Dr. BRENDALYN A.

GALLEBO
DEPARTMENT OF HISTOPATH AND LABORATORIES
 PORTAL TRIAD

CENTRAL VEIN
VIRUS HEPA A HEPA B HEPA C HEPA D HEPA E

VIRUS TYPE ssDNA dsDNA ssRNA ssRNA ssRNA

VIRAL FAMILY Hepatovirus Hepadnavirus Flaviviridae Deltaviridae Hepevirus

Picornavirus family
ROUTE OF Fecal-oral Parenteral;Sex Parenteral Parenteral Fecal-oral
TRANS MISION
ulCon;perinatal
INCUBATION 2-6 wks 2-26wks (mean 4-26 wks Same HBV 4-5 wks
PERIOD
8 wks) (mean 9wks)
FREQUENCY OF Never 5- 10% >80% 10%(co-infxn Immunocom
CHRONIC LIVER
DISEASE
90100%(supe promised
rinfxn) hosts
DIAGNOSIS IgM HBsAg or anti-HBc; ELISA Ab IgM ; IgG; HDV IgG ;IgM
PCR for HBV DNA PCR HCV RNA RNA; HDAg liver PCR HEV RNA
 Scant mononuclear infiltrate Portal
Portal Dense mononuclear infiltrate
tract
tract Bridging necrosis

Portal
fibrosis Bridging fibrosis
Ballooning degeneration
Ductular reaction
Apoptosis Interface
hepatitis
Ground-glass cells
Macrophage (Hepatitis B)
aggregates
Apoptosis
Cholestasis Fatty change
Lymphocytes (Hepatitis C)
Apoptosis
Macrophage
aggregate
Central vein
- Ballooning degeneration
- Swellin g
- Cholestasis
- Apoptosis
- Lymphocytic intralobular infiltration
(scant to m0derate)
 Liver cell
pleomorphism
(including ballooning
of hepatocytes)
Canalicular
bilirubinostasis
mononuclear (mainly
lymphocytic)
inflammatory
infiltration (minimal)
 Eosinophil condensation
of hepatocellular cytoplasm
(MalloryDenk body-like)

Apoptotic hepatocyte
Few adjacent mononuclear
inflammatory cells
 Dense mononuclear infiltrate and
macrophage aggregate
Bridging necrosis and fibrosis
Portal fibrosis
Ductular reaction
Apoptosis
Ground glass cells (Hepa B)
Fatty change (Hepa C)
 Bridging confluent
lytic necrosis
Extensive lytic necrosis
in phase and early
fibrosis
Abundant
mononuclear
infiltrates
 Ground glass
hepatocytes

Lymphoid follicle
formation
 Ground glass
hepatocytes
- homogenous pink
cytoplasm
 Moderately dense
portal infiltrate

Macro- and
mediovesicular
steatosis
Most common:

1. Cytomegalovirus
2. Epstein- Barr virus
3. Herpes virus
4. Adenovirus infections
1. Toxic shock syndrome Staph. Aureus
2. Typhoid fever Salmonella typhi
3. Secondary/ Tertiary Syphilis Treponema
pallidum
4. Ascending cholangitis E. coli
 Histoplasmosis : Histoplasma capsulatum
Tuberculosis : Mycobacterium tuberculosis
1. Malaria
2. Schistomiasis
3. Strongyloidiasis
4. Cryptosporidiosis
5. Leishmaniasis
6. Echinococcosis
7. Amoebiasis
8. Liver fluke infection
 Chronic, progressive hepatitis
Features in general:
1. Genetic predisposition
2. Association with other autoimmune diseases
3. Presence of autoantibodies
4. Therapeutic response to immunosuppression
-More common in middle-aged
Usually seen in children and
to older individuals -
teenagers
Presence of:
Antinuclear (ANA) Serologic markers:
Antismooth muscle actin - Antiliver kidney
(SMA) microsome-1
Antisoluble liver antigen/liver- (anti-LKM-1) antibodies
pancreas antigen antibodies - mostly directed against
(anti-SLA/LP) CYP2D6 Anti liver
Anti-mitochondrial (AMA) cytosol-1 (ACL-1)
antibodies - less commonly antibodies
Simplified Diagnostic Criteria (2008) of the International
Autoimmune Hepatitis Group
POINTS
Autoantibodies ANA or ASMA or LKM > 1 : 80 2
ANA or ASMA or LKM > 1 : 40 1
SLA/LP Positive (>20 units) 0
IgG (or >1.10 times normal limit 2
gammaglobulins) Upper normal limit 1

Liver histology Typical for autoimmune hepatitis 2

Compatible with autoimmune hepatitis 1
Atypical for autoimmune 0
Absence of viral YES 2
hepatitis NO 0

Points 7: Definite AIH ; Points 6 : Probable AIH

Lobular hepatitis with
prominent plasma cells
 Liver is the major drug metabolizing and detoxifying organ in
the body (Direct toxicity)

Acetaminophen: most common hepatotoxin of acute liver

failure
Alcohol : most common hepatotoxin causing chronic liver
failure
Toxic metabolite is produced by the cytochrome P-450
system in acinus zone 3 hepatocytes
 Other Drugs:

1. Chlorpromazine
2. Halothane
1. Mild, reversible hepatic steatosis
= short-term ingestion 80 gms of alcohol
(6 beers or 8 ounces of 80-proof liquor)
over 1 to several days
2. Severe hepatic injury
= daily intake of 80 gms or more of ethanol
= significant risk

3. Consistently with severe injury

= ingestion of 160 gms or more for 10 to 20 years

Only 10% to 15% of alcoholics, however, develop cirrhosis

3 distinctive forms of alcoholic liver injury:

(1) hepatocellular steatosis or fatty change

(2) alcoholic (or steato-) hepatitis
(3) steatofibrosis (patterns of scarring)

cirrhosis in the late stages of

disease
1. Gender
= Women more susceptible to hepatic injury than men
= Estrogen increases gut permeability to endotoxins,

LPS receptor CD14 in Kupffer cells

proinflammatory cytokines and chemokines

2. Genetic differences

- ALDH*2, a variant of aldehydedehydrogenase (ALDH)

found in 50% of Asians. Has a very low activity

- Homozygous for ALDH*2 are unable to oxidize

acetaldehyde and do not tolerate alcohol, leading to
alcohol intolerance characterized:
-Upper body flushing
- Nausea
- Lethargy
3. Comorbid conditions
- Iron overload
- Infections with HCV and HBV synergize with alcohol
- Increased severity of liver disease
(1) Hepatocellular steatosis or fatty change
(2) Alcoholic hepatitis
(3) Steatofibrosis
 Small and large fat droplets

Some fibrosis
(characteristic perisinusoidal
chicken wire fence pattern)
 Clustered inflammatory cells
Hepatocyte swelling and
necrosis
Mallory Denk body

Ballooned hepatocytes
Positive immunostaining for
keratins 8 and 18 (brown) with
most hepatocytes
Results from:
(1) shunting of normal substrates away from catabolism and
toward lipid biosynthesis, as a result of:
generation of reduced NADH by 2 major enzymes of
alcohol metabolism
1. Alcohol dehydrogenase
2. Acetaldehyde dehydrogenase

(2) Impaired assembly and secretion of lipoproteins

(3) Peripheral catabolism of fat, thus releasing free fatty acids

into the circulation
Factors:
1. Acetaldehyde - major intermediate metabolite of alcohol
- induces:
Lipid peroxidation
Acetaldehyde protein adduct formation
Further disrupting cytoskeletal and membrane function

2.Cytochrome P-450 metabolism

-Produces reactive oxygen species (ROS) + cellular proteins

1. Damage membranes
2. Alter hepatocellular function
Cytochrome P-450 metabolism:
- glutathione levels (liver prone to oxidative injury)

- alcohol catabolism in the ER and enhances the conversion of

other drugs (e.g., acetaminophen) to toxic metabolites

Activation of inflammatory responses in the liver, due to the

activation of TNF, IL-6, and TGF-

release of endothelins causing :

-vasoconstriction and contraction of activated,
myofibroblastic stellate cells
 Syndromic constellations
Hepatomegaly
Mild elevation of:
Bilirubins
ALPs
Aminotransferases
Neutrophilic leukocytosis

*Other chronic liver diseases: serum ALT > serum AST

* Alcoholic liver disease: serum AST > serum ALT levels
in a 2:1 ratio or higher
 5-year survival approaches 90% in abstainers
- no jaundice
- no ascites
- no hematemesis
50% to 60% continue alcoholic drinking
End-stage alcoholic causes of death:
(1) hepatic coma
(2) massive gastrointestinal hemorrhage
(3) intercurrent infection
(4) hepatorenal syndrome
(5) hepatocellular carcinoma
 end stage of ALL chronic liver
disease, often many years, often several
months
1. Nonalcoholic Fatty Liver Disease (NAFLD)
2. Hemochromatosis
3. Wilson disease
4. 1-antitrypsin deficiency
5. Neonatal hepatitis
-Presence of hepatic steatosis (fatty liver) in
individuals who do not consume alcohol or
do so in very small quantities
(less than 20 g of ethanol/week)
- most common cause of chronic liver disease
ONE OF Diabetes mellitus
or
impaired glucose tolerance
or
impaired fasting glucose
or
insulin resistance
two of: BP: 140/90 mm Hg
Dyslipidemia: (TG): 1.695 mmol/L and
(HDL-C) 0.9 mmol/L (male)
1 mmol/L (female)
Central obesity: waist-hip ratio > 0.90 (male);
> 0.85 (female), o
body mass index > 30 kg/m2
Microalbuminuria: urinary albumin excretion rate of 20 g/min
or albumin-to-creatinine ratio 30 mg/gm
 Insulin resistance gives rise to hepatic steatosis
Hepatocellular oxidative injury resulting in liver cell
necrosis and the inflammatory reactions to it
 Maybe asymptomatic; Others have general symptoms such
as fatigue or right-sided abdominal discomfort
Serum AST and ALT( 90% of patients with NASH)
Cardiovascular disease: frequent cause of death in
patients with NASH
 mixed small and large
fat droplets
Steatosis and steatofibrosis
extending along sinusoids in
chicken wire fence pattern
 excessive iron absorption
deposited in:
-liver and pancreas
-heart
-joints
-endocrine organs

Hereditary hemochromatosis: Genetics

Secondary hemochromatosis: Acquired
 Total body iron pool: 2 to 6 gms in N adult;
- 0.5 gm is stored in the liver, 98% of which is in
hepatocytes
Severe forms: total iron accumulation: > 50 gms,
> 1/3 accumulates in the liver
*Main regulator of iron absorption: protein hepcidin
encoded by the HAMP gene and secreted by the
Hepatocellular protein with bacbactericidal
activities

*Deficiency in hepcidin causes iron overload

Fully developed cases exhibit:
(1) Micronodular cirrhosis in all patients
(2) DM in 75% to 80% of patients
(3) Abnormal skin pigmentation in 75% -80% of
patients

*hereditary hemochromatosis affects:

males > females
(ratio of 5 to 7 : 1)
(1) Hemojuvelin (HJV)

(2) Transferrin receptor 2 (TFR2)

(3) HFE
(1) Hemojuvelin (HJV)
- expressed in the liver, heart, and skeletal
muscle
- Mutations of HAMP and HJV cause
severe juvenile hemochromatosis
(2) Transferrin receptor 2 (TFR2)
- highly expressed in hepatocytes
-mediates the uptake of transferrin-bound
iron
(3) HFE
-Product of the hemochromatosis gene
- Mutation caused adult form of
hemochromatosis
- Gene location: p- arm of chromosome 6 at
6p21.3
-Encodes an HLA class I-like molecule:
intestinal absorption of dietary iron

-
(3) HFE
MUTATIONS:
Cysteine-to-tyrosine substitution at amino acid 282 (called
C282Y)
- Most common HFE mutation
- Present in 70% to 100% of patients diagnosed with HH
-Other common mutation:
H63D (histidine at position 63 to aspartate)
-H63D homozygous state (WW distribution)
-C282Y/ H63D compound heterozygous (White people)
 (1) deposition of hemosiderin (decreasing order of severity)
- liver
-pancreas
-myocardium
-pituitary gland
-adrenal gland
-thyroid and parathyroid glands
-joints
-skin
(2) Cirrhosis
(3) Pancreatic fibrosis
 Prussian blue-stained
section
-hepatocellular iron
appears blue
 A.k.a Congenital hemochromatosis
severe liver disease and extrahepatic hemosiderin
deposition
Not an inherited disease
Maternal alloimmune injury to the fetal liver
Extrahepatic hemosiderin deposition by buccal
biopsy
Result from: Transfusions
Increased absorption

- severe forms of thalassemia

-myelodysplastic syndromes
 autosomal recessive disorder caused by mutation
of the ATP7B gene , located on chromosome 13,
resulting in impaired copper excretion into bile
and a failure to incorporate
copper into ceruloplasmin
 Marked by the accumulation of toxic levels of
copper in many tissues and organs, principally:
- Liver
-Brain
-Eye
 Normally, 40% to 60% of ingested copper (2 to 5
mg/day) is absorbed in the duodenum and
proximal small intestine
- Mutations in the ATP7B gene
causing:
1. copper transport into bile
2. Impairs its incorporation into ceruloplasmin
3. Inhibits ceruloplasmin secretion into the blood

- copper accumulation in the liver

-decrease in circulating ceruloplasmin
1) Promoting the formation of free
radicals by the Fenton reaction
2) Binding to sulfhydryl groups of
cellular proteins
3) Displacing other metals from hepatic
metalloenzymes
1. Brain: Toxic injury primarily affects the basal
ganglia (putamen): atrophy and even
cavitation
2. Eye : Kayser-Fleischer rings, green to brown
deposits of copper in Descemet membrane
in the limbus of the cornea
- acute or chronic liver disease
- 6 and 40 y/o
- Neurologic involvement:
Movement disorders (tremor, poor coordination, chorea or
choreoathetosis)
Rigid dystonia (spastic dystonia, mask like facies, rigidity
and gait disturbances)
-Psychiatric symptoms: depression, phobias, compulsive
behavior, and labile mood
-Hemolytic anemia may occur due to toxicity of copper to red
cell membranes
1. serum ceruloplasmin

2. hepatic copper content

(most sensitive and accurate test)
3. urinary excretion of copper
( most specific screening test)
 Early recognition
Longterm copper chelation therapy
with D-penicillamine or Trientine or zinc-based
therapy
Liver transplantation for individuals with hepatitis
or unmanageable cirrhosis
 Autosomal recessive disorder of protein folding

1AT :small 394amino acid plasma glycoprotein

:member of the serine protease inhibitor (serpin) family
:gene location : chromosome 14

Major function :inhibition of proteases (Pi), particularly

- neutrophil elastase
-cathepsin G
-proteinase 3
1. PiMM - 90% of individuals (the wild-type)
- Some deficiency variants:\

A. PiS variant- moderate reduction of 1AT

without clinical manifestations
B. Pi-null variant - have no detectable serum 1AT

2. PiZZ
A. PiZ : most common clinically significant
 Mutant polypeptide (1AT-Z) is abnormally
folded and polymerized, creating
endoplasmic reticulum stress and triggering
the unfolded protein response

apoptosis
Cholestasis : systemic retention of bilirubin
and other solutes eliminated in
bile
Jaundice and Icterus
- Tissue deposition of bile evident as yellow
discoloration of the skin and sclera
- Due to: bilirubin overproduction
hepatitis
bile flow obstruction
Events:

1. Uptake from the circulation

2. Intracellular storage
3. Conjugation with glucuronic acid
4. Biliary excretion
- Normal serum bilirubin levels:
0.3 - 1.2 mg/dL
- Jaundice becomes evident:
> 2 to 2.5 mg/dL
- Severe disease:
30 to 40 mg/dL
2 forms of bilirubin:
1. Unconjugated bilirubin
2. Conjugated bilirubin (bilirubin glucuronides)
UNCONJUGATED BILIRUBIN
- insoluble in water ( normal pH)
- cannot be excreted in the urine
even when blood levels high
- Severe HDN (erythroblastosis
fetalis)
- Kernicterus
CONJUGATED BILIRUBIN
-water-soluble
-nontoxic
-only loosely bound to
albumin
- excess amount in plasma
can be excreted in urine
2 conditions:

1. Neonatal Jaundice
2. Hereditary Hyperbilirubinemias
- Physiologic jaundice of the newborn
Conjugating and excreting bilirubin function
of the liver is immature until about
2 weeks of age
UGT1A1 gene

-located on chromosome 2q37

- catalyzes the glucuronidation of
bilirubin, steroid hormones,
carcinogens and drugs
- mutations produces hereditary
unconjugated hyperbilirubinemias
1. Excess production of bilirubin
2. Reduced hepatic uptake
-hemolytic anemias
-resorption of blood from internal
hemorrhage
( GIbleed, hematomas)
- ineffective erythropoiesis
(pernicious anemia, thalassemia)
-Drug interference with membrane
carrier systems
- Some cases of Gilbert syndrome
3. Impaired bilirubin - Physiologic jaundice of the newborn
( decreased UGT1A1 activity,
conjugation decreased excretion)
- Breast milk jaundice
(-glucuronidases in milk)
- Genetic deficiency of UGT1A1 activity
(Crigler-Najjar syndrome types I&II)
-Gilbert syndrome
-Diffuse hepatocellular disease (e.g.,
viral or drug-induced hepatitis,
cirrhosis)
1. Deficiency of canalicular -Dubin-Johnson syndrome
membrane transporters -Rotor syndrome

2. Impaired bile flow from duct

obstruction or autoimmune
cholangiopathies
DISORDER INHERITANCE BILIRUBIN LIVER CLINICAL
METABOLISM PATHOLOGY COURSE
DEFECTS

Crigler-Najjar Autosomal Absent UGT1A1 None Fatal in neonatal

syndrome type I recessive activity period

Crigler- Najjar Autosomal Decreased None Generally mild,

syndrome type II dominant UGT1A1 activity kernicterus
(variable (occasionally)
penetrance)
Gilbert Autosomal Decreased None Innocuous
Syndrome recessive UGT1A1 activity
DISORDER INHERITANCE BILIRUBIN LIVER CLINICAL
METABOLISM PATHOLOGY COURSE
DEFECTS

Dubin- Autosomal Impaired biliary Pigmented Innocuous

Johnson recessive excretion of bilirubin cytoplasmic
syndrome glucoronides due to globules
mutation in canalicular
multidrug resistance
protein 2 (MRP2)

Rotor Autosomal Decreased hepatic None Innocuous

Syndrome recessive uptake and storage
Decreased biliary
excretion
impaired bile formation and bile flow

bile pigment accumulation

Due to:
1. extrahepatic or intrahepatic obstruction of
bile channels
2. defects in hepatocyte bile secretion
 Laboratory findings:

serum alkaline phosphatase

serum -glutamyl transpeptidase (GGT)

Causes in adults:

1. Extrahepatic cholelithiasis (gallstones)- MC

2. Malignancies
3. Strictures
Causes in Children:
1. Biliary atresia
2. Cystic fibrosis
3. Choledochal cysts
4. Syndromes of insufficient intrahepatic
bile ducts
Subtotal or intermittent obstruction
Ascending cholangitis
Secondary bacterial infection of the biliary tree

Common culprits: coliforms and enterococci

Most severe form: suppurative cholangitis
Extrahepatic biliary obstruction
- Surgery

Intrahepatic cholestasis/ biliary obstruction

-worsened by an operative procedure
 Intrahepatic bacterial infection
(abscess formation or bacterial cholangitis)

Ischemia
(hypotension caused by sepsis ; cirrhotic liver)
or in response to circulating microbial products

Cholestasis of sepsis

canalicular cholestasis, with bile plugs within centrilobular

canaliculi
 Intracellular cholestasis

- bile pigments in the

cytoplasm
 Bile plug

expansion of bile
canaliculus by bile
 pigmented calcium
bilirubinate stones
in distended
intrahepatic bile ducts
leads to:

1. Repeated bouts of ascending

cholangitis
2. Progressive inflammatory destruction of
hepatic parenchyma
3. Predisposes to biliary neoplasia
 Prolonged conjugated hyperbilirubinemia
in the neonate

Major causes:
(1) Cholangiopathies (biliary atresia)
(2) Conjugated hyperbilirubinemia
(neonatal hepatitis)
 multinucleated giant
hepatocytes
 complete or partial obstruction of the
lumen of the extrahepatic biliary tree
within the first 3 months of life

Single most frequent cause of death from

liver disease in early childhood
50% to 60% of children referred for liver
transplantation
1. Fetal form
- 20% of cases
- commonly associated with:
A. Situs inversus malrotation of abdominal viscera,
B. Interrupted inferior vena cava
C. Polysplenia
D. Congenital heart disease
-Presumed cause: aberrant intrauterine
development of the extrahepatic biliary tree
2. Perinatal form
- normally developed biliary tree is destroyed
following birth
- etiology remains unknown
- leading suspects: viral infection and
autoimmune reactions

1. Reovirus
2. Rotavirus
3. Cytomegalovirus
 salient features:
1. Inflammation
2. Fibrosing stricture of the hepatic or CBD

When biliary atresia is unrecognized or

uncorrected, cirrhosis develops
within 3 - 6 months of birth
1. TypeI Disease: limited to the common duct
2. Type II Disease: limited to right and/or left hepatic
bile ducts
- surgically correctable (Kasai procedure)
3. Type III Disease:
- 90% of patients have biliary atresia
- with obstruction of bile ducts at or above the
porta hepatis
- not surgically correctable
2 main types:

1. Primary biliary cirrhosis (PBC)

2. Primary sclerosing cholangitis (PSC)
2 main types:

1. Primary biliary cirrhosis (PBC)

2. Primary sclerosing cholangitis (PSC)
FEATURES Primary Biliary Primary Sclerosing
Cirrhosis (PBC) Cholangitis (PSC)

AGE Median Age 50 Median age 30 years

(30 to 70)

GENDER 90% Female 70% Male

CLINICAL Progressive Unpredictable but

COURSE progressive

ASSOCIATED Sjogren syndrome(70%) IBD (70%)

CONDITIONS Scleroderma(5%) Pancreatitis (</= 25%)
Thyroid disease (20%) Idiopathic fibrosing dses
(Retroperitoneal fibrosis)
FEATURES Primary Biliary Primary Sclerosing
Cirrhosis Cholangitis

SEROLOGY 95% AMA- POSITIVE 0-5% AMA- POSITIVE

(low titer)
6% ANA- POSITIVE
65% ANCA- POSITIVE

RADIOLOGY NORMAL STRICTURES AND BEADING OF

LARGE BILE DUCTS; PRUNING OF
SMALLER DUCTS

DUCT LESION FLORID DUCT LESIONS AND INFLAMMATORY DESTRUCTION

LOSS OF SMALL DUCTS ONLY OF EXTRAHEPATIC AND LARGE
INTRAHEPATIC DUCTS; FIBROTIC
OBLITERATION OF MEDIUM AND
SMALL INTRAHEPATIC DUCTS
LIVER PORTAL TRACT EXPANSION
ENLARGEMENT, NODULARITY - INFILTRATES OF LYMPHOCYTES
GREEN DISCOLORATION - FLORID DUCT LESION
 Ductular reaction
- scarring
 6

degenerating bile duct 5

is entrapped in a 4
dense, onion-skin
3
concentric scar Series 1
2 Series 2
Series 3
1

0
 Choledochal Cysts
Fibropolycystic disease
 Congenital dilations
of the common bile
duct
Clinical Presentation:
1. Children < 10 y/o as jaundice and/or recurrent
abdominal pain( biliary colic)
2. Female-to-male ratio is 3 : 1 to 4 : 1
3. Risk of bile duct carcinoma In older patients
 Predisposing factor to:
1. Stone formation
2. Stenosis and stricture
3. Pancreatitis
4. Obstructive biliary complications within the liver
 Forms:
1. Segmental or cylindric dilation of the common bile
duct
2. Diverticula of the extrahepatic ducts, or
3. Choledochoceles
- cystic lesions that protrude into the duodenal lumen
 Heterogeneous group of lesions in which the
primary abnormalities are congenital
malformations of the biliary tree
 3 sets of pathologic findings:

1. Von Meyenburg complexes

2. Single or multiple, intrahepatic or
extrahepatic biliary cysts
3. Congenital hepatic fibrosis
 small bile duct
hamartomas
dilated and irregularly
shaped bile ducts
common in otherwise
normal individuals
Caroli Disease
- Symptomatic due to ascending cholangitis

Caroli syndrome
- When biliary cysts occur along with congenital
hepatic fibrosis
 multiple biliary cysts
1. Enlarged portal tracts
by irregular, broad bands of
collagenous tissue, forming
septa

2. Dilated remnants of ductal

plates along the margins of the
stroma

3. Relatively normal intervening

parenchyma
 Impaired Blood Flow into the Liver
Impaired Blood Flow Through the Liver
Hepatic Venous Outflow Obstruction
IMPAIRED BLOOD INFLOW Esophageal varices
-Portal vein obstruction Splenomegaly
-Intra- or extrahepatic Intestinal congestion
-Thrombosis

IMPAIRED INTRAHEPATIC Ascites (cirrhosis)

BLOOD FLOW Esophageal varices
-Cirrhosis (cirrhosis)
-Sinusoid occlusion Hepatomegaly
Elevated
aminotransferases
HEPATIC VEIN Ascites
OUTFLOW OBSTRUCTION Hepatomegaly
-Hepatic vein thrombosis Abdominal pain
(Budd-Chiari syndrome) Elevated
-Sinusoidal obstructive Syndrome aminotransferases
Jaundice
 Distal hepatic tissue is pale,
Hepatic Artery Compromise
with a hemorrhagic margin
1.Thrombosis or compression of
an intrahepatic branch of the
hepatic artery by embolism
2. Neoplasia
3. Polyarteritis nodosa
4. Sepsis
Portal Vein Obstruction and Thrombosis

1. Extrahepatic portal vein obstruction

Ex: Pancreatitis and pancreatic cancer

2. Intrahepatic portal vein radicles obstruction

by acute thrombosis

infarct of Zahn
(demarcated area of red-blue discoloration )
Schistosomiasis egg deposition
- most common cause
 Cirrhosis : most common cause
Other causes:
1. Sickle cell disease
2. Disseminated intravascular coagulation
3. Eclampsia
4. Diffuse intrasinusoidal metastatic tumor
 Sickle cell crisis in liver

sinusoids containing
sickled red cells
 sinusoidal dilation occuring in impeded hepatic
blood efflux
Seen in:
1. Bartonella infected AIDS patients
2. Cancer
3. Tuberculosis
4. Posttransplantation immunodeficiency
5. Sex hormone administration (e.g., anabolic
steroids, oral contraceptives, danazol)
 Hepatic Vein Thrombosis
- obstruction of 2 major hepatic veins

Budd-Chiari syndrome
1. liver enlargement
2. pain
3. ascites
 Associated Conditions :

1. Myeloproliferative disorders: polycythemia vera

2. Inherited disorders of coagulation
3. Antiphospholipid antibody syndrome
4. Paroxysmal nocturnal hemoglobinuria
5. Intraabdominal cancers(hepatocellular CA)
6. Pregnancy or oral contraceptive use
 Thrombosis of the
major hepatic veins

hemorrhagic liver
necrosis
2 settings of occurence:

(1) Following allogeneic hematopoietic stem cell

transplantation (within the first 3 weeks)
(2) Cancer patients receiving chemotherapy

Mortality rates can be > 30%

 Marked sinusoidal
congestion
Hepatocyte atrophy and
loss
Organizing thrombus
within the vein lumen
 hepatic manifestations of systemic circulatory
compromise

Nutmeg Liver : combination of hypoperfusion

retrograde congestion

centrilobular
hemorrhagic necrosis
variegated mottled red
appearance
-Organ or Hematopoietic Stem Cell
Transplantation
- Graft-Versus-Host Disease and Liver Graft
Rejection
- Acute
- Chronic
 - Occurs 10- 50 days after hematopoietic
stem cell transplantation
- donor lymphocytes attack the epithelial cells
of the liver:
1. Hepatitis with necrosis of hepatocytes
and bile duct epithelial cells
2. Inflammation of the parenchyma and
portal tracts
- usually > 100 days after transplantation
- Manifestations:
1. Portal tract inflammation
2. Selective bile duct destruction
3. Fibrosis
- Acute cellular rejection
- Mixed inflammatory
cell infiltration in
portal tracts

- eosinophils
- lymphocytes
- endotheliitis
 Viral hepatitis (HAV, HBV, HCV, or HBV + HDV)
- most common cause of jaundice in pregnancy
HEV infection: more severe course in pregnant
patients
: fatality approaching 20%
Preeclampsia
- affects 3% to 5% of pregnancies
- Manifestation:
-maternal hypertension
-proteinuria
-peripheral edema
- coagulation abnormalities
Eclampsia
- Pre- eclampsia + hyperreflexia and convulsions occur
- life-threatening

HELLP syndrome
- subclinical hepatic disease
- primary manifestation of preeclampsia
- syndrome of:
hemolysis
elevated liver enzymes
low platelets
Fatal case
Subcapsular hematoma
dissecting under Glisson
capsule
 subclinical or modest hepatic
dysfunction ( serum aminotransferase)
Can lead to hepatic failure, coma, and
death
Usually in 3rd trimester
Rare
 primary treatment: Pregnancy termination
- Generally a benign condition
- Manifestations:
1. Pruritus in the 3rd trimester
2. Darkening of the urine
3. Light stools
 Laboratory exams:
- Serum bilirubin (mostly conjugated) rarely
exceeds 5 mg/dL
-Sl. Elevated alkaline phosphatase
-Bile salts level increased greatly
Can cause:
Fetal distress
Stillbirths
Prematurity
 Solitary or multiple
2 Conditions:
1. Focal nodular hyperplasia
2. Nodular regenerative hyperplasia
- well-demarcated but poorly encapsulated
nodule
- presents as a spontaneous mass lesion in an
otherwise normal liver
- mostly affects young to middle-aged adults
- Light-yellow to yellow
(steatosis) lesion

- Central gray-white,
depressed stellate scar
- broad fibrous scar with
hepatic arterial and bile
duct elements

- chronic inflammation
present
 blood vessel tumor
most common benign liver tumor
Discrete red-blue, soft nodules
<2 cm generally located beneath the capsule

chief clinical significance:

mistaken radiographically or intraoperatively
for metastatic tumors
 Blood-filled vascular
channels separated by a
dense fibrous stroma
 Benign neoplasms developing from hepatocytes
Associated with the use of:
-oral contraceptives
-anabolic steroids
 Three large subtypes:

1. HNF1- Inactivated hepatocellular adenomas

2. -Catenin Activated Hepatocellular Adenomas
3. Inflammatory hepatocellular adenomas
 90% :mutations of HNF1-
10% :germline mutations
Heterozygous germline mutations:
Autosomal dominant MODY-3
(maturity onset diabetes of the young, type 3)
- More commonly found in women
- Oral contraceptive pills use is implicated in some
 Associated with neoplasia and malignancy
Management: Resection even when
asymptomatic
Associated with: oral contraceptive
anabolic steroid use
Affects Male = Female
 Affects Male = Female
Associated with non-alcoholic fatty liver disease
Definite risk of malignant transformation
Management: Resection even asymptomatic
 activating mutations in gp130

1. JAK-STAT signaling
2. Overexpression of acute phase
reactants
- C-reactive protein
- serum amyloid A
 pendulous mass arising
from the liver

cords of hepatocytes,
with an arterial vascular
supply
 can be primary or metastatic
Most primary liver cancers :
1. hepatocellular carcinoma (HCC)
2. cholangiocarcinomas
3. hepatoblastoma
 most common liver tumor of early childhood
rarely occurs > 3 years of age
Incidence: 1 to 2/ 1 million births
characteristic feature:
1. activation of the WNT signaling pathway
2. mutations in APC gene
 Associated with :

1. Familial adenomatous polyposis

2.Chromosomal abnormalities
3. Beckwith-Wiedemann syndrome
2 primary anatomic variants:
1. epithelial type
2. mixed epithelial and mesenchymal type
 12-week-old infant
well circumscribed and has a
variegated appearance
 2 anatomic variants:

1. epithelial type
- small polygonal fetal cells
or smaller embryonal cells
forming acini, tubules or
papillary structures
 mixed epithelial and
mesenchymal type

- foci of mesenchymal
differentiation that may
consist of primitive
mesenchyme, osteoid,
cartilage, or striated muscle
- a.k.a: hepatoma
Southeast asia: >85% of cases with high rates of
chronic HBV infection
Western counties: associated with high rates of
hepatitis C epidemic

5th most common cancer and 3rd cause of cancer-

related mortality WW
Case : 500,000 to 1M new cases every year
1. Activation of -catenin
2. Inactivation of p53
3. IL-6/JAK/STAT pathway
Most important Factors:
1. viral infections (HBV, HCV)
2. toxic injuries (aflatoxin, alcohol)
Metabolic diseases such as:
- hereditary hemochromatosis: high frequency
-1AT deficiency: high frequency
- Wilson disease: less frequency
 unifocal neoplasm
replacing most of the
right hepatic lobe

distorted architecture
large pseudoacinar spaces
Thickened hepatocyte
trabeculae
 HEPATOCELLULA SMALL CELL LARGE LOW GRADE HIGH GRADE
R ADENOMA CHANGE CELL DYSPLASTIC DYSPLASTIC
CHANGE NODULE NODULE
FOCALITY IN single or multiple diffuse diffuse single or single or
LIVER (adenosis) multiple multiple
PREMALIGN yes yes in some uncertain yes
ANT HBV
ASSOC W/ rare common Common usual usual
CIRRHOSIS
COMMONLY NAFLD,sexhorm HBV, HCV, HBV, HCV, HBV, HCV, HBV, HCV,
ASSOC W/ Glycogen Alcoh,NAFLD Alc,NAFD, Alc,NAFLD, Alc,NAFLD,
DISEASES storage diseases A1AT, A1AT, HH A1AT, HH,PBC A1AT, HH,PBC
HH, PBC PBC
Occurrence Occasional NO NO NO NO
w/outpredis
Condition
Surveillance Depends on the YES YES YES YES
& screening presence of PDFs
LARGE CELL CHANGE SMALL CELL CHANGE
 distinctive variant of HCC
constitutes < 5% of HCCs
85% occur < 35 y/o
no gender predilection or identifiable
predisposing conditions
- usually presentation:
- single
-large
- hard scirrhous
tumor
- fibrous bands
coursing through it
- composed of well-
differentiated cells
rich in mitochondria
(Oncocytic cells)

- growing in nests or
cords
-parallel lamellae of
dense collagen bundles
1. Laboratory studies:
- rising serum -fetoprotein: 50% of persons
with advanced HCC
- insensitive as a screening test for premalignant/ early lesion

2. Imaging studies: most valuable for small tumors

- ultrasonography (ID for distinctive nodules)
- CT scan and MRI with vascular/contrast studies
(1) Cachexia
(2) Gastrointestinal or esophageal variceal
bleeding
(3) Liver failure with hepatic coma
(4) Rupture of tumor with fatal hemorrhage

5-year survival: w/in the first 2 years

 2nd most common 1 malignant tumor of
the liver
malignancy of the biliary tree, arising from
bile ducts within and outside of the liver
 Accounts for 7.6% of cancer deaths WW a
It is more common in Southeast Asia
northeastern Thailand, Laos, and
Cambodia
due to infestation with liver flukes
 Most important:

Biliary intraepithelial neoplasias

(low to high grade, BilIN-1, -2, or -3)
1. Intrahepatic (10%)

2. Extrahepatic
A. Perihilar tumors (Klatskin tumors) (50%-60%)
- located at the junction of the right and left
hepatic ducts
B. Distal tumors (20% to 30% )
- arising in the CBD (posterior to the duodenum
 Poor
Survival for extrahepatic tumors :
About 15% at 2 years after diagnosis

Median intrahepatic CCAs

median time from diagnosis to death:6 months
 Infestation by the liver
fluke Clonorchis
sinensis
 Invasive malignant
glands in a reactive,
sclerotic stroma

Perineural invasion by
malignant glands,
forming a wreathlike
pattern around the
central, trapped nerve
1. Endothelial malignancies:
1.1. Angiosarcoma :associated with:
vinyl chloride
Arsenic
Thorotrast
- fatal
1.2. Epithelioid hemangioendothelioma
- much more variable prognosis
2. Hepatic lymphomas
- primarily diseases of middle aged men a
- Most common: diffuse large B-cell lymphomas
MALT lymphomas (2nd)

- Delta-gamma T cell lymphoma

- most common in young adult males
- predilection for hepatic and splenic
sinusoids as well as the marrow
 more common than primary hepatic
neoplasia (95%)

Adenocarcinoma: Most common

-GIT (Most common)
- Breast
-Pancreas
- Lung
 1 L of bile/ day : liver secretion
Bile storage and concentration
Adult gallbladder has a capacity of 50 mL

Cholelithiasis (gallstones)
>95% of biliary tract disease
Congenital Anomalies:
1. Phrygian cap most common
- folded fundus
2. Agenesis
3. Hypoplastic narrowing of biliary channels
4. Choledochal cysts
 Phrygian cap
Folding inward
2 general classes of gallstones:

1. cholesterol stones
- >50% of crystalline cholesterol
monohydrate
2. pigment stones
- composed predominantly of bilirubin
calcium salts
 Thickened wall of the
gallbladder
with fibrosis due
faceted black gallstones
Mostly made up of
calcium salts of unconjugated
bilirubin
 - precipitated in 90% of cases by obstruction of
the neck or the cystic duct by a stone
- primary complication of gallstones and the
- most common reason for emergency
cholecystectomy
- Salmonella typhi and staphylococci
Acalculous Cholecystitis (10%)
- without gallstones
- may occur in severely ill patients
- sequel to repeated bouts of mild to severe
acute cholecystitis
>90% associated with cholelithiasis
at-risk patient population is the same as that for
gallstones
E. coli and enterococci
 Mononuclear infiltrates

Mucosal fusion and folds

giving rise to buried crypts
of epithelium within the
gallbladder wall
(Rokitansky- Aschoff
sinuses)
 most common malignancy of the
extrahepatic biliary tract
women 2x than men
majority of patients are diagnosed at an
advanced, surgically unresectable stage
Mean 5-year survival: < 10%
 Overexpression of:
oncoprotein ERBB2 (Her-2/neu)
- seen in a third to two-thirds of cases

Mutation of chromatin remodeling genes

(PBRM1 and MLL3)
- seen in > quarter of cases
 Adenocarcinomas: MC

large, exophytic tumor

that virtually fills the
lumen

Malignant glands
infiltration in fibrotic
gallbladder wall