HEPATIC INJURY
5 General responses :
1)INFLAMMATION (in form of) :
(i) Diffuse inflammation (Hepatitis)
(ii) Localized area of suppuration (liver abscess)
asscociated with infiltration by acute/chronic inflammatory cells
may be limited to : (i)portal tracts
(ii)parenchyma
2)DEGENERATION due to:
(i) Toxic / immunologic insult incucing swollen edematous hepatocytes (ballooning degeneration)
(ii) Accumulation of fat droplets within hepatocytes (steatosis)
3)NECROSIS :
According to causes
Coagulative necrosis
-ischemic necrosis
Councilman
necrosis
-toxic/immunology
reaction
-affecting wide area
-isolated necrosis
According to distribution
Focal necrosis
-limited to scattered cells
within hepatic lobules
Extensive Necrosis
(a)Piece meal necrosis
(a)Bridging necrosis
-between periportal
parenchyma & inflamed portal
tracts
(b)Drop out necrosis
-extends between adjacent
lobules in:
portal to portal
portal to central
central to central
(c)Centrilobular necrosis
(b) Submassive necrosis
-around the central vein
-characteristic of ischemic
injury & number of drgugs &
toxins reactions
-entire lobules
(c)Massive necrosis
-most of liver affected
-associated with liver failure
4)FIBROSIS
 Initial : around portal tracts / central vein /within sinusoids
 Late : fibrous strands link regions of liver – bridging necrosis
5)CIRRHOSIS
-with continuing fibrosis & parenchymal injury,the liver is subdivided into nodules of regenerating hepatocytes
surrounded by fibrous tissue.
LIVER ABSCESSES
Developing countries  liver abscesses due to parastic infections
Western countries  most are pyogenic due to bacterial or fungal infections
Sources of pyogenic infections (reach liver through):
(i) Ascending infection in biliary tract (ascending cholangitis)
(ii) Vascular seedling through portal vein or arterial supply
(iii) Direct infection of the liver from a nearby organ
(iv) Penetrating injuries
Morphology:
Pyogenic liver abscess
Amoebic liver abscess
- Solitary /multiple
- Usually SOLITARY
- Small / large
- Formed of necrotic tissue
- Bacteremic spread through arterial/portal system
produce small multiple abscess
- But NO PUS (note a true abscess)
- Direct extension & trauma cause SOLITARY LARGE
abscess
- Biliary abscess are asscociated with purulent
material in adjacent liver ducts
CLINICAL FEATURES
- Fever
- Right upper quandrant pain
- Tenderness
- Hepatomegaly
- Jaundice may occur due to extrahepatic biliary
obstruction
COMPLICATIONS
(i) Rupture of subscapular hepatic abscess lead to:
Peritonitis
Localized peritoneal abscess
(ii) Rupture of amoebic abscess lead to:
Amaebic abscess in subdiaphragmatic region
which may burrow into thoracic cavity to
produce empyema or lung abscess
LIVER CIRRHOSIS
Definiton : (i) clinically : diffuse chronic progressive liver disease
(ii)pathologically : end stage of liver disease
Characteristics (criteria) :
1) Diffuse parenchymal injury in form of hepatocellular necrosis
2) Healing by:
(a)Bridging fibrous septa
form of delicate bands or broad scars replacing & connecting multiple adjacent lobules
(b)Formation of regenerating nodules
micronodules or macronodules
3) Loss of normal architecture of liver
ETIOLOGIC CLASSFICATIONS OF CIRRHOSIS
1)
2)
3)
4)
5)
6)
7)
8)
Post hepatic cirrhosis mainly due to HBV & HCV
Alcoholic cirrhosis (Laennec’s cirrhosis / portal cirrhosis)
Biliary cirrhosis
Genetic hemochromatosis
Wilson’s disease (rare)
α1 antitrypsin deficiency (rare)
cryptogenic cirrhosis
Others :
drugs, galactosemia, tyrosinosis, diffuse infiltrative cancer ,syphillis and severe cases of central hepatic necrosis
PATHOGENESIS :
“Continuing liver cell necrosis and it’s replacement by progressive fibrosis”
1) Injured hepatocytes & infllammed cells release cytokines stimulate Ito cells  secrete type I & III collagens

Form fibrous tissue
2) Necrotic walls being replace by regenerating hepatocytes  regenerating nodules
3) Net result :
(i) Severe distruption of bloodflow and impaired diffusion of solutes (esp. albumin ,clotting factors,lipoproteins)
(ii) Obstruction of portal circulation  porto-systemic shunts  splanchnic congestion & ascites
Gross
Early : enlarged liver
Progression : become smaller
due to cell loss & fibrosis
Firm consistency
Microscopically
Early : fibrous septa are delicate and extend through
sinusoids
Progression :
wider bands of fibrous tissue (scar) surrounds
regenerating nodules in which regenerating hepatocytes
organized into irregular plates
Multiple nodules (micro /macronodular)
Clinical Features
Complications
-may be silent
1)
-1st sign : complications of portal hypertension
ascites
splenomegaly
caput medusae
hematemesis
hepatic encephalopathy
liver failure
2) Portal hypertension
-non-specific symptoms :
malaise
anorexia
weakness
weight loss
-followed by jaundice,ascites & peripheral edema
-Biochemically :
elevation of serum transaminase level
hyperbilirubinemia
alkaline phosphatase
hypoproteinemia
anemia
3)
Liver failure
Hepatocellular carcinoma
Post necrotic Cirrhosis
Alcoholic Cirrhosis (Laennec’s /Portal Cirrhosis)
-most common type in egypt
-common type in Western countries
Causes:
-mainly by HCV (25%)
-starts with fatty liver
-HBV (1 -5 %)
-history of acute liver damage caused by
hepatotoxins or drugs
Morphology:
(i) exhibits nodules of varying size
(ii) broad bands of scarring
(iii) shrunken liver due to severe collapse
Morphology :
Early : (i) enlarged
(ii)yellow-tan colour
(iii)greasy
Late : (i) size decreases
(ii)brown colour
(iii)uniformly sized micronodules
(iv)mixed micronodular& macronodular pattern
Microscopically :
(i)Broad bands of fibrous tissue
(ii)Mallory bodies
degenerated hepatocytes showing eosinophilic
cytoplasmic inclusions
are characteristics BUT NOT specific features
of alcoholic liver disease
BILIARY CIRRHOSIS
Causes :Obstruction/ destruction of the intrahepatic or extrahepatic branches of biliary tree
Clinical features:
-
Onset is insidious
Pruritis ( due to retention of bile & bile salts)
Jaundice
Portal hypertension
Liver failure
Increase serum level alkaline phosphatase
Increase cholestrol level (markers of cholestasis)
Gross :
- Yellow –green pigmentation
- Finely granular external surface
Primary Biliary cirrhosis
Etiology :
- an autoimmune disease
- characterized by primary destruction of the
intrahepatic biliary branches by granulomatous
inflammation.
- Scarring which progress into liver cirrhosis &
Failure
Age:
- Middle-aged women
- Peak incidence 40-50 years old
- Formation of autoantibodies especially
antimitochondrial Ab (90% cases)
Microscopically
Secondary Biliary Cirrhosis
Etiology :
- Prolonged obstruction of extrahepatic biliary tree
resulting liver damage
Cause of obstruction:
(i) Gall stones (most common)
(ii) Congenital biliary atresia
(iii) Maglinancies of biliary trees and head of
pancrease
(iv) Stricture from previous surgical procedure
Microscopically
- inflammatory infiltrate within portal tracts
- followed by fibrosis & scarring
- inflammatory infiltrate within portal tracts
- followed by fibrosis & scarring
- Inflammation is granulomatous
- mixture of acute & chronic inflammatory cells
- Interlobular bile ducts are destroyed
- interlobular bile ducts are:
dilated
contained inspissated bile (bile thrombi)
proliferation os smaller bile ductules
- End stage is indistinguishable from other forms of
cirrhosis
- End stage is indistinguishable from other forms of
cirrhosis
Genetic (primary) Hemochromatosis
Def :
- A systemic autososomal recessive(AR) disorder
- Characterized by elevated serum iron
- with excessive accumulation o f hemosiderin in
body
(liver,pancreas,myocardium,skin,synovial membrane &
endocrine glands)
Pathogenesis ;
primary defect in intestinal absorption of dietary iron
resulting excessive iron absorption increase serum
level
1/3 accumulates in liver liver injury
Clinical features:
- usually affects male
- rarely becomes evident before 5th decade of life
- liver cirrhosis ( 100% cases)
- panceatic fibrosis (80% cases)
- Diabetes mellitus (80% cases)
- skin pigmentaion (80% cases)
- cardiomegaly in some cases
- hypogonadisim in some cases
- arthritis in some cases
Morphology:
- micronodular cirrhosis
- chocholate in colour
Causes of death:
- liver cirrhosis & it’s complications
- hepatocellular carcinoma
- cardiac dysfunction (arrythymia,cardiomyopathy)
Wilson’s Disease
Def:
- autosomal recessive (AR) disorder of copper
metabolism
- marked toxic levelsof copper in many tissues
(liver , eye ,brain)
Pathogenenis :
copper absorption & transport ARE NORMAL
absorped copper FAILS to form ceruloplasmin
absorped copper fails to reach circulation

Accumlate in liver
age of 5 :non-ceruloplasmin bound copper spills into
circulation

Hemolysis & pathologic changes at other organs
Morphology of liver:
- mild to severe damage
(fatty change,acute & chronic hepatitis,cirrhosis)
- intracellular accumulation of copper
Clinical features :
-rarely manifest itself before age of 6
Most common:
(i) Chronic hepatitis/cirrhosis
(ii) Associated with elevated hepatic copper level
(iii) Increased urinary excretion of copper
(iv) Decreased serum level of ceruloplasmin
Others:
(i) Neuropsychiatric manifestations due to
degeneration of basal ganglia in brain
(behavourial changes,frank psychosis)
(ii) Kayser-Fleischer ring
green to brown ring in Descement’s
membrane in the limbus of cornea
due to copper depostion
doesn’t affect the vision
α1 antitrypsin deficiency
α1 antitrypsin (AAT):
plasma glycoprotein
synthesized predominantly by hepatocytes
a protease inhibitor
(particularly neutrophil elactase released at the sites of
inflammation)
it’s deficiency permits tissue destruction
Definition:
- Autosomal recessive disorder
- Low serum levels of α1 antitrypsin
- Abnormalities in gene forming abnormal α1 antitrypsin
molecules

Accumulation in liver cytoplasm
Morphology:
Hepatocytes contains strongly positive Periodic acid-Schiff(PAS)
stanined around cyoplasmic inclusions of abnormal AAT that persist
after application of diastase enzyme
Clinical features:
(i) Cholestasis in newborn (10-20%)
due to swollen hepatocytes
(ii) Chronic hepatitis,cirrhois or pulmonary disease
in adolescents,adults,older people
due to unopposed activity
(iii) Hepatocellular carcinoma
in 2-3 % homozygous adults
due to chronic & continuous irritation
Cryptogenic Cirrhosis
Hepatic cirrhosis is said CRYPTOGENIC when
complete evaluation of the patient failed to
identify the cause
TUMORS OF THE LIVER
BENIGN TUMOURS (uncommon):
Cavernous Hemangioma
- Most common benign tumor
Gross :
- Discrete red-blue soft nodules
less than 2cm in diameter
beneath the liver capsule
Microscopically :
- Well circumscribed lesions
- Composed of vascular channels lined by
endothelial cells
- Seperated from each other by interverning stroma
Compliaction:
- May rupture leading to life-threatening
intra-abdominal hemorrhage
(especially after blind per-cutaneous needle biopsy)
Liver Cell Adenoma
- Tends to occur in young women
- Regresses on discontinuous of the oral
contraceptive pills
Gross :
- Pale-yellow tan
- Well demarcated
- Frequently bile staineed nodule
- Often beneath the liver capsule
- May reach up 30 cm
Microscopically :
- Composed of sheets & cords of cells
- Resemble normal hepatocytes BUT with NO portal
tracts
- May be mistaken with hepatocellular carcinoma
Complication:
- May rupture particularly during pregenancy
due estrogen stimulation
lead to intra-abdominal haemorrhage
rarely progress to hepatocellular carcinoma
MAGLINANT TUMORS
PRIMARY TUMORS
Type & it’s origin :
(i) Hepatocellular carcinoma (hepatocytes-adults)
(ii) Hepatoblastoma (hepatocytes-children)
(iii) Cholangiosarcoma (intrahepatic bile ducts)
(iv) Angiosarcoma (intrahepatic vasculature)
METASTATIC TUMORS
- Most common maglinant neoplasms involve liver
- Origin of maglinant tumor are found anywhere in
Body
Common primary sites:
- Colon
- Lung
- Breast
- Maglinant melanoma
Characterized by:
- Massive liver enlargement
- Multiple nodules
- Show central necrosis & umbilication
- α-fetoprotein is NOT elevated
HEPATOCELLULAR CARCINOMA (HCC)
- COMMONEST primary maglinant tumour of liver
- Linked strongly prevalance of HBV infection
Etiology
Age
Sex
(i) HBV infection
chronic carrier state may confer 200 fold
increased risk for HCC in adulthood
High incidence area :
3rd – 5th decades of
life
High incidence area :
Male to femae ratio
8:1
(ii)HCV infection
Low incidence area :
6th – 7th decade of
life
Low incidence area :
Male tofemale ration
3:1
(iii) Liver cirrhosis
80% for those having cirrhosis
Due to increased in liver turnover in
regenerating nodules cytologic
abnormalities
due to greater prevalance
of HBV,alcoholism & chronic
liver disease among males
(iv) Aflatoxins
a hepatocarcinogen
from fungus Aspergillus flavus
grows on improperly stored grain &nuts
Morphology
- Soft mass
- Unifocal / multifocal / diffusely infiltrating
Microscopically
(i) Conventional type (99%)
Ranging from well differentiated with
intracytoplasmic bile globules to poorly
differentiated
(ii) Fibrolamellar carcinoma (1%)
A rare type
Characterized by fibrosis
Occurs in young males &females
(20-40 years old)
NO association with CIRRHOSIS / OTHER RISK
FACTORS
Distinctly better prognosis
Clinical Feature & Laboratory Findings
(i) Rapid increase in liver size
(ii) Pain (due to involvement of hepatic capsule)
(iii) Loss ofweight
(iv) Ascites portal hypertension
(v) Paraneoplastic syndrome (ectopic hormones)
Insulin-like polypeptide hypogycemia
Erythropoeitin polycythemia
Parathyroid-like hormone hypercalcemia
(vi) 90% of patients have elevated α-fetoprotein (>1000 ng/ml)
Spread
tends to metastasis early
(i) Direct spread  dipharagm,pleural or peritoneal cavity
(ii) Blood stream  lumgs
(iii) Lymphatics regional lymph nodes
Prognosis
natural history is grim
death occurs within 6 months of diagnosis
Best prevention :
-comphrehensive program for immunizing high
risk world population against HBV
Cholangiosarcoma
- Uncommon tumor
Angiosarcoma
- Rare
- Originates from the intrahepatic biliary tree
- Most arise without evidence/antecedent risk
conditions
- Highly maglinant vascular tumor
- NOT associated with hepatitis / cirrhosis
- Linked to :
Gross:
- Indistinguishable from HCC
Microscopically:
- Adenocarcinoma
- Mucous production
- Abudant fibrous stroma
“DESMOPLASTIC REACTION”
Lab.Findings:
- α-fetoprotein is NOT elevated
(i)polyvinyl chloride (plastic industry)
(ii)thorotrast (radioactive dye)
HEPATIC FAILURE
Definition : Loss ofmore than 80 -90 % of the hepatic functional capacity
Causes
(i) Chronic Liver disease
Most common cause
(ii) Massive hepatic necrosis
Due to fulminant hepatits/drugs
(iii) Hepatic dysfunction without
overt necrosis
Hepatocytes are viable but
unable to perform normal
metabolic function
E.g:Rye’s syndrome
Tetracycline toxicity
Acute fatty liver of pregnancy
Preciptating factors
In form of:
- GiT bleeding
Clinical features
(i) Jaundice
Mainly form of conjugated
Hyperbilirubinemia
- Systemic infection
- Electrolyte disturbance
- Severe stress as major
surgery
- Heart failure
(ii) Hypoalbuminemia
Predispose to peripheraledema
& ascites
(iii) Coagulopathy
(iv) Hyperammonemia
(v) Fector Hepaticus
Formation of mercaptans in gut
(vi) Impaired estrogen metabolism
&hyperestrogenemia leading to:
–gynecomastia
–testicular atrophy
–palmar erythema
–spider angiomas
(vii)Hepatic encephalopathy
(viii) Hepatorenal failure
(ix) Respiratory failure with
pneumonia &sepsis
(x) Coma
usually follow enchephalopathy
& preceds death
BILIARY TRACTS
CHOLELITHIASIS (GALL STONES)
-affect 10-20% of all adults populations in developed countries
Cholestrol stones
- Constitute more than 80% of gallstones
- Type :
(i)pure cholesterol stones (rare)
(ii)mixed stones (common)
Pathogenesis:
(i) Increased cholestrol level
(ii) Decreased bile salts in bile
Risk factors (5 F):
(i) Female
(ii) Above age of 40 years
(iii) Ethic group (Native American population)
Genetic biliary hypersecretion of cholesterol
(iv) Persistent estrogen stimulation
During pregnancy
Effect of oral contraceptive
(v) Obesity
(vi) Rapid weight loss
(vii) Treatments with hypocholesterolemic agents
Morphology:
(i)Pure cholesterol stones:
SOLITARY
oval
pale yellow
maybe translucent
2-3 cm in length
associated with excessive cholesterol in bile
(ii)mixed stones
mixture of cholesterol ,Ca carbonate,
Ca Phosphate and blirubin
always MULTIPLE
Faceted
radio opaqe
Pigment stones
- Constitute less than 20% of gallstones
Pathogenesis:
- Presence of excess unconjugated bilirubin in
biliary tree (as in chronic hemolytic anaemia)
Morphology:
- Small
- MULTIPLE
- FRiABLE
- BLACK
- Radio opaque
- Gall bladder is healthy,NOT inflamed &
normal thin wall
Complications of gall stones :
1) Chronic Cholecystitis
2) Obstruction of cystic duct at the bladder neck leading to :
(i)Acute cholecystitis
(ii)Mucocele
Gall bladder is transformed into a bag full of bile
Bile is graduaaly absorbed
Gallbladder is transformed into a bag full of mucus
(iii)Emphyema
if secondary infection occurs,gallbladder is transformed into bag full of pus
3) Obstruction in of common bile duct leading to:
(i)Ascending cholangitis
(ii)Obstructive cholestasis
(iii)Jaundice
(iv)biliary colic is common
(v)Acute pancreatitis
4) Gallstone ileus
Very rarely
May ulcerate intointestine leading to fistula
Causing intestinal obstruction
5) Carcinoma of gallbladder
Chronic irritation of gallbladder wall by gallstones
CHOLECYSTITIS
Def : Inflammation of gall bladder
Type:
Acute cholecystitis
-usually associated with gallbladder stones
(acute calculous cholecystitis)
-absence of gall stones (5-12%)
(acute acalculous cholecystitis)
Gross:
- Enlarged gallbladder
- Tense & bright red
- Frank pus / gangrenous necrosis
- Lumen is filled with turbid bile
Microscopically:
- Edematous wall
- Infiltrated by acute inflammatory cells
Acute calculous cholecystitis
Acute acalculous
cholecystitis
- Obstruction by gallstones
Occur in seriously ill
patients:
- Lead to obstruction of bile
flow
- Postoperative state after
major surgery
- Distruption of normal
(non-biliary surgery)
protective glycoprotein
- Severe trauma
mucous layer
- Sever burn
- Sepsis
- Exposyre of mucosal
- Postpartum state
epithelium to direct
detergent action bile salts & toxic effect of lysolecithin
- Increased intraluminal
pressure may compromis
blood flow
- Release of prostagladin
leading to inflammation
- Occur in absecnce of
bacterial infection
- Later on,bacterial
contaminatin &
infectionmay develop
Chronic cholecystitis
- Occur either as :
(i)sequal of repeated bouts of acute
cholecystitis
(ii)de novo
- May occur :
(i)chronic calculous cholecystitis
(ii)chronic acalculous cholecystitis
- Most cases are associted with gallstones
- BUT gallstones DO Not play direct role in
initiation of inflammation
- Cause of chronic cholecystitis is SUPER
SATURATION of bile
Gross:
- Gall bladder wall maybe:
contracted
normal in size
enlarged
(when associated with gallstones)
Microscopically:
- Wall is thickened by fibrosis
- Infiltration by chronic inflammatory cells
Acute calculous cholecystitis
Acute acalculous
cholecystitis
Chronic cholecystitis
Clinical features
- Steady upper abdominal
pain
- Radiating pain to right
shoulder
- Are markedly
obscured by the
severe clinical
conditions of patients
Clinical features
- Recurrent attacks of either :
steady or colicky epiastric pain
right upper quandrant pain
- Nausea
- Fever
- Vomiting
- Nausea
- Intolerance to fatty meal
- Vomitting
- Tender,rigid right subcostal
region
- Conjugated
hyperbilirubinemia
Course :
(i) Mildattacks subsides spontaneously over 1-10
days
(ii) Surgical intervention for cholecystectomy
Complications of cholecystitis :
1) Superadded infection leading to:
empyema
cholangitis
sepsis
2)Perforation of gall bladder due to gangrenous necrosis leading to
 local abscess formation
diffuse peritonitis
-
CARCINOMA OF GALL BLADDER
Frequency : 5th most common cancer of GIT
Age & sex :
- Most common in female
- Most frequent in 7th decade of life
Etiology & Pathogenesis ;
Certain factor that lead to recurrent trauma & inflammation :
(i) Gallstones
(ii) Pyogenic & Parasitic diseases in biliary tree
Gross
Form of either:
- Fungating mass
- Diffuse mass infiltrating
Microscopically
- Adenocarcinoma (majority)
- Adenosquamous (rare)
- Sq.cell carcinoma (5 %)
Spread
(i) Local invasion to liver (main)
(ii) Extension to cystic ducts &
portahepatic lymph nodes
(iii)Seedling of the peritoneum &
viscera
(iv)Metastasis to the lungs
Clinical features
Insidious & indistinguishable
symptoms drom those cause by gall
stones
Prognosis
- Extremely poor
- Usually unresectable
- Fortunate patients develop
early obstruction & acute
cholecystitits before their
extension to liver