A - picornavirus
B - hepadnavirus
C - flavivirus
D - defective virus
Physically
E - calcivirus
Cycling
Handicapped
Fellow
Died
 Acute
hepatitis(<6 months )
-It is based upon the following:
 incubation period
 preicteric phase- malaise , fever, fatigue,
nausea muscle and joint ache etc.
 icteric phase- jaundice –conjugated type
 convalescence
Microscopically: (acute hepatitis)
-hepatocyte swelling ( ballooning
degeneration)
- presence of apoptotic hepatocytes are
known as Councilman bodies
-cholestasis –due to bile plug formation
-cytolysis or apoptosis
-lobular disarray- due to loss of architecture
-regenerative changes- hepatocyte
proliferation.
Severe lesions may present with confluent
necrosis of hepatocytes-Bridging Necrosis
 There
are many attributable causes of
hepatitis, which include:
-viruses- CMV, EBV, herpesvirus, etc
-autoimmune
 The
term viral hepatitis is often thought to
be synonymous with diseases caused by the
known hepatotropic viruses, including
hepatitis viruses (HAV), B (HBV), C (HCV),
D (HDV), and E (HEV)
Chronic hepatitis(>6 months)
-continuous inflammation and necrosis
The presence of Fibrosis is the hallmark of chronic
hepatitis. Hence Bridging fibrosis is a characteristic
finding.
-other etiological factors play a an important role that
contribute to the chronicity of the disease
-these factors include: Wilson disease, alcoholism etc.
Microscopically:
it may be confined to portal tracts- known as chronic
persistent hepatitis
it may spillover into the adjacent parenchyma and lead
to “interface hepatitis”- known as piecemeal necrosis
of limiting plate

findings con’t:
HBV type may produce a
ground glass appearance- due
to the accumulation of HBsAg
M/E
Lab
findings:
increased ALT/AST
ALT/AST ratio at least 2:1
Diagnosis
markers
is done by serological
Acute viral hepatitis
 Fulminant
Hepatitis:
 Hepatic failure that progresses within 2-3
weeks period to hepatic encephalopathy in
the absence of chronic liver disease.
 Viral
hepatitis accounts for 12% of Fulminant
hepatic failure.
 Mainly Hep.B and HAV viruses.
 Massive necrosis of contigous hepatocytes
with or without accompanying inflammation.
 Mortality is 80% without treatment, with
renal transplant mortality drops to 35 %.
Hepatitis A
 Type of virus: ssRNA related to
picornavirus
 Transmission: feco-oral route
 Mean incubation period: 2-4 weeks
 Chronicity or carrier state: No
 Clinical disease: acute hepatitis
 Diagnosis: anti-HAV IgM Ab’s
Hepatitis A
 This is a benign and self limited disease
 Clinical disease is usually mild or
asymptomatic
 Factors predisposing humans to HAV
include: overcrowding, poor sanitation
and lack of a reliable clean water
 Since viremia is transient, donated blood
is not screened for
Hepatitis A
 Clinical features include: mild flu like
symptoms, anorexia, abdominal pain,
fever, headache, hepatomegaly
 Prevention: 1)hygiene 2)passive
immunization with immune serum
globulin for individuals exposed to
the virus or those traveling to highexposure areas and
 3) pre-exposure prophylaxis using a
virus inactivated vaccine.
Hepatitis B
Hepatitis B is a worldwide
healthcare problem, especially in
developing areas. An estimated one
third of the global population has
been infected with the hepatitis B
Prevention: vaccines and blood
donor screening
Hepatitis B serological markers
HBsAg
HBeAg, HBV
DNA
HBcAb IgM
HBcAb IgG
HBsAb IgG
Acute
infection
+
+
_
_
Window
period
_
+
_
_
Prior
infection
_
_
+
+
Immunization _
_
_
+
Early phase
of infection
-
-
-
HBsAg + only
Hepatitis C
 Type of virus: ssRNA Flaviridae
 Route of transmission: parenteral or
sexual
contact
 Mean incubation period: up to 2
months
 Chronicity or carrier state: yes
 Clinical disease: acute or chronic
hepatitis/cirrhosis/HCC
 Diagnosis :PCR HCV/ anti-HCV Ab with
3rd
generation ELISA
Hepatitis C
 Hepatitis C is the major cause of
chronic hepatitis in the United
States. HCV infections account for
20% of all cases of acute hepatitis
 Patients may present
asymptomatically or with
subclinical disease.
 Persistence of infection is key in
HCV infections
Hepatitis D
Type of virus: ssRNA Deltaviridae
Transmission: parenteral or sexual
Mean incubation period: same as
HBV
Chronicity or carrier state: yes
Clinical disease: acute or chronic
hepatitis/cirrhosis/HCC
Diagnosis: anti-HDV IgG and IgM;
HDV RNA
HDV
causes a unique infection
HBV infection must be present,
in order for the development of
HDV virion
Co-infected individuals recover
completely, whereas, individuals
with super-infection progress to
severe chronic hepatitis
Hepatitis E
 Type of virus: ssRNA calcivirus
 Transmission:feco-oral
 Mean incubation period: 4-5 weeks
 Chronicity or carrier state: no
 Clinical disease: acute hepatitis
 Diagnosis: anti-HEV Ab for IgM and
IgG/PCR
HEV RNA
 Extremely
fatal in pregnant women
 Pathologic
changes observed in
patients with alcohol-induced liver
disease can be divided into the
following 3 groups: alcoholic fatty
liver (hepatic steatosis), alcoholic
hepatitis, and cirrhosis.
 All
three forms of disease may
present as a spectrum of disease, or
they may occur independently of one
another
 Mild
and reversible changes, as seen in
fatty liver, occur when an individual
ingests as much as 80 g/day of alcohol
 Chronic intake of alcohol of 50 -60
g/day may lead to severe forms of liver
disease
 Females are at an increased risk of liver
disease, when compared to males
 Genetics may play a role; however, no
identifiable genetic markers are known
 Alcohol
metabolism:
most of the alcohol is catabolized by several
pathways, which include:
1) ADH – alcohol dehydrogenase
2) Cytochrome P-450
3) MEOS- microsomal enzyme oxidation
system
Fatty liver (hepatic steatosis)
 Fatty liver is the accumulation of
triglycerides and other fats in the
liver cells
 In some patients, this may be
accompanied by hepatic
inflammation and liver cell death
 Alcoholic fatty liver is an early and
reversible consequence of
excessive alcohol consumption
Fatty liver (hepatic steatosis)
There is a defect in fatty acid
oxidation and lipoprotein synthesis.
This leads to peripheral conversion
of fat and subsequent
hyperlipidemia
 Grossly: large, yellow, greasy liver
 Microscopically : macrovesicular
globules (lipid accumulation within
the hepatocyte displaces the
nucleus to the periphery)
Fatty liver (hepatic steatosis)
con’t
 Lab findings: increased
bilirubin and ALP
 Clinical findings: hepatomegaly
 Treatment: cessation of
alcohol
Gross: fatty liver
Enlarged, yellow, greasy liver
M/E: Two patterns of hepatic steatosis are recognized: (1)
microvesicular steatosis: the cytoplasm is replaced by bubbles of
fat that do not displace the nucleus; and (2) macrovesicular
steatosis: the cytoplasm is replaced by a large bubble of fat that
displaces the nucleus to the edge of the cell.
Alcoholic hepatitis aka steatohepatitis
 Alcoholic hepatitis is a syndrome of
progressive inflammatory liver injury
associated with long-term heavy
intake of ethanol- up to 2 decades
 The MEOS system  forms the
reactive oxygen species (ROS)
release cytokines i.e. TNF, IL-6, IL-8,
IL-18
 The combination of acetaldehyde and
ROS leads to hepatic injury especially
in the centrilobular region
Alcoholic hepatitis con’t
 Microscopically
• Hepatic swelling (ballooning) and
necrosis
• Mallory bodies- intermediate
filaments and proteins appear as
eosinophilic cytoplasmic inclusions
• Neutrophil infiltration- these are
present around degenerating
hepatocytes
• Perivenular fibrosis
Alcoholic hepatitis
 Grossly: red and mottled liver
 Lab findings: increased ALP/ bilirubin /
AST/ ALT
 Clinical findings: malaise, anorexia,
weight loss, hepatomegaly, abdominal
tenderness.
 Prognosis: complete cessation of
alcohol may
heal slowly; it may
progress to
cirrhosis
M/E:
Mallory body is shown within a ballooned
hepatocyte.
Alcoholic cirrhosis
 This is the irreversible form of
alcoholic liver disease
 It has the same features as any other
cirrhosis- abnormal liver
architecture, fibrosis, and vascular
changes
 Grossly : uniformly micronodular
nodules
< 0.3 cm in diameter. The
liver initially is very large; it
eventually transforms into a
shrunken form
Alcoholic cirrhosis
 Clinical findings:
portal hypertension
hepatic encephalopathy
jaundice
other findings thiamine and vitamin B12
deficiency
 Lab findings: increased
ALT/AST/bilirubin/ALP/ hypoproteinemia
 AST/ALT ratio is increased to at least 2 to
1
Gross:
There is diffuse nodularity of the livermicronodular cirrhosis- <3mm in size
 http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC3866949/
NAFLD,Hemochromatosis,Wilson’s
Disease
NAFLD
 Non-alcoholic Fatty Liver Disease
 Group of disorders with the common
features of :Fatty liver and low
(<20g/week)or absent alcohol
consumption. Commonest cause of
chronic liver disease in the U.S.
 Includes: Simple hepatic steatosis,
Steatosis with minor inflammation
and NASH(non-alcoholic steatohepatitis)
NAFLD/NASH
 Pathogenesis :unclear
 Two underlying events:1.Hepatic fat
accumulation 2. Hepatic oxidative stress
 Simple steatosis is usually asymptomatic
but NASH presents with hepatocyte injury
and may lead to cirrhosis(10-20%)
NAFLD/NASH
NASH
 strongly
associated with other components
of the metabolic syndrome :Obesity,
dyslipidemia, insulin resistance,
hyperinsulinemia.
 Lab:
 Elevated AST/ALT
 AST /ALT ratio less than 1.compared with
alcoholic hepatitis where the ratio is
between 2-2.5.
 It
is the abnormal accumulation of
iron in parenchymal organs,
leading to organ toxicity.
 Males: females = 5:1(menstrual
loss reduce progression in women)
 The organs involved are the liver,
heart, pancreas, pituitary, joints,
gonads,skin ETC
 Seen more commonly in people of
northern European ancestry.
 Hereditary
hemochromatosis (primary)
 Genetic mutations
 HFE gene mutation responsible for most
disease. This gene is located close to the
HLA gene on chromosome 6
 HFE regulate the levels of
hepcidin.Mutation leads to low level of
Hepcidin=>increased iron absorption and
transport into plasma.
 Disease becomes evident over the course
of several years. Liver iron stores
approaches 20g/l in symptomatic patients.
 Secondary
hemochromatosis: this is the
acquired form of iron overload, which may
be due to:
• blood transfusions, β-thalessemia,
sideroblastic anemia
 Hemosiderin gets deposited in various
organs.Deposition of hemosiderin without
clinical disease is referred to as
hemosiderosis.
 Grossly:
micronodular cirrhosis
Clinical findings:
Hepatomegaly
Abdominal pain
Hyperpigmentation of skin
Pancreas –diabetes
Heart: arrythmias, cardiomyopathy
Arthritis
Ammenorrhea in females / impotence in males
Liver is affected in 100% of patients. The pancreas and
skin in 80% of patients.
Bronze diabetes is diabetes mellitus plus skin
hyperpigmentation.
 Diagnosis:
liver biopsy –hemosiderin
granules stain with prussian blue
increased levels of iron and ferritin
 Treatment:
desferoxamine and
phlebotomy
 200
fold risk of developing HCC
Gross:
The liver has a dense, rusty colored appearance
M/E:
Prussian blue staining stains the hemosiderin
granules in the cytoplasm
Rare
 Autosomal recessive inherited
disorder of copper metabolism.
 Characterized by excessive
deposition of copper in the
liver, brain, and other tissues.
 It mainly affects the liver,
brain, and eye
It usually presents with Liver
cirrhosis,behavioral changes,
psychosis

 The
genetic defect, localized to
chromosome arm 13q, has been shown to
affect the copper-transporting ATPase gene
(ATP7B) in the liver
 Normally the process of copper metabolism
is as follows:
absorption of ingested copper copperalbumin complex goes to liver formation
of ceruloplasmin  gets released into the
bloodstream  senescent copper returns to
the liver and gets degraded by lysosomes
free copper gets secreted into bile
eliminated from gut
The
gene (ATP7B) mutation
prevents copper to be excreted
into the bile
There is also inhibition of
ceruloplasmin release into plasma
Thus, copper accumulates in the
liver and causes free radical
injury.
 There
is increased urinary excretion
of copper
 In
the brain, affects basal ganglia, the
putamen is mainly affected.
 Grossly:
it may present as fatty change of
liver, acute or chronic hepatitis,
micronodular cirrhosis
Diagnosis:
decreased
ceruloplasmin levels
liver biopsy- increased
copper
increased urinary
copper
Measurement of serum copper
level is not a reliable test to
make diagnosis.
Kayser- Fleischer rings are due to deposition of
copper in the limbus of the cornea. It is usually an
orange brown discoloration
 Histologic
examniation of liver biopsy
specimen from a 24 year old college student
who presents with a chronic history of
recurrent jaundice shows normal looking
hepatocytes. Laboratory findings are shows
unconjugated hyperbilirubinemia. Which of
the following is most likely responsible?
A. Criggler Najar syndrome
B. Gilbert syndrome
C. Rotor syndrome
D. Dubin-Johnson syndrome
 Chronic
and progressive cholestatic disease of
the liver.
 Considered to be an auto immune disorder.
 Inflammation and granulomatous destruction
of intrahepatic bile ducts
 Destruction of the small-to-medium bile ducts,
which leads to progressive cholestasis and
often cirrhosis and end-stage liver disease
 Anti-mitochondrial Ab’s in patients with PBC
 F:M= 6 is to 1
Other
serological associations include:
ANA and ANCA Ab’s
Associated with other auto immune
disorders: Sjogren syndrome ETC
Subsequent to the loss of the
intrahepatic bile ducts, a disruption of
the normal bile flow occurs with
retention and deposition of toxic
substances, which are normally
excreted into bile.
 The
retention of toxic substances, such as
bile acids, can cause further secondary
destruction of the bile ducts and the
hepatocytes
 Clinical findings:
pruritus/ fatigue/ xanthomas/
xanthelasma/ elevated serum cholesterol/
cirrhosis
 Lab findings: Elevated AST/ALT,ALP
bilirubinemia
 Postive anti-mitochondrial antibody test
End stage liver shows yellow green pigmentation
M/E: Lymphocytic and granulomatous destruction
of interlobular bile ducts
Chronic
liver disease
characterized by cholestasis
with inflammation and fibrosis
of the intrahepatic and
extrahepatic bile ducts.
May
lead to cirrhosis of the
liver with portal hypertension
 Associated
with ANCA Ab’s. Note:
anti-mitochondrial Ab’s are present
in minority
 Associated with inflammmatory
bowel disease i.e ulcerative colitis
 Clinical findings:
fatigue/pruritus/jaundice
 Diagnosis ERCP- multiple strictures
and dilations of the intrahepatic and
extrahepatic biliary ducts
Lab
findings: ALP
There
is increased chances of
developing of
cholangiocarcinoma
Involvement of the cystic duct by primary sclerosing cholangitis ERCP
image shows mural irregularity of the cystic duct (arrows) due to primary
sclerosing cholangitis. The intrahepatic and extrahepatic bile ducts show
similar changes associated with this disease
M/E: there is periductal ‘onion skin’ fibrosis
around the bile duct/ lymphocytic infiltration
 Hepatocellular
adenomas occur
mostly in women of childbearing
age and are strongly associated
with the use of oral contraceptive
pills (OCPs) and other estrogens
 Hepatic
adenomas consist of sheets
of hepatocytes without bile ducts
or portal areas.

Hepatic adenomas are tan in color, smooth,
well circumscribed, fleshy in appearance, and
vary from 1 to 30 cm in size.

They have large blood vessels on the surface,
and the lesions may outgrow their arterial blood
supply, causing necrosis within the lesions.

A fibrous capsule may be present or absent; if
absent, this may predispose to intrahepatic or
extrahepatic hemorrhage
 Hepatocellular
carcinoma is the
most common primary malignancy
of the liver.
 It is also known as hepatoma
 Hepatocellular carcinoma occurs
predominantly in patients with
underlying chronic liver disease
and cirrhosis
Note: HCC may also occur in the
absence of cirrhosis
 Risk
factors include:
HBV or HCV infection
 Chronic alcoholism
 Aflatoxin exposure
 Hemochromatosis
 Tyrosinemia
 PBC,PSC
 AAT deficiency
Note: HCV is the most important risk factor (in the
western world)
Hereditary Tyrosinemia (rare) is the condition with the
greatest association with PLCC(40% of cases would
develop cancer)

 Pathogenesis-
unclear
it may develop from pre-existing
nodules high grade dysplastic nodules
i.e cirrhosis
 DNA damage may be caused by cell
death, inflammation, and hepatocyte
replication
 Hepatocyte replication may be due to
point mutations or β-catenin
overexpression or p53
 Clinical
findings:
Hepatomegaly
History of cirrhosis- blood in ascitic fluid
Diagnosis: α-FP (non specific).Useful for
monitoring disease progression
Treatment: liver transplantation or surgical
resection
Gross: this is an example of a multifocal tumor, which is made up
of nodules of varying sizesThere is also cirrhotic liver present
below the cancerous liver
M/E:This is malignant epithelial tumor consists of scant stroma and
central necrosis because of the poor vascularization. In well
differentiated forms, tumor cells resemble hepatocytes, form cords
and nests, and may contain bile pigment in cytoplasm.
 Gallstone
formation occurs because certain
substances in bile are present in
concentrations that approach the limits of
their solubility
 When bile is concentrated in the
gallbladder, it can become supersaturated
with these substances, which then
precipitate from solution as microscopic
crystals
 There
1)
2)
are mainly two types of stones:
Cholesterol stones –it is due to
supersaturation of bile with cholesterol/
calcium salt precipitation/stasis of bile/
mucus hypersecretion
Pigment stones- it is due to the presence
of unconjugated bilirubin
Cholesterol stone risk factors
Age- older individuals
Gender- F>M
Heredity-family history
Estrogen- OCP’s, pregnancy
Weight loss
Hyperlipidemia
Spinal cord injury
Obesity
Gallbladder stasis




Cholesterol stones:
These arise in the
gallbladder mainly
Pure cholesterol
stones are pale
yellow
Cholesterol stones
are radiolucent – if
calcium is present,
they may appear
radiopaque
Pigment stones risk factors
Hemolytic anemias
Biliary tract infections (e.coli,ascariasis,liver
fluke)
Ileal defects- Crohn’s disease/ ileal resection
Cystic fibrosis
Note:
the pigment stones can appear brown or black.
Black stones are usually exclusive to the
gallbladder; brown stones are typically found
in the bile ducts
Pigment stones
Black stones are formed by combination of
unconjugated bilirubin and calcium
Brown stones are formed when bacterial
hydrolysis of lecithin leads to the release
of fatty acids, which complex with calcium
and precipitate from solution. The
resulting concretions have a claylike
consistency and are termed brown pigment
stones




Pigment stones
These stones can
arise anywhere in the
biliary tree
Black stones are
mainly radiopaque
because of calcium
carbonate
Brown stones are
radiolucent due to
the presence of
calcium soaps
 Clinical
features:
it is asymptomatic mainly
if symptomatic- biliary colic- spasmodic
pain
complications include: inflammation of the
biliary tree/ empyema/ perforation/ fistula/
obstructive cholestasis/ pancreatitis
 It
is defined as inflammation of the
gallbladder, which is due to obstruction of
the cystic duct- most common cause:
gallstone impaction
 It manifests in several forms, which
include: acute calculous cholecystitis,
acute non-calculous cholecystitis, and
chronic cholecystitis
 Diagnosis: ultrasonography- thickened
gallbladder wall
Acute calculous cholecystitis
It is inflammation of the gallbladder that is
caused by obstruction of the cystic duct by
gallstones
Obstruction of the ductlecithin converts to
lysolecithin toxic to mucosal layer chemical
type of irritation distension increases
intraluminal pressure  this leads to
compromised blood flow
This condition may require emergent
cholecystectomy or it may subside on its own
Acute calculous cholecystitis
Clinical findings:
fever, nausea,vomiting
mid-epigastric pain to RUQ colicky
pain- may radiate to the tip of the
shoulder
jaundice- obstruction may be present
leukocytosis
gallstone ileus/ perforation/ gangrene
Acute non-calculous cholecystitis
This is not associated with stones
It is associated with serious conditions
i.e. trauma, burns, sepsis, major
surgeries (post-operative)
Predisposing factors include:
dehydration, gallbladder stasis, bacterial
infection, vascular insufficiency
Chronic cholecystitis
Repeated attacks of acute cholecystitis,
which is most commonly due to gallstones
There is consistent chronic inflammation
and stone formation due to the presence of
supersaturated bile
Infection is uncommon, if present, bile
culture will reveal E.coli
Clinical findings: epigastric pain or RUQ
pain
Choledocholithiasis occurs as a result of:
1)The primary formation of stones in the
common bile duct
2)the passage of gallstones from the
gallbladder through the cystic duct into
the CBD
 Cholangitis refers to the inflammation
of the bile ducts. Bacterial infections
are very common – due to E coli,
Klebsiella, Bacteroides, Clostridium,
Bacteroides etc.
 Cholangitis
con’t
Ascending cholangitis
It is an infection of the bile ducts that
ascends up-to the liver and intrahepatic
biliary ducts
Clinical findings:
Fever, chills, and jaundice
Liver abscess
 It
is the most common of all gall
bladder cancers. It is an
adenocarcinoma
 The most common risk factor for
gallbladder cancer is gallstones,
which are present in 75%-90% of
gallbladder cancer cases
 Thus,
chronic inflammation and
trauma predispose the individual to
this type of cancer
 It
may be associated with porcelain
gallbladder- there is dystrophic
calcification within the chronically
inflamed gallbladder wall. Gallstones are
found in over 90% of cases.
 Clinical
findings include:
it may remain asymptomatic
enlarged gallbladderabdominal pain/ jaundice/anorexia
Adenocarcinoma growing in diffuse fashion in the
distal wall of the gallbladder, associated with
extensive involvement of the liver. Most common
type
Adenocarcinoma of the gallbladder having a
predominantly papillary configuration.
 Cholangiocarcinomas
are
malignancies of the biliary duct
system that may originate in the liver
and extrahepatic bile ducts
 The tumor may arise from the
bifurcation of the right and left
hepatic bile ducts- known as Klatskin
tumor(60% of CCA)
 They
can arise more distally as well
 Risk
factors include: primary sclerosing
cholangitis ,caroli disease,HCV infection or
thorotrast dye exposure
 O. sinensis and related liver flukes in South
East asia.
 Clinical findings:
weight loss and anorexia-intrahepatic
jaundice, clay colored stools
Lab findings: increased ALP/ AST/ALT