Malaise, nausea and vomiting, anorexia,
fever, muscle and joint pains, right upper
quadrant pain
In HBV Fever, rash and arthralgias due to
circulating immune complexes (serumsickness syndrome)
Glomerulonephritis may be present
Lab exam: Elevated SGPT and SGOT
3. Icteric phase
Jaundice, tea-colored urine, alcoholic stools
Hepatomegaly Liver tenderness d/t distension
of liver capsule secondary to inflammation
4. Convalescent period
Recovery period or resolution with development
of antibodies.
Chronic hepatitis may develop
- Diagnosis of Acute Viral Hepatits
Clinical history
Laboratory Liver Function Test
Serologic study (other cause present with
similar clinical picture) Very critical to determine
etiology
Liver biopsy
Newer tests: PCR (DNA or RNA) to get viral load

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7 | 13

.
Fig. 20. Grossly: Liver is enlarged. There are areas of necrosis that are seen here
as ill-defined soft, pale yellow areas. Green areas are due to accumulated bile
(cholestasis)

Histology of Acute Viral Hepatitis

1. Hepatocytes undergo ballooning degeneration and
death by apoptosis (Councilmans bodies not
apoptotic body)
2. Focal infiltration of liver by lymphocytic cells associated
with necrosis
3. Increased number of lymphocytes in the portal tracts
4. Mild cholestasis
5. Hyperplasia of the Von Kupffer Cells
6. Lobular disarray but not as serious as compared to
cirrhosis (milder)
7. Inflammatory cells around area of necrosis
8. Severe: Bridging / interface necrosis
Note:
Bridging necrosis: Severe cases. Forerunner of progressive
liver damage. Seen more often in chronic viral hepatitis
Microscopic changes similar to all types of virus

Fig. 21. Left: (+) Ill-defined pale-tan area of necrosis, presence of inflam cells
around areas of necrosis, arrows point to councilmans bodies Right: Fresh stain
Necrosis appears as dark hemorrhagic areas, ballooning of hepatocytes (a more
serious form of cloudy swelling) It is vacuolated because of fluid in cytoplasm, death
by apoptosis.

Fig. 22. Ground glass hepatocytes: Deep finely granular acidophilic material in
cytoplasm Accumulation of surface Ag in the cytoplasm of hepatocyte. Seen in
HBV.

4. Chronic Hepatitis
- Not all hepatotropic viruses lead to chronic hepatitis
- Serologic studies very important: Reactive to HBsAg
Chronic hepatitis
- Persistence of symptoms, biochemical changes (liver
enzymes) and serologic evidence for >6 months
- May result from any of the viral hepatitides except HAV or
HEV infection
- Other causes include drugs, alcohol abuse, Wilsons
disease, autoimmune, alpha-1 antitrypsin deficiency
Note:
Only Hep B and C can cause chronic hepatitis. Other causes
of chronic hep are: drugs (isoniazid), chronic alcoholism.
- Classification of Chronic Hepatitis (Histological and
Clinical)
a. Chronic Persistent Hepatitis
- Patient is clinically asymptomatic
- Persistently abnormal amino transferases (mildly
elevated)
- Cirrhosis does not develop
- Liver biopsy: Presence of inflammatory cells in
the portal tract (chronic triaditis) but absence of
liver necrosis

SECTION B

b. Chronic Active Hepatitis

- Serious progressive liver disease marked by
continuous necrosis and fibrosis
- More severe
- Characterized by:
1. Focal, random liver cell necrosis
2. Piecemeal necrosis
Histological hallmark of chronic hepatitis
Spillage of inflammatory cells from
portal tract to adjacent lobule
Necrosis spreads to limiting plate and
causes necrosis of neighboring lobule
3. Bridging necrosis
Inflammatory infiltrates in the portal tract
(predominantly lymphocytes)
Major causes of death:
1. Cirrhosis
2. Massive hematemesis
3. HCC
c. Chronic Lobular Hepatitis
Viral Hepatitis C
- Presence of lymphoid aggregates (chronic)
- Stenosis

Fig. 23. Left: There is bile duct epithelial hyperplasia, lymphoid aggregates are a
sign that is is a chronic infection, presence of fatty change or steatosis. Right: This
is a figure where lymphoid aggregates is appreciated thus only seen in chronic
hepatitis c infection.

Note:
All hepatotropic viruses will give almost the same histologic
findings (thus, serologic is very critical) with little clues suggestive
of what infection it is
Example: Ground glass appearance is suggestive of HepB;
mild fatty steatosis, bile duct cell epithelial hyperplasia, and
formation of lymphoid aggregates are suggestive of HepC
5. Fulminant Hepatitis
- Hepatic insufficiency that progesses from onset of
symptoms to hepatic encephalopathy within 2-3 weeks
who do not have chronic liver disease. (Robbins)
- Sudden appearance of signs and symptoms of hepatic
failure during the course of hepatitis.
- Patient can only be saved with liver transplantation
- 50-65% of the cases are associated with viral hepatitis
- 25-30% are associated with drugs or chemical injury
Drugs can act as either directly hepatotoxic or as a
reaction to the idiosyncrasy of the drug
- Gross:
Liver is small with wrinkled capsule massive/
submassive necrosis Liver size Capsule
loosens and become wrinkled
Muddy red, mushy (in cut surface)
- Histology:
Diffuse or submassive liver cell necrosis because
there are still viable parenchyma
No inflammation because no time ot produce inflam
response
Collapsed liver parenchyma

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Note:
Amebiasis : Amoebic Liver Abscess
Not true abscess: (-) of neutrophil
From amebic colitis
More common in developing countries
(+) Central softening of lesion
Irregular necrosis: Shaggy appearance of abscess
Fig. 24. Left: This is a gross liver of someone who have fulminant hepatitis. Small
and mushy consistency in cutsurface. Right: 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.

Laboratory Findings in Viral Hepatitis

- Chemistry Specimen sample, serum
- AST or SGOT: Aspartate aminotransferase
- ALT or SGPT: Alanine aminotransferase
- ALT and AST are both markedly elevated (usually >8 fold
increase) and both enzymes are elevated to a similar extent
- The pattern of markedly elevated AST and ALT with
mildly elevated Alkaline Phosphatase and LDH is
virtually diagnostic of acute hepatits
- Serologic study
Summary on Hepatitis:
- Viral hepatitis most common primary liver infection
- HAV causes a self limited disease, that never becomes chronic
- HBV can produce carrier, acute, chronic & fulminant, frequency
of chronic is 10%
- HCV causes, carrier, acute & chronic, frequency of chronic is
high (85%), cirrhosis development in 20%.
- Longstanding HBV or HCV Increased risk of development of
HCC.

Common in developed countries

Most common: Staph. aureus and E. coli.
Route of transmission:
1. Systemic blood spread (most commonly via arteries and
portal vein coming from GIT)
2. Ascending spread from bacterial colonization of the biliary
tree aka ascending cholangitis (most common route)
3. Direct: e.g. penetrating injuries and trauma

Fig. 25. Pyogenic liver abscess. Left: Gross Discreet yellow green lesions all
over parenchyma. Right: Microscopically Microabscess of liver contains
numerous neutrophils in the center. The beginning of an organizing abscess wall
with some pink fibrin is seen here.

Fig. 26. Hepar Lobatum. The liver is divided into large nodules with smooth
surfaces . A feature of syphilitic hepatitis seen in tertiary syphilis.

Protozoan Infections
Amebiasis

Amebic abscess conatins nectrotic material

resembling anchovy paste

Malaria

Causes enlarged liver. Kupffer cells are

hyperplastic and and contain malarial pigments
ague cake
Liver is enlarged. Kupffer cells contain Leishmania
which appear as Donovan bodies.

SECTION B

Parasitic Infections
Schistosomiasis:
o Chronic granulomatous necrosis, fibrosis = pipe stem
fibrosis
o Not a true cirrhosis (true cirrhosis = (+) of degeneration)
Ascariasis
Schistosoma
Liver fluke
(C.Sinensis)
Hydatid
disease

Eggs from worms in the biliary tract cause cholangitis

Eggs from worms cause fibrosis in portal tracts Pipe
stem fibrosis
Biliary obstruction. Predispose to development of
cholangiocarcinoma
Multiple liver cysts develop, containing the scolices of
developing worms

AUTOIMMUNE HEPATITIS

Bacterial Infections

Visceral
Leishmaniasis

Fig. 27. This is an amebic abscess of liver. It develops when there is seeding of
infection from the bowel, because the infectious agents are carried to the liver from
the portal venous circulation.

Also known as Lupoid hepatitis

Unknown etiology
Women between 20 to 40 years old
Hypergammaglobulinemia, auto AB (anti smooth muscle,anti
nuclear, anti mitochondrial)
IgG
Inflammatory cells predominantly plasma cells
Clusters of plasma cells in the interface of portal tracts and
hepatic lobules are fairly characteristic for autoimmune
hepatitis (Robbins)
Two types:
o Type I: Presence of anti-nuclear antibody (ANA)
Anti-soluble liver antigen/liver pancreas antigen (AntiSLA/LP)
Anti-actin (AAA)
Anti-smooth muscle (SMA)
Type 1 is more common associated with HLA-DR3
o Type II: Presence of anti-liver kidney microsome 1
(ALKM1)
Which is directed against CYP2D6 and anti-liver
cytosol 1 (ACL-1)
Relapsing and remitting course
Clinical and histological findings are similar to viral hepatitis
Note:
The following features makes it differ from the viral hepatitis
Absence of serologic markers for viral hepatitis
Increase in serum IgG and gamma globulin
Increase in serum titer of autoantibody
Plasma cells is the predominant inflammatory cells

TOXIC LIVER DISEASE

Alcoholic Liver Disease (ALD)
Constellation of hepatic changes associated with excessive
alcohol intake
Most common form of liver disease in USA
Three overlapping forms ALD (may present at the same
time): Fatty Liver Change, Alcohol Hepatitis, Alcoholic
Cirrhosis

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Fig. 31. Gross and histological section of Laennecs liver damage due to alcohol.
Notice the macronodular appearance of the liver, this indicates long standing
disease

Fig. 28. Types of ALD

Fatty change/ Fatty Steatosis

Most frequent morphologic abnormality form

Reversible
More of macrovesicular: Large heavy liver
No necrosis! Only fats inside hepatocytes
In developed countries Common cause is alcoholism
In developing countries Kwashiorkor in children

Fig. 29. Fatty change. This is the histologic appearance of hepatic fatty change.
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 developing nations, kwashiorkor in
children is another cause. Diabetes mellitus, obesity, and severe
gastrointestinal malabsorption are additional causes. No liver cell necrosis

Alcoholic hepatitis
Reversible
Characterized by 4 histologic features: Fatty change, focal
liver cell necrosis, infiltrates of PMNs and Mallory bodies
(in Robbins, fibrosis is one of the histologic changes)
Often associated with fibrosis that surrounds central veins
and individual liver cells, and can eventuate into cirrhosis
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
Mallory Bodies
o Chains of sharply defined eosinophilic cytoplasmic
globules, surrounding the nucleus in an enlarged,
ballooned clear cell
o Composed of masses of intermediate keratin filaments
from cytoskeleton
o Seen in: Alcoholic liver disease, Wilsonss disease
o Not diagnostic for any specific disease

Catabolism of fat More fatty acids.

o Lipid synthesis stimulation due to excess NADH produced
by alcohol metabolism
o Decreased oxidation of fatty acids by mitochondria
o Decreased transport of lipoproteins from the liver due to
acetaldehyde
o All those factors will lead to fat accumulation in the
hepatocyte
Pathogenesis of ALD
- Ingestion of up to 80 gm/ ethanol
(8 beers maam; 6 beers Robbins. Hmmm..)
Mild, reversible hepatic changes is Fatty liver
- Daily intake of 80 gms of more Significant risk for severe
hepatic injury (50-60g is the bodys threshold)
- Daily ingestion of 160 gms or more for 10-20 yrs.
Associated with severe injury
- Female are more susceptible
- Alcohol causes increase mobilization of lipid from adipose
tissue stores Excessive entry of FFA into the liver
- Increased the esterification of FA to triglycerides
- Decreased FA oxidation
- Decreased formation and secretion of lipoprotein
- Malnutrition and vitamin deficiency
- Induces release of vasoconstricting endothelins Activates
the Ito cells to contract Decreased sinusoidal perfusion

Drug and Toxin Induced Liver Disease

Drugs are important and common cause of L.D.
Hepatotoxic drugs may be divided into
a. Intrinsic Dose dependent, predictable
b. Idiosyncratic Unpredictable (hypersensitivity or
abnormal drug metabolism)
Hepatocellular Damage
Microvesicular fatty change
Macrovesicular
Centrilobular necrosis
Diffuse necrosis
Hepatits
Fibrosis/Cirrhosis
Granuloma
Cholestasis

Fig. 30. At high magnification can be seen globular red hyaline 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 cirrhosis/Laennecs cirrhosis

Typical micronodular (<3mm nodules)
In late stages, the nodules tend to become larger and
irregular forming macronodular
Mallory body is rarely seen
Irreversible: Final
o The end stage of alcoholic liver disease is resemble both
macro and micronodule of other types of cirrhosis(post
necrotic cirrhosis.

SECTION B

Example
Tetracycline, aspirin, ethanol
Ethanol, methotrexate
CC14, acetaminophen, rimpin, halothane
INZ, methyldopa, amanita phalloides
Methyldopa, INZ, nitrofurantoin
Ethanol methotrexate
Sulfonamide, quinidine, allupurinol,
hydrazine
Oral contraceptives, chlorpromazine,
erythromycin, anabolic steroids

Note:
Clinically and histologically indistinguishable from viral
hepatitis, hence serologic testing is critical in diagnosis. That is
why Dr. Dy always tells us that use serologic test to rule out viral
hepatitis. Remember! Serologic Serologic Serologic!!

METABOLIC LIVER DISEASE

Non-Alcoholic Fatty Liver Disease (NASH)
General term given to a group of conditions in which fatty
change is a common finding
Not associated with alcohol intake
3 Forms
a. Simple hepatic steatosis
b. Hepatic steatosis with minor non specific inflammation
c. Nonalcoholic steatohepatitis (NASH): Similar to alcoholic
hepatitis; also called cryptogenic cirrhosis due to cirrhosis
of unknown origin

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 Features of NASH:
o Ballooning degeneration
o Steatosis
o Lobular inflammation
o Men and women are equally affected
o Risk factors: Obesity, dyslipidemia, hyperinsulinemia &
insulin resistance
o Pathogenesis: 2 hypothesis
Fat accumulation
Oxidative stress
o Histologic findings are similar to ALD (That is why
history taking is important to know if the patient is really
alcoholic or not)
o NASH: AST/ALT<1 (differentiate it with ALD: AST/ ALT
>2.0)
o Toxicity to mitochondria = SGOT

Fig. 32. Left: The dark brown color of the liver, as 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. Right: The Prussian blue iron stain reveals
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.

Wilsons Disease
Autosomal recessive disorder of copper metabolism
Mutation in copper transport ATP7B gene (chromosome 13)
Pathogenesis:
o Dietary copper is taken to the liver, complex to
ceruloplasmin Plasma
o Circulating ceruloplasmin is recycled by liver and the free
copper is re-exerted into the bile
o Ceruloplasmin = Copper + albumin
Marked by the accumulation of toxic level of copper in
many tissues and organs Liver, brain, eye (Robbins)
Characterized by:
o Basal ganglia degeneration Atrophy and degenration
o Liver cirrhosis
o Kayser-Fleisher ring (cornea) Green to brown depostis
of copper in the Descemets membrane in the limbus of
the cornea (Robbins)
Decreased ceruloplasmin and increased liver copper are
important in diagnosis
Histologic features:
o Fatty change
o Piecemeal necrosis
o Mallory bodies
o Copper accumulation
Macronodular

Hemochromatosis
Caused by excessive deposition of iron
A. Primary Hemochromatosis
Familial defect of iron absorption (mutation of HFE gene)
Triad:
Micronodular cirrhosis
DM
Increased skin pigmentation
Bronzed Diabetes (because of the triad)
Primary HCC development in 14%
Diagnosis; Increased serum iron, increased saturation
of transferrin
B. Secondary Hemochromatosis (Hemosiderosis)
Result of excessive iron accumulation caused by other
primary diseases and repeated blood transfusion
Frequent transfusion Hemosiderin overload
Pigment Cirrhosis (dark-colored )
Triad of pigment cirrhosis:
Hepatomegaly
Skin pigmentation
DM
Common in patients with hemolytic anemia, major
thalassemia

Fig. 33. 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).

Alpha-1 Antitrypsin Deficeincy

Failure to produce normal active cellular protease inhibitor
Homozygote (Pizz) Liver disease and emphysema
Morphology:
Characterized by the presence of round to oval cytoplasmic
globular inclusions in hepatocytes
PAS + and diastase resistant
Clinical Feature:
Neonatal hepatitis with cholestatic jaundice
Adolescence: hepatitis with cirrhosis
Smoking patient: develop emphysema due to deficiency

VASCULAR DISEASE OF THE LIVER

Infarct
Note:
Liver infarction rarely develops d/t dual blood supply
True infarction of the liver is rare
Causes
o Hepatic artery compromise
o Portal vein obstruction and thrombosis
o Surgical trauma
o Therapeutic arterial embolization
o Bacterial endocarditis
o Eclampsia
o Poly arteritis nodosa
Gross: Geographic areas of yellow necrotic tissue

Chronic Passive Venous Congestion

Impaired flow through liver due to
a. Cirrhosis
Because of the compression of the sinusoid and the
central vein by thick fibrous connective tissue
Blood flow impeded
c. Passive Congestion and Centrilobular necrosis
Sinusoidal spaces are congested and compressed
Narrowing of the sinusoids by the cloudy swelling of
hepatocytes Blood flow impeded.
d. Tumors

Budd Chiari Syndrome

Occlusion of main hepatic vein.
o Ascites, jaundice and painful hepatomegaly

SECTION B

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HEPATIC TUMORS
Bening Tumors
Hemangioma

Malignant Tumors

Most common benign tumor of the liver

Can be multiple, found underneath the capsule
Rupture Peritoneal hemorrhage
Accidental finding
Their chief clinical significance is the importance of not
mistaking them for metastatic tumors
Blind percutaneous needle biopsy may cause severe intraabdominal bleeding

A. Primary carcinoma
1. Hepatocellular carcinoma (HCC)
Post-necrotic cirrhosis
Most common primary malignancy of the liver
Frequent complication of cirrhosis
Rare in the US & Europe
Common in the Far East & Africa
Has been associated with aflatoxin B,viral hepatitis
and NASH
Sites of Metastasis: lung, bone, heart, adrenal
Prognosis is poor. Usually 6-7mos after diagnosis
Death is usually due to:
Cachexia
Intercurrent Infection
Liver failure
Hemorrhage
Morphology:
Gross: 3 forms of Hepatocellular carcinoma
1) Solitary
2) Multiple
3) Diffuse
Histology
Composed of malignant cell that resemble the liver
cells & grow in cord like pattern
N:C ratio
Bile production [(+) of bile differentiates HCC from
cholangiocarcinoma (?)]
Shows a high tendency for invasion of Blood vessels
Varies from well-differentiated to highly anaplastic
undifferentiated lesions
Diagnosis:
1) Clinical history
2) Elevated alpha fetoprotein
3) Elevation of dysgammaprothrombin

Fig. 34. This is a benign hemangioma of the liver just beneath the capsule. This is
typically just an incidental finding, since most are 1 cm or less. They can sometimes
be multiple. Histologic: consists of vascular channels on the beds of fibrous
connective tissue.

Hepatic Adenoma
Related to prolonged use of oral contraceptives
Mass that is well-circumscribed from the rest of the
parenchyma. they have propensity to rupture and cause fatal
hemorrhage
Consists of liver cells growing in sheaths but lacks portal tract
& bile ducts
3 reasons of having clinical significance:
1. Present as intrahepatic mass that can be mistakenly for
Hepatocellular CA
2. Subscapular adenoma Highly tendency to rupture
especially in pregnant women which will cause
intraperitoneal hemorrhage
3. Transform into carcinoma
Morphology:
Pale, yellow-tan and frequently bile-stained
Well demarcated nodules found anywhere in the liver but
often found beneath the capsule.
It can be single or multiple.
Histologically appear normal with steatosis commonly present
Portal tract is absent: predominantly solitary arterial vessel
and draining veins are distributed throughout the substance
of tumor
Abundant glycogen may generate large hepatocyte with
clear cytoplasm (looks like fat cells with nucleus push to the
periphery)

Fig. 35. A yellow green solitary mass found beneath the liver.

Fig. 37. Left: 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. Right: The
malignant cells of this hepatocellular carcinoma are well differentiated and
interdigitate with normal, larger hepatocytes. 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.

2. Bile duct Ca (Cholangiocarcinoma) (CCA)

2nd most common hepatic malignant tumor
Associated with clonorchis sinensis infection
It is an adenoCa arising from the bile duct
Not associated with cirrhosis nor HBV infection
Does not produce bile (produce mucin, not bile): This
classification differentiates with HCC since HCC
produces bile
The feature common to the risk factors for
cholangiocarcinomas is that they all cause chronic
cholestasis and inflammation.
Poor prognosis

Morphology:

Fig. 36. 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.

SECTION B

UERMMMC Class 2014

2 forms Extrahepatic and Intrahepatic

Extrahepatic:
Firm gray nodules of bile duct wall
With Klatskin tumor (perihilar tumor which is located at
the junction of right and left hepatic duct)
Intrahepatic
Along the hepatic-portal tract
Resemble adenoCA
Desmophytic with dense collagenous stroma
separating glandular elements thus extremely gritty
and firm

Pathology

12 | 13

Mixed variants of both HCC and CCA

1. Separate tumor masses of both HCC and CCA with in the
same liner
2. collision tumor: both commonly at identifiable interface
3. Tumors in chich both elements are intimately mized at
microscopic level

SHOUTOUTS!
If youre reading this right now, congratulations! You have
the right to say
MERRY CHRISTMAS!!
..
To
th
Pharmacology, Medicine, Psychology 4 LEs
and
st
Surgery, Parasitology 1 LEs

Fig. 38. There is a white mass with a few satellite nodules seen here in the liver.
This primary liver cancer ismuch less common than hepatocellular carcinoma.
Cholangiocarcinomas are not related to viral hepatitis

Fig. 39. The carcinoma 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.

3. Fibrolamellar Carcinoma
Variant of HCC (5%)
Present as single large hard scirrhous tumor
Seen in young adults, no associated risk factor
Good prognosis
Histologically it is composed of well-differentiated
polygonal cells growing in nests or cords
Separated by parallel lamellae of dense collagen
bundles.
B. Metastatic or Secondary Tumors
More common than pimary
(+) of central umblication
HIstology: Clear demarcation of metastatic and normal
hepatocytes

Fig. 40. Left: Note the serrated edges of the tumor and the prominent central
necrosis seen in the larger nodules. Metastases are usually multiple throughout the
liver. Right: Microscopically, metastatic infiltrating ductal carcinoma from breast is
seen on the right, with normal liver parenchyma on the left.

REFERENCES
1. Robbins and Cotran Pathologic Basis of Disease
2. 2013 Transes
3. Lecture and powerpoint of Dr. Dy

SECTION B

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