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The normal liver is brown
with a smooth surface. Wt:
1200 - 1600 grams. In
conditions like steatosis, theliver has a yellow
appearance. In severe
cholestatic disease, the liver
has a greenish appearance,
http://library.med.utah.edu/WebPath
External surface of a normal liver (anterior & posterior view).
http://www.daviddarling.info/encyclopedia/L/liver.html
Portal Vein
Hepatic
artery Hepatic (central) Vein
Bile ducts
Bile duct
Cut surface of a normal liver (near the hilum) Dual Blood supply of the liver:
systemic and portal circulation
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Limiting plate THE PORTAL TRACT:
Each portal tract contains a bile duct, several bile
ductules, a branch of the hepatic artery and a
branch of the portal vein, embedded in connectivetissue. Normal portal tracts contain a few
lymphocytes, macrophages & mast cells but no
neutrophils or plasma cells.
The hepatocytes bordering the portal tracts are
joined together and form a distinct row called thelimiting plate (arrows). Destruction of this limiting
plate by apoptosis and/or necroinflammation is a
hallmark of chronic hepatitis (piecemeal
necrosis/interface hepatitis)
TERMINAL HEPATIC VENULE (“central vein”):
There is no limiting plate around the terminal
hepatic venule. Vessel walls have Type I collagen
and there is generally less fibrosis around the central
vein compare with portal vein.
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The structural organization of the
liver is based on its blood supply:
The lobule is a hepatic unit centeredaround the hepatic vein.
The acinus is a unit centered around
the terminal branches of the portal
vein and hepatic artery.
The acinus is separated into zones 1, 2
and 3 with the most oxygenated areasbeing zone 1.
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As shown in the figure, the central
veins join to form the right. left or
middle hepatic veins, which empty
into the inferior vena cava.
The Bile ducts converge to form the
hepatic duct
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Central Vein
Portal
track
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A lobule is defined as the hepatic unit surrounding a hepatic (central) vein. The black
concentric lines separate the hepatic lobule into zones 1-3 (Zone 3 is closest to the central
vein). The distribution & extent of liver injury is often described in terms of zones involved.
The blue line shows the border of one lobule.
Normal liver showing portal tract (PT) and a central vein/terminal hepatic venule (TV). Theblack concentric lines separate the hepatic lobule into zones 1-3. The distribution andextent of liver injury can also be described in terms of zones involved. The blue line showsthe border of one lobule.
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STRUCTURE AND FUNCTION OF A HEPATIC LOBULE
ZONE 1: Periportal zone. It is nearest to the entering vascular supply and gets the most
oxygenated blood. Functionally, zone I hepatocytes are also specialized for oxidative liver
functions such as gluconeogneeis , B-oixidation of fatty acids and cholesterol synthesis. It isalso the area first exposed to (and affected by) infectious agents.
ZONE 2: The intermediate zone.
ZONE 3: Pericentral (centrilobular zone). This zone is the most vulnerable to ischemic
damage, because it has the poorest oxygenation. Zone 3 is more important for glycolysis,
lipogneneiss and and contains the cytomchrome P450 complex, which is used in the
metabolism and elimination of certain drugs.
ZONE 1
ZONE 2ZONE 3 Under normal
conditions, each
hepatocyte shouldbe in contact with
the canalicular
space and the
sinusoidal space
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Zone 3 is most vulnerable to ischemic damage. This can occur during conditions
that lead to hypoperfusion of the liver. E.g. hypovolemic shock, a myocardialinfarction, or any other condition causing heart failure..
Old area of centrilobular (Zone 3) necrosis
secondary to cardiogenic shock
Portal tract
Central Vein
Zone 3
Zone 1
Zone 2
The microscopic figure shows
an old area of centrilobular
necrosis in a patient with a
history of a myocardial
infarction. Note the paucity of
zone 3 hepatocytes. The pale
pink staining is due to
replacement fibrosis.In this example, the ischemic
damage also extends partially
into Zone 2. The hepatocytes
in zone 1 are relatively spared
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Sinusoids
Plates are one cell layer thick in a normal adult liver
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• Hepatocytes are arranged in sponge-like plates that are normally one cell layer
thick and separated by sinusoids.
• The individual hepatocyte is polygonal in shape and 70% of the surface area is
basolaterally oriented (ie facing the sinusoids)
• >1 cell layer plates suggests regeneration. In children up to 5-6 years, the liver
cells are arranged in two-cell thick plates
• In the middle panel, straight black arrows indicate the location of bile canaliculi.
Curved arrows show the endothelial cells in the sinusoids.
Sinusoids
Cholestasis showing bile
accumulation in canaliculi
Plates
Bile canaliculi
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TEST SERUM MEASUREMENT
Hepatocyte Integrity Cytosolic hepatocellular enzymes†
Serum aspartate aminotransferase (AST)
Serum alanine aminotransferase (ALT) Serum lactate dehydrogenase (LDH)
Biliary Excretion Substances secreted in bile†
and function Serum bilirubin
Total: unconjugated plus conjugated
Direct: conjugated only
Delta: covalently linked to albumin
Urine bilirubin
Serum bile acids
Plasma membrane enzymes (from damage to bile canaliculi)
Serum alkaline phosphatase
Serum γ-glutamyl transpeptidase (GGT)
Serum 5'-nucleotidase
Hepatocyte Function Proteins secreted into the blood
Serum albumin‡
Prothrombin time† (factors V, VII, X, prothrombin, fibrinogen)
Hepatocyte metabolism
Serum ammonia†
Aminopyrine breath test (hepatic demethylation)Galactose elimination (intravenous injection)
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Serum lab test abnormalities are frequently the first or only sign of liver disease. Some
common lab tests and their clinical significance are discussed below:
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): Very high AST levels (~3000 U/L) are most consistent with acute process like acute viral
hepatitis, toxic injury (e.g acetaminophen), or centrilobular necrosis due to hypotension.
Elevations of ALT and AST in the 100-300 U/L range are typically associated with chronicdiseases such as alcoholic liver disease and chronic viral hepatitis.
Elevated ALT and AST with an AST/ALT ratio 2:1 is classically associated with alcoholichepatitis, whereas the reverse is more common in viral hepatitis.
ALT elevations are more specific for liver disease than AST elevations.
Gamma-glutamyltranspeptidase (GGT):
Released by damaged hepatocytes & bile duct epithelial cells. It is highly sensitive for liver
disease. If GGT is normal, there is generally only a 1 –2% chance of liver disease.
Alkaline phosphatase (ALP):
Elevated in both liver and bone disease. A concomitant elevation in both ALP and GGT isconsistent with cholestatic liver disease.
Prothrombin time (PT) and albumin levels:
While GGT, AST and ALT indicate hepatocyte damage, prothrombin time (PT) and serum
albumin are more reflective of the functional status of the liver. Factor VII has a serum-
half life of ~4 hrs, making the PT a good assessment of an acute change in liver function.
Albumin levels are more accurate at assessing a chronic change in liver function.
INTERPRETATION OF LABORATORY TESTS IN LIVER DISEASE
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REASONS FOR PERFORMING A LIVER BIOPSY
Evaluation of abnormal liver function tests
Evaluation of fever of unknown origin
Evaluation of jaundice of unclear etiology
Evaluation of portal hypertension and ascite
Evaluation of hereditary or metabolic disease
Evaluation of abnormal serum iron studies
Grading and staging of chronic hepatitis
Monitoring the effects of new or established therapy
Grading and staging of chronic biliary disease
Confirmation of fatty liver and grading and staging of Steatohepatitis
Diagnosis of space-occupying lesions
Evaluation of transplanted liversOdze Surgical Pathology of the GI Tract
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Percutaneous Suction needle or
cutting needle.
The most common, least expensive, and least
invasive type of liver biopsy.
Transjugular
(transvenous)
Catheter through the
internal jugular vein,
right atrium, and
inferior vena cava
• 2nd-line procedure in patients with acoagulation disorder, gross ascites, obesity, or
fulminant hepatic failure.
• Multiple specimens easily obtained.
• Can concurently measure hemodynamics.
• Complications: arrhythmias & rxn to contrastmaterial.
Laparoscopic or
open biopsy
Direct visualization of
the liver and
peritoneal cavity.
Needle or wedge
biopsy
More sensitive for diagnosis of cirrhosis and
chronic liver diseases, such as primary
sclerosing cholangitis, viral hepatitis, and
nodular regenerative hyperplasia.
CT or US-guided
<1-mm needle
usually used.
Ultrasound or CT is
used for visualization
of lesion and to avoid
intersecting vessels.
For histologic or cytologic diagnosis of space-
occupying lesion or when the patient's
anatomy makes finding landmarks difficult.
Types of Liver Biopsies
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Types of Hepatic Injury and patterns of injury
HEPATOCYTE RESPONSES TO INJURY
•Cell death (Necrosis, apoptosis): Several patterns of necrosis can be seenin the liver: Interface hepatitis, bridging necrosis, spotty/lobular
necrosis, submassive necrosis (necrosis of entire lobule) and massive
necrosis (necrosis of almost the entire liver, e.g. Tylenol overdose or
fulminant viral hepatitis)
• Intracellular accumulations : e.g. micro and macrovesicular steatosis
• Inflammation (acute or chronic)
• Regeneration
• Fibrosis
Although many different toxins, infections, and other conditions affect the liver, the liver only
has 5 general responses to injury: inflammation, cellular accumulations, cell death, fibrosis, &
regeneration. The distribution of these patterns of injury (e.g periportal vs. centrilobular,
etc) is also very important in determining the etiology.
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Hepatocyte apoptosis: Councilman
bodies (arrow) represent apoptotic
hepatocytes. Common in chronic
Hepatitis C
Periportal chronic inflammation
Most common in chronic Hepatitis
C infection.
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Interface Hepatitis (“Piecemeal necrosis) is a hallmarkof chronic hepatitis.
Interface hepatitis.
Portal tract
Normal portal tract
The hepatocytes bordering the portal tracts form a distinct row called the limitingplate (arrows). Destruction of the limiting plate by apoptosis and/ornecroinflammation is a hallmark of chronic hepatitis (interface hepatitis). Note
that the limiting plate in interface hepatitis is irregular due to expansion oflymphocytes and hepatocyte injury.
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Ballooning degeneration is classically seen
in alcohol-related steatohepatitis. Theclumpy eosinohpilic material at the
periphery of the nuclei is called “Mallory’s
Hyaline” and represents detached
intermediate filaments form the damaged
cell membranes.
Microvesicular steatosis (e.g.
fatty liver of pregnancy)
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CENTRILOBULAR NECROSIS
Centrilobular necrosis:
Necrotic hepatocytes around
central vein, usually due to
ischemia, drugs or toxins. It is a
common finding at autopsy,because it is associated with
circulatory failure or shock which
is common before all deaths
Central Vein
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Masson
s Trichrome: Stains collagenType I (highlights fibrosis)
Reticulin Stain: Collagen Type III
(lines sinusoids)
PAS/PAS-D: PAS stains Albumin and
Glycoproteins (eg alpha-1-antitrypsin
inclusions or ceroid in macrophages).
Iron stain: The lower panel showsiron accumulating in kupffer cells.
Gram, AFB, Fungal stains
Trichrome stain (blue)
Iron stain (blue)
Normal medium-sized portal tract
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Reticulin stains Collagen Type III (lining
sinusoids), thus outlining the hepatic plates
Reticulin
PAS
PAS and PAS-Diastase (PAS-D):PAS stain glycogen and glycosylated
proteins. Strong PAS staining in the
cytoplasm of hepatocytes is due mainly toglycogen stores.
Concurrent digestion of tissues with
diastase in PAS-D stains ( PAS+ Diastase)
prevents PAS from detecting albumen and
other glycoproteins (e.g. mucin). However,certain proteins that are resistant the
diastase digestion (e.g. alpha-1-antitrypsin)
can still be detected wit PAS-D.
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Cirrhosis is a term used to describe diffuse fibrosis & nodular
regeneration resulting in severe scarring and disruption of the
hepatic architecture
Cirrhotic liver
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•
Alcohol abuse: 6 –15% of chronic alcoholics develop cirrhosis• Viral hepatitis; hepatitis C (about 50% of chronic HCV patients.
Hepatitis B is less likely to progress to cirrhosis, unless a chronic
infection develops.
•
Nonalcoholic fatty liver disease (NAFLD) or non-alcoholicsteatohepatitis (NASH). Incidence is rising dramatically. Up to 10%
of patients.
• Metabolic diseases: e.g. hereditary hemochromatosis, Wilson’s, a-
1-antirypsin disease• Biliary Diseases: e.g. PBC and PSC
• Crypotgenic: A term is used when there is no recognizable cause of
the cirrhosis.
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Gross findings: Diffusely nodularliver with micronodules ( <3 mm
diameter) or macronodules ( >3 mm
diameter).
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Microscopic findings: In most cases of cirrhosis, The liver has a nodular appearance at
low power. The nodules are bound by bands of fibrosis that bridge the portal tracts.
Liver, trichrome stain
Low power microscopic view showing portal
to portal bridging fibrous bands (blue)
C t f f i h ti li h i i d l
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Cut surface of a cirrhotic liver showing micronodules
(< 3 mm) and macronodules (> 3 mm).
White areas rounding the nodules represent bands of bridging fibrosis. On H&E sections,
these fibrous bands bands stain pale pink and on trichrome-stained sections, the fibrous
bands stain blue.
Macronodule
MicronodulesFibrosis
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CIRRHOSIS
Micronodular cirrhosis: This type of cirrhosis is often due to
metabolic insult, such as alcohol, hemochromatosis, Wilson’s.
Liver, sectioned
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In cirrhosis, hepatic myofibroblasts, known as Ito, or “stellate” cells are activated to deposit
collagen & matrix material in the lobule and perisinusoidal spaces, creating septal tracts. This blocks
endothelial fenestrations preventing free exchange of materials from the blood. The ito cells also
constrict sinusoidal vessels forcing blood to be shunted around the parenchyma. Activated Kuppfer
cells also produce cytokines that promote fibrosis . Bile channels are obliterated, due to disruptionof interface between parenchyma & portal tracts, causing jaundice.
Normally, collagen types I & III are present predominantly in the portal tracts, around
central veins and occasionally in the space of Disse .
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• Progressive hepatic failure, due to hepatocellular dysfunction: This leads
to impaired protein synthesis (e.g., decreased albumin and decreased clotting factors),
which result in numerous complications, including bleeding tendencies and contributes to
ascites, low BUN levels, and elevated ammonia levels (which can cause hepatic
encephalopathy).
• Portal hypertension and related problems (see portal hypertension section)
• Ascites: (see ascites section)
• Increased risk Hepatocellular Carcinoma• Spontaneous bacterial peritonitis (SPB): Infection of ascitic fluid, usually by
Enterobacteriaceae or Pneumococcus. The source of the infection is generally unknown,
and there is no evidence of perforation, etc. in these cases.
• Portal vein thrombosis
• Hyperestrinism: Causes Gynecomastia and testicular atrophy in men. Spider
angiomas and palmar erythema are also related to hyperestrinisim.
TREATMENT: Liver transplant is the only current “cure”.
Portosystemic shunts can partially
alleviate portal hypertension
PORTAL HYPERTENSION
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Portal hypertension occurs when there is increased
resistance to portal venous blood flow. This resistance
forces blood returning to the heart (via the liver) to
take alternate routes (formed by portocavalanastomoses). These portocaval anastomoses often
become engorged due to high pressures, and may
even varicose or rupture as a consequence (e.g.
Esophageal varices). Portal hypertension contributes
to the development of ascites and splenomegaly.
The most common cause of portal hypertension iscirrhosis.(~60% of cirrhotics have portal
hypertension), , followed by portal vein obstruction
Treatment: Transplant, Transjugular intra-hepatic
portal-systemic shunting (TIPS),
PORTAL HYPERTENSION
Figure: The Porto-Caval System showing areas
most affected by portal hypertension.
Transjugular intra-hepatic
portal-systemic shunting
(TIPS)
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CAUSES OF PORTAL
HYPERTENSION
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TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC
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TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC
SHUNT (TIPS)
Complications of TIPS
• Occlusion of shunt
• Uncontrollable hepatic encephalopathy
(since a portion of blood bypasses the
liver the body will be less efficient at
removing ammonia)
•
Hepatic venous stenosis• Formation of intrahepatic haematomas,
which may rupture, causing
haemorrhage.
• Infection and sepsis.
A transjugular intrahepatic portosystemic shunt (TIPS) is a treatment for
portal hypertension, in which a direct communication is formed between
a hepatic vein and a branch of the portal vein, thus forming a shunt that
bypasses the liver.
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Hepatic encephalopathy is a complex neuropsychiatric syndrome that occurs in advanced
liver disease, when the liver’s ability to remove & metabolize nitrogenous compounds is
impaired. Therefore high levels of NH3 accumulates in the blood. This excess ammonia is
converted to glutamine in the brain, which has a harmful effect in high concentrations.
Common precipitating factors include GI bleeds, infections, high dietary protein loads,
sedatives, portosystemic shunts, constipation, alkalosis, dehydration.
CLINICAL PRESENTATION:
Asterixis and hyperreflexia. Fetor hepaticus (musty odor of breath).
Changes in personality, sleep & cognitive function.
TREATMENT:
Lactulose: This is a non-absorbable disaccharide metabolised by colon flora to acetic acid
& lactic acid, thus lowering gut pH. The increased H+ ions draw out NH3 from the blood
to form insoluble NH4+. The osmotic property of lactulose also helps to draw out fluids
and hasten the transit of colonic content.
Antibiotics: Clears colon of urea-splitting bacteria (e.g. neomycin)
Probiotics: Lactobacillus acidophilus & Enterococcus faecium compete with &
lower/replace the gut’s urea splitting bacteria, which reduces NH3 reabsorption.
Liver transplantation: Restores liver’s ability to detoxify NH3
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AMMONIA (NH3) METABOLISM
Ammonia is produced from dietary amino acids & other nitrogenous compounds.Most NH3 (> 80%) is metabolized in hepatocytes, where it is converted to urea .
The rest is metabolized in peripheral tissues
When the liver’s function is compromised, NH3 levels rise and peripheral tissues
such as the brain take up more NH3 than usual. The brain normally metabolizes
NH3 by converting it to glutamine. When serum NH3 levels are high the glutamineproduct accumulates in the astrocytes, causing cerebral edema & symptoms of
hepatic encephalopathy.
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VIRAL HEPATITIS
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Viral hepatitis can be asymptomatic, or it can present with malaise and weakness,
nausea and anorexia, jaundice, or dark urine. Laboratory studies show markedly
elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) .
ACUTE VIRAL HEPATITISThis is defined to be viral hepatitis with signs and symptoms for <6 months. It can be
caused by any of the hepatitis viruses. Microscopically, the liver shows lobular
disarray, hepatocyte swelling (balloon cells) , apoptotic hepatocytes (Councilman
bodies), lymphocytes in portal tracts and in the lobule, hepatocyte regeneration, and
cholestasis.
CHRONIC VIRAL HEPATITIS:
This is the term used for viral hepatitis with signs and symptoms for >6 months. It can
be caused by hepatitis viruses B, C, and D.Microscopically, chronic persistent hepatitis shows inflammation confined to portal
tracts. Chronic active hepatitis shows inflammation spilling into the parenchyma,
causing interface hepatitis (piecemeal necrosis of limiting plate). Hepatitis B often has
"ground glass" hepatocytes (due to cytoplasmic HBsAg).
VIRAL HEPATITIS
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The sequence of serologic markers in acute hepatitis A infection. HAV, hepatitis A virus. There
are no routinely available tests for IgG anti-HAV; therefore the presence of this antibody is
inferred from the difference between total and IgM-HAV.Downloaded from: StudentConsult (on 28 October 2013 01:30 PM)
© 2005 Elsevier
Hepatitis A virus (HAV) is transmitted solely
by the fecal-oral route. Person-to-person
spread of HAV is enhanced by poor personal
hygiene and overcrowding. Outbreaks, have
been traced to consuming contaminated
food, water, milk, and shellfish. It is not
spread by blood transfusion and sexual
contact.
Hepatitis A usually is a benign, self-limiteddisease with an incubation period of 2 to 6
weeks (average 28 days). HAV does not cause
chronic hepatitis or a carrier state. Rarely
there is fulminant hepatitis; fatalities occur at
a rate of only 0.1%. The disease tends to be
mild or asymptomatic in children, with severeHAV infections occurring mainly in adults.
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HBV is a DNA virus (whereas the other hepatitis viruses are RNA
viruses). Unlike HAV and HEV, which are transmitted via the faecal-
oral route, HBV, HCV & HDV are transmitted via the parenteral
route. Its major antigens are: HBsAg, A surface protein) and HBcAg
& HBeAg: Core proteins. Antibodies to HBsAg (anti-Hbs) areprotective in HBV infections. Persons with anti-HBs (from prior
infection or immunization) are protected against reinfection with
the virus.
Acute hepatitis B infection is diagnosed by the presence of hepatitis
B surface antigen (HBsAg) in the clinical context of elevated serum
transaminase levels & jaundice
© 2005 Elsevier
Downloaded from: StudentConsult (on 28 October 2013 01:30 PM)
There is often a “window period” of a few
wks between the disappearance of HBsAg &
appearance of anti-HBsAb. During this
interval, the presence of anti –hepatitis B core
antigen IgM (anti –HBc IgM) is indicative of
acute HBV infection.
Hepatitis B precore antigen (HBeAg)
represents a high level of viral replication. It
is usually present during acute infection, but
its persistence after 6 wks of illness is a sign
of chronic infection & high infectivity.
Persistence of HBsAg or HBeAg is a marker for
chronic hepatitis or a chronic carrier state;
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The vast majority of patients with acute HBV infection (~96%) fully recover. Only 4% develop
chronic HBV hepatitis. Of those 4%, ~ 20-30% eventually progress to cirrhosis. Once cirrhosis
has developed in chronic HBV, there is a 2.5% risk/year of developing hepatocellularcarcinoma (HCC). This differs from HCV infection, which has a much higher risk of chronicity.
HBV infection, Clinical Outcome:
• Sublicinal disease (60-65%)
• Acute hepatitis with recovery and clearanceof the virus (20-25%)
• Fulminant hepatitis with massive liver
necrosis (< 1 %)
• Nonprogressive chronic hepatitis
• Progressive chronic disease (< 4%). A subset
may progress to cirrhosis or HCC.
• An asymptomatic carrier state (5-10%)
*The likelihood of chronicity after acute HBV infection isrelated to age: Young infected immunocompetent adultshave a very low risk of chronniciity, infected newbornshave a a 90% chance of chronic infection;
HBsAg – The ‘s’ stands for surface, and refers to a protein on the surface of the virus. It is the
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H sAg The s stands for surface, and refers to a protein on the surface of the virus. It is the
first detectable antigen to appear after someone has been infected, and can be positive in
acute or chronic disease. It appears before symptoms begin, peaks during overt disease and
declines to undetectable levels in 3 to 6 months if the patient has effectively cleared the
infection. . Patients who still carry this antigen after 6 months are termed hepatitis carriers
(i.e. they will either be asymptomatic or develop chronic hepatitis). It is this antigen that isused to make the hepatitis B vaccine
Anti-HBs antibody – This is an IgG antibody that appears after the host has cleared the
infection, and indicates recovery. It appears around the time of disappearance of HBsAg and
indicates complete recovery. It is also found in persons who has been effectively vaccinated
against hepatitis B
HBeAg – the ‘e’ (envelop protein) antigen is often used as a marker of infectivity, as it is only
found in the blood when the virus is actively replicating It peaks during acute disease and
disappears before HBsAg is cleared. Persisistence of HBeAg is an important indicator of
continued viral replication with probable progression to chronic hepatitis. If a patient is able
to clear HBeAg but not HBsAg, then they will usually be asymptomatic carriers.
Anti-HBc IgM – (“c” stands for core) This indicates that the patient has recently been infectedwith hepatitis B, and is a marker of acute infection
Anti-HBc IgG – (“c” stands for core). This is produced in response to the core antigen, and
often persists for life. IgM and IgG antibodies which can tell you whether the infection is
acute or chronic. Therefore, with normal recovery from hepatitis B, both antibodies to the
surface protein and core protein should both be present. Patients who have been immunized
will only have anti-HBs
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Chronic HBV infection is characterized by a periportal chronic inflammatory infiltrate.
Active HBV infection is characterized by the presence of viral inclusions in the hepatocyte
cytoplasm, imparting a pale, smooth pink (“ground glass”) appearance (blue arrow). A liver
biopsy is not needed to diagnose hepatitis B; serologic tests are sensitive enough to make thatdiagnosis. However, a liver biopsy may be indicated in order to grade the degree of inflammation
& fibrosis and to monitor disease progression.
Active hepatitis B
Portal tract
Bile ducts
Normal
hepatocytes
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Hepatitis C accounts for most (but not all) cases of Hepatitis viral-related cirrhosis. It was formerly
called "non-A, non-B hepatitis". Both chronic HBV and HCV are characterized by a mononuclear
periportal chronic inflammatory infiltrate (i.e. predominantly (lymphocytes). However, progression
to chronicity is far more common in HCV. Acute infection with HCV is often subclinical, an unlikeactive HBV which manifests as “ground glass” opacities, Hep C inclusions are not visible on H&E .
J. Glickman, BWH, Boston, MA
Periportal chronic inflammation
Periportal chronic inflammation
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Interface hepatitis
The presence of apoptotic hepatocytes,
known as “acidophil” bodies or“councilman bodies” are another common
feature of chronic viral hepatitis. These
apoptotic hepatocytes (arrows) have
condensed bright eosinophilic cytoplasm
and dark condensed nuclei that are often
not visible.
The region of hepatocytes in direct contact with
the “border” of portal tract is called the limiting
plate (arrows). Inflammation of this region is
called interface hepatitis (previously called
“piecemeal necrosis” . The presence of
hepatocellular necrosis at the interface is one of
the hallmark histologic findings in chronic viral
hepatitis. In the above figure, the inflammation
has extended beyond the limiting plate, into the
lobular areas.
Interface hepatitis, high power: (Arrows
demonstrate apoptotic hepatocytes)
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• ~80-85% of patients with acute HCV
infection will develop chronic HCV hepatitis.• Of those patients, ~20% will eventually
develop cirrhosis.
• Once cirrhosis has developed, the risk of
developing hepatocellular carcinoma is 2-
5% per year.
HCV: Factors that promote disease
progression & severity.
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Sequence of serologic markers for HCV. HCV infection can be diagnosed by serologic
studies or viral PCR studies
Anti –hepatitis C antibody is present in acute hepatitis C, but the test result
may be negative for several weeks. The hepatitis C RNA assay, which
becomes positive earlier in the disease course, often aids in the diagnosis.
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Hepatocellular necrosis may be followed by repair in the form of bridging fibrosis, where the
fibrosis extends from one portal tract to another. Continued damage and fibrosis may lead to
widespread bridging and architectural distortion called cirrhosis. The finding of bridging fibrosis in a
liver biopsy is usually a sign of impending cirrhosis.
LIVER, Trichrome stain
BRIDGING FIBROSIS (ARROW)
Cirrhosis in a patient with chronic HCV
LIVER, Trichrome stain
CIRRHOSIS
Cirrhosis in a patient with chronic HCV
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Gross section of a cirrhotic liver (micronodular & macronodular) due to chronic Hep
C, exacerbated by the patient’s history of alcohol abuse. Microscopically these
nodules are all surroundED by bands of bridging fibrosis (blue on trichrome stain)
Cirrhosis in a patient with chronic HCV
CIRRHOSIS
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Portal/periportal
activityLobular Activity Fibrosis
None/minimal 0 None 0 None 0
Portal only 1Inflammation 1No neccrosis
Portal 1
Mild Piecemeal 2
NecrosisFocal Necrosi s 2 Septal 2
Moderate Piecemeal 3
Necrosis
Severe Focal 3
Necrosis
Bridging, 3
Early Nodules
Severe Piecemeal 4
NecrosisBridging Necrosis 4 Cirrhosis 4
J. Glickman
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SUMMARY OF GENERAL MICROSCOPIC FEATURES OF
CHRONIC HBV AND HCV INFECTION
• Portal tract mononuclear inflammation
• Interface hepatitis: Periportal inflammation that extends
beyond the limiting plate (“piecemeal necrosis”)
• Lobular Activity: Lobular mononuclear inflammation,
Lobular hepatocyte necrosis
• Later stages: Fibrosis, Cirrhosis
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What diseases are depicted in each liver?
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PRESENTATION: Most pts .are asymptomatic. However, moderate congestion causes RUQ
discomfort (from stretching of liver capsule) & tender hepatomegaly. Severe congestion leads
to massive hepatomegaly & jaundice. Congestive hepatopathy should be suspected in
patients who have rt-sided heart failure, jaundice, and tender hepatomegaly. Ascites may
result from the transmitted central venous hypertension; Infrequently, splenomegaly occurs.
FINDINGS. When congestion is related to central venous hypertension (e.g. right heart
failure), patients will have a positive hepatojugular reflex**. When related to Budd Chiari
syndrome, the hepatojugular reflex will be absent.
Lab test results are modestly abnormal and may include unconjugated hyperbilirubinemia, ↑
elevated aminotransferases & prolonged PT/INR. However, because these lab abnormalitiesare nonspecific, recognition of congestive hepatopathy is ultimately clinical.
TREATMENT: Treatment is directed at the underlying cause.
Hepatic congestion (or congestive hepatopathy) refers to diffuse venous congestion within
the liver. It is most commonly caused by right-sided heart failure (usually due to
cardiomyopathy, tricuspid regurgitation, cor pulmonale or constrictive pericarditis) or any
disease that impedes hepatic venous outflow, such as Budd Chiari-syndrome. The resultingincreased central venous pressure is transmitted to the liver via the IVC & hepatic veins.
**Hepatojugular reflex: The clinician presses firmly over the RUQ for 10 seconds. A positive result is
defined as a sustained increase in JVP > 3 cm (Whereas in healthy individuals, the JVP remains
constant or temporarily rises for 1-2 heartbeats before returning to normal )
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“Nutmeg” liver
Markedly dilated sinusoids
Microscopically, hepatic congestion is
chacterized by marked sinusoidal dilation that
is most pronounced around the central vein,
which is also usually dilated.
The “nutmeg” appearance of the liver on gross
examination is due to backup of the blood into
the liver, giving the liver a mottled appearance.
The dark red congested areas represent
accumulation of RBC's in centrilobular regions.
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Chronic hepaticcongestion withfibrosis
CentralVein
CentralVein
Portaltract
Centrilobular fibrosis
If the condition persists, centrilobular congestions
and necrosis can occur. The findings are most
pronounced when there is biventricular heart
failure (ie. Concurrent right-sided and left-sided
heart failure). Left-sided heart failure results in
hypoperfusion of the liver, causing hepatocyte
necrosis that is most pronounced in centrilobular
areas (hepatocytes surrounding the central
veins/Zone 3), since this area is most vulnerable to
ischemic damage.
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If the passive congestion is pronounced, then there can be centrilobular
necrosis, due to poor oxygenation in zone 3 of the hepatic lobule
If chronic hepatic passive congestion continues for a long time, a condition called
"cardiac cirrhosis" may develop in which there is fibrosis bridging between central
zones, so that the portal tracts in zone 1 appear to be in the center of the reorganized
lobule. This process is best termed "cardiac sclerosis" because, unlike a true
cirrhosis, there is minimal nodular regeneration.
Centrilobular hepatocytenecrosis due to congestion
Bridging
fibrosis
“Cardiac cirrhosis)
Central veinZone 1
Zone 3
Zone 2
“CARDIAC CIRRHOSIS”
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Gross image of cut liver surface showing
nodular subdivision of liver parenchyma
Low-power image of reticulin stain
showing bridging fibrous septa betweenterminal hepatic veins, with intact portal
tracts within the center of parenchymal
islands.
CARDIAC CIRRHOSIS
Reticulin stain
BUDD CHIARI SYNDROME
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Budd-Chiari syndrome is caused by occlusion of the inferior vena cava or the
hepatic veins. It results in centrilobular congestion and cetnrilobular necrosis.
If unresolved, it leads to congestive liver disease, characterized by hepatomegaly,ascites, abdominal pain and eventual liver failure. Patients usually develop varices
and have visible abdominal and back veins.
It can usually be distinguished from right heart failure by the absence of jugular
venous distension (JVD).
Etiology: Budd Chiari most
commonly arises in:
• Hypercoagulable states
•
Polycythyemia vera• Pregnancy
• Hepatocellular
carcinoma.
In this example of Budd Chiari syndrome, Thrombosis of the major hepatic
veins has caused profound hepatic congestion.
Sinusoidal obstructive syndrome (formerly known
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y ( y
as veno-oclusive disease/VOD)
HISTOLOGIC CHARACTERISTICS
• Striking centrilobular congestion
• Centrilobular hepatocellular necrosis
• Intact portal tract
• Accumulation of hemosiderin-laden
macrophages.
• Obliteration of the terminal hepatic
vein with collagen deposition.
A central vein is occluded by cells and newly formed
collagen (stained blue by trichrome) . There is also fibrosis
in the sinusoidal spaces.
The key feature of sinusoidal obstruction syndrome is Liver toxicity due to obliteration ofsmall hepatic veins.• Most commonly encountered following bone marrow transplants, usually within 1st month.
• Results from toxic doses of drugs given in preparation for bone marrow transplant: Also seen
following overdose of certain herbal medicines (e.g. Jamaican bush tea) or following radiation injury.
• Patients present with jaundice, tender hepatomegaly, RUQ pain, unexplained weight gain and
substantially elevated transaminases.
• Mechanism: Drugs cause toxic injury of the sinusoidal endothelial cells which slough off of the
sinusoidal walls and embolise downstream obstructing sinusoidal blood flow.
• Differential: Other causes of venous outflow obstruction such as CHF, Budd-Chiari syndrome, drug
reactions, GVHD.
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Slightly enlarged liver with a yellowish appearance,
Microvesicular steatosis
Macrovesicular Steatosis: results from an imbalancebetween the uptake, utilization and mobilization of fat from
the liver cells. Microscopically it is characterized by
hepatocytes with one large cytoplasmic fat vacuoles. It
tends to be most prominent around the central veins. I is
Associated with alcohol (most common cause), obesity, drug
reactions (e.g. to steroids), malnutrition (e.g. kwashiorkor)
and diabetes.
Microvesicular steatosis: Many small vacuoles in each
hepatocyte. It is associated with acute fatty liver of
pregnancy, Reye syndrome (occurs in children with viral
illness when given aspirin), alcohol, and certain drugs (e.g.,
tetracycline). It is related to mitochondrial damage.
Macrovesicular steatosis
Effects of alcohol in the liver:
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1. Accumulation of triglycerides: Alcohol and its metabolites affect virtually every aspect of lipid
metabolism in the liver, resulting in accumulation of triglycerides within the cells.
2. Mitochondria; effect: Alcoholic mitochondria have defects in Kreb's cycle enzymes and are thus
slow energy producers. The mitochondria may sometimes swell. Although most alcohol is
metabolized by alcohol dehydrogenase in the cytoplasm, ~ 20% is metabolized in the smooth
endoplasmic reticulum, causing expansion of the SER, resulting in swelling of the hepatocytes
and relative clearing of the cytoplasm.
3. Steatohepatitis: A subset of alcoholics develop a central zone hepatitis which is characterized by
cellular swelling, patchy necrosis, Mallory bodies and a neutrophil infiltrate. Portal tracts are
spared. The mechanism is poorly understood.
4. Perivenular fibrosis
5. Progressive chronic dz - Cirrhosis.
The interrelationships among hepatic
steatosis, alcoholic hepatitis, & alcoholic
cirrhosis are shown, along with a
depiction of key morphologic features at
the microscopic level. It should be noted
that steatosis, alcoholic hepatitis, &
cirrhosis may also develop
independently and not along a
continuum.
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In this microscopic H&E stain, there is
marked perisinusoidal & centrilobular
fibrosis (pink areas) along with marked
hepatocyte injury, characterized by
ballooning hepatocytes (arrow)
Some of the ballooned hepatocytes contain
Mallorys hyallin (clumped eosinophilic
material adjacent to the nuclei).
Steatohepatitis is an increasingly common cause of chronic liver disease &
cirrhosis.
• It falls under the category of “Fatty liver diseases”
• Key morphologic findings: A combination of steatosis and hepatocellular injury.
• Etiology of steatohepatitis: : obesity, diabetes, hyperlipidemia, drug/toxin (esp. alcohol)
• NASH = Non-alcoholic steatohepatitis (most commonly seen in diabetics)
Histologic Features of alcohol-induced steatohepatitis
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g p
Classic histologic findings of steatohepatitis:
1. Macrovesicular steatosis
Mild: 0-33%, moderate 33-67%, severe 67-100%
Typically Zone 3 predominant (exception:. Pediatric NASH)
2. Lobular activity (especially neutrophilic)
3. Ballooning degeneration: hepatocytes are 2x normal size with “dilute cytoplasm”
4. Mallory’s hyaline: ropy eosinophilic material
5. Pericellular/perivenular/perisinusoidal/ ”chicken-wire” fibrosis
Ballooning
degeneration
Mallory’s hyaline
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Micronodular cirrhosis due to chronic alchoholism. Note the pallor of
the hepatocytes due to extensive steatosis.
Liver: Alcoholic-related cirrhosis.The nodules are often smaller and less
prominent than in HCV-related cirrhosis.
Liver, cut surface: Alcoholic-related
cirrhosis.
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Micronodular cirrhosis due to chronic alchoholism. Note the pallor
of the hepatocytes due to extensive steatosis.
Bridgingfibrosis
Portal tract
“Nodule”
“Nodule”
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Adapted from J. Glickman, BWH
HISTOLOGIC PATTERNS OF DRUG-INDUCED LIVER
DISEASE ARE EXCEEDINGLY DIVERSE
Non-alcoholic fatty liver disease (NAFLD)
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Non alcoholic fatty liver disease (NAFLD)Non-alcoholic fatty liver disease characterized by lipid accumulation in hepatocytes that is
not associated with heavy alcohol use. However, it closely resembles alcoholic liver disease.
It resembles a spectrum of liver injuries that start with steatosis, with or without associated
hepatitis (NASH), and progress to bridging fibrosis and cirrhosis. Progression to cirrhosis is
often insidious and many patients remain asymptomatic, with only moderate increases in
serum liver enzymes. Weight reduction tends to help patients but no definitive treatment is
available.
Microscopic findings are very similar to those seen in alcoholic liver disease. They include:
Steatosis, lobular and portal inflammation, hepatocyte necrosis, Mallory bodies and fibrosis
Major risk factors for NAFLD and
NASH:
Type II diabetes:
Obesity: About 50% of peoplewith both severe obesity and
Diabetes have NASH and ~ 1/5
progress to cirrhosis.
Hyperlipidemia.
MECHANISMS
• Oxidant damage to the liver.
• Insulin Resistance in Type II diabetics is
associated with increased hepatic
mitochondrial oxidation of free fatty
acids, increased oxidative stress and
lipid peroxidation
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Drug toxicity in the liver is usually caused by formation of hepatotoxic
reactive metabolites, which often involve the cytochrome P-450 system.
The cytochrome P-450 system is located predominantly in the liver
within the centrilobular hepatocytes.It functions by metabolizing and eliminating liposoluble substances as
well as most clinical drugs.
The process of drug metabolism often involves formation of unstable
reactive intermediates that can be harmful in high doses.
The centrilobular hepatocytes are usually most vulnerable to damage in
such instatnces.
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CLINICAL COURSE AND MANAGEMENT
• Best outcomes occur when patients seek
help within 8 hrs after overdose. However,
many patients delay treatment due to thedelay in onset of symptoms (~24-48 hrs).
• Treatment depends on time of overdose
and serum acetaminophen levels.
• Activated charcoal can be used in the first
4 hours of ingestion to prevent absorption
from the gut.
• If serum levels are high, N-acetyl cysteine
(NAC) can be administered to eliminate
the toxic intermediate NADQI.
Acetaminophen overdose is characterized by extensive hepatocyte necrosis, most
pronounced in the centrilobular areas (where acetaminophen is normally metabolized).
The damage is caused by the toxic intermediate NADQI formed via the cytochrome p-450
pathway. If untreated (or treatment is delayed), this can progress to massive hepaticnecrosis with fulminant liver failure., requiring transplant.
(Zone 3)
The classic microscopic finding is extensivecentrilobular (zone 3) necrosis, which canprogress to massive hepatic necrosis.
Acetaminophen metabolism and hepatotoxicity.
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At high acetaminophen doses, the
increased levels of NAPQI rapidly
deplete the glutathione stores,
causing accumulation of NAPQI,
leading to hepatic injury.
Administration of NAC (N-
acetylcysteine, which acts as a
glutathione substitute, is one of
the main forms of treatment for
acetaminophen overdose.
At therapeutic doses, 90%of acetaminophen is
metabolised in the liver to
yield non-toxic sulphats &glucoronide conjugates.These are then excreted inthe urine.Of the remaining 10%, a fraction is
metabolized by the hepatic cyt p450
complex to yield the toxic, NAPQI.
At normal levels, the toxic NAPQI
is rapidly conjugated to
glutathione in the liver, yieldingnon-toxic products, cysteine &
mercapturic acid.
MASSIVE/FULMINANT HEPATIC NECROSIS
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Massive or fulminant hepatocyte
necrosis occurs when there is death of
nearly all of the normal hepatic lobule,.Most commonly occurs due to drugs
that cause submassive centrilobular
necrosis (e.g. acetaminophen). It can
also be seen in a small subset of
patients with acute Hepatitis A or Acute
hepatitis B infection.
MOST COMMON CAUSES OF MASSIVE
HEPATIC NECROSIS:
•
Acetaminophen toxicity (35 –40% of cases).• Other toxins: Halothane, isoniazid.
• Acute hepatitis A (4% of cases).
• Acute hepatitis B (8% of cases)
• Reye syndrome
• Other: Acute fatty liver of pregnancy, Wilson disease,
hepatic ischemia, Amanita mushroom poisoning
REYE’S SYNDROMEReye’s syndrome is an often fatal condition characterized by encephalopathy and fatty degeneration
of liver in children due to mitochondrial dysfunction. It occurs after a febrile viral-like illness (e.g.
chicken pox, influence B) that has been treated with aspirin.
SYMPTOMS: Reye syndrome presents as vomiting a few days after treatment of a viral infection
with aspirin; it can progress to seizures, cloudy sensorium, and coma.
MICROSCOPIC FINDINGS: Diffuse microvesicular fatty change. The microvesicular fatty change is
due to mitochondrial abnormllities caused by aspirin metabolites that derease B-oxidation by
reversible inhibition of the mitochondrial enzyme.
Recommendation: Aspirin should be avoided in children, except in those with Kawasaki’s disease.
/
Acute fatty liver of pregnancy.
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Acute fatty liver of pregnancy.Acute fatty liver of pregnancy occurs in approximately 1 in every 15,000 pregnancies often
in the 3rd trimester. It is characterized by minimal to moderate hepatic dysfunction due to a
defect in mitochondrial fatty acid oxidation.
PATHOGENESIS: The pathogenesis of acute fatty liver of pregnancy is related to a deficiency
in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). LCHAD is a mitochondrial
enzyme that catalyzes the third step in the beta-oxidation of long-chain fatty acidsin
mitochondria (the formation of 3-ketoacyl-CoA from 3-hydroxyacyl-CoA). The accumulation
of long-chain 3-hydroxyacyl metabolites is toxic to the liver. The defect is recessive and most
female carriers will have normal fatty acid oxidation. However, if they become pregnant witha fetus that is homozygous for the deficiency, then fetus will not be able to oxidize fatty acids
normally. The excess unmetabolized fatty acids enter maternal circulation, where they
cannot be processed adequately due to reduced enzyme activity in the mother.
Signs /Symptoms: Females usually present in the 3rd trimester. The most frequent initial
symptoms are nausea or vomiting (~75% of patients), abdominal pain (50%), anorexia,
jaundice and bleeding. About ½ of patients have signs of preeclampsia at presentation or atsome time during the course of illness. The symptoms are usually mild, but In a subset of
cases, the disease may progress to liver failure and sometimes death. Acute fatty liver of
pregnancy should be ruled out in any female presenting in late pregnancy with unexplained
jaundice. HELLP syndrome, which is characterized by hemolysis, elevated liver enzymes, and
a low platelet count should be excluded and can have a very similar clinical presentation.
Acute fatty liver of pregnancy: Microscopic features.
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Acute fatty liver of pregnancy:
Microscopically, there is extensive
microvesicular steatosis , especially
in zones 2 and 3 of the liver. In
severe cases there may be
cholestasis & hepatocellular
necrosis. The small cytoplasmic
vacuoles can sometimes mimic the
appearance of ballooning
hepatocytes.
MANAGEMENT: Treatment of acute fatty liver of pregnancy is a combination of
maternal stabilization and prompt delivery of the fetus, regardless of gestational
age.Because the diagnosis of LCHAD-deficiency in the newborn can be life-saving,
all women with acute fatty liver of pregnancy and their children should undergo
molecular testing for LCHAD
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CONGENITAL & GENETIC DISORDERS OF
THE HEPATOBILIARY SYSTEMDISORDERS OF BILE CONJUGATION• Unconjugated hyperbilirubinemia of the newborn
• Gilbert syndrome
• Crigler-Najjar syndrome
• Dubin-Johnson syndrome
METABOLIC LIVER DISEASES
• Glycogen storage disease• Alpha-1-antitrypsin deficiency
• Hereditary Hemochromatosis
• Wilson’s disease
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CHOLESTASIS refers to an accumulation of bile (bilirubin +bile salts + cholesterol). It
can be caused by bile duct obstruction, bile duct damage, drug toxicity, sepsis, Graft
vs Host disease, acute viral hepatitis, cholestasis of pregnancy, etc. It can be caused
by intrinsic liver disease ( intrahepatic cholestasis) or by obstruction of the large bileducts (extrahepatic cholestasis)
JAUNDICE refers to an accumulation of unconjugated or conjugated bilirubin in skin
that produces a golden yellow colour. Jaundice is evident in skin when the serum
bilirubin level is 2.5 –3 mg/dL or higher. Yellow discoloration of the sclerae is called
icterus.
Cholestasis and jaundice occur when the equilibrium between bilirubin production
and clearance is disturbed by one or more of the following mechanisms:
1. Excessive extrahepatic production of bilirubin (e.g. excess hemolysis)
2. Reduced hepatocyte uptake of bilirubin3. Impaired bilirubin conjugation
4. Decreased hepatocellular excretion of bile;
5. Impaired bile flow (e.g. due to duct obstruction)
The first three mechanisms produce unconjugated hyperbilirubinemia, and the latter
two produce predominantly conjugated hyperbilirubinemia. Un
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Bilirubin metabolism occurs by the following steps:
I. Extrahepatic bilirubin (mainly from RBCs) is bound by
serum albumin & delivered to the liver (2)II.Hepatocytes take in bilirubin from the sinusoids (3) and
conjugate it to glucuronic acid using uridine diphosphate-
glucuronosyltransferase (UGT). This generates water
soluble bilirubin monoglucuronides & diglucuronides,
III.The bilirubin conjugates are secreted into the bile
canaliculi (4) and transported to the GB for storage, or
transported to the gut.
IV.Gut bacteria deconjugate the bilirubin & degrade it to
urobilinogens and urobilins (5), or further to stercobilins
(5). Which are predominantly excreted in the faeces.
Approximately 20% of the urobilinogens are reabsorbed inthe ileum & colon, returned to the liver, and re-excreted
into bile. A much smaller amount of reabsorbed
urobilinogen is excreted in the urine. Stercobilin, which is
responsible for the brown colour of feces is excreted in the
faeces or reabsorbed into the enterohepatic circulation.
Most bilirubin (0.2-0.3 g/day) is
derived from breakdown of
senescent RBCs cells, or
degradation of tissue heme-containing proteins.
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• Jaundice
• Pruritus: as a result of deposition of bile
salts in tissue• Clay-colored stools: Resulting from failure
of bile to reach the intestines.
• Dark colored urine
•
Elevated bilirubin (unconjugated orconjugated, depending on the cause of
jaundice);
• Increased alkaline phosphatase (ALP),
which is made by bile duct epithelium &
the canalicular hepatocytes . ALP isreleased by detergent action of bile.
Cholestatic injury: Characterized by “feathery”
degeneration of hepatocytes. Note increased bile
accumulation, (golden-yellow on H&E)
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CAUSE OF JAUNDICE OR
CHOLESTASIS LABS ASSOCIATED DISEASES
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CHOLESTASIS LABS ASSOCIATED DISEASES
bilirubin production
unconjugated bilirubin.
No urine bilirubin, urine UBG.
Hemolytic anemia,
MDS, Megaloblastic anemia: Due to
ineffective erythropoiesis
↓
hepatic uptake
Unconjugated
hyperbilirubinemia.
Gilbert syndrome
Rifampin (competes for bilirubin uptake)
Impaired conjugation
Unconjugated
hyperbilirubinemia.
Normal UBG.
Physiologic jaundice of newborn
Crigler Najjar syndrome
Diffuse hepatocellular damage.
↓
Hepatic excretion
Conjugated
hyperbillirubinemia
Dubin-Johnson syndrome
Diffuse hepatocellular damage.
Impaired intrahepatic
bile flow
conjugated bilirubin.
urine bilirubin
Decreased urine UBG
Primary biliary cirrhosis,
Primary sclerosing colangitis
Impaired extrahepatic
bile flow
conjugated bilirubin.
urine bilirubin
↓
urine UBG
Gallstones
Pancreatic carcinoma
Extrahepatic biliary atresia, strictures, PSC.
CAUSES OF EXTRAHEPATIC CHOLESTASIS
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LABS for extrahepatic cholestasis
↑ conjugated bilirubin.
↑ urine bilirubin
↓ urine UBG
Causes?
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PHYSIOLOGIC JAUNDICE OF THE NEWBORN (Unconjugated
hyperbilirubinemia of newborns)
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Lab studies: Low levels of conjugated bilirubin. i.e.
conjugated (direct) bilirubin ≤15% of the total
bilirubin. These Infants generally don’t have
bilirubinuria, because uncongugated bilirubin is
insoluble and cannot be renally excreted.
Treatment: Phototherapy. Exchange transfusion if
condition is more severe.
hyperbilirubinemia of newborns).
Newborns whose total serum bilirubin levels exceed 12 mg/dL (205 mmol/L) are always identified as “jaundiced”. Jaundice can
be difficult to see in infants with dark skin; examination of the sclera is often more helpful in those instances.
The hepatic machinery for conjugating bilirubin does not fully mature until ~2 wks of age.
Therefore, ~70% of normal newborns have transient & mild unconjugated hyperbilirubinemia,
termed neonatal jaundice or physiologic jaundice of the newborn. It is more pronounced inpremature infants because the hepatic clearance of bilirubin is less developed and also due to
increased erythrocyte turnover .
Physiologic jaundice of newborns, usually resolves by 14 days of age. However, 2-15 % of
newborns are still jaundiced at two weeks of age. Most of these infants have benign breast
milk jaundice (due to bilirubin-deconjugating enzymes in breast milk). Breast milk jaundice
usually starts after day 3-5 and slowly improves over 3 to 12 weeks. However, more serious
causes, such as biliary atresia should be ruled out.
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Phototherapy is routinely used to treat neonatal jaundice when necessary (esp. in premature
infants). Absorption of light by unconjugated bilirubin generates water-soluble bilirubin
isomers which can then be renally excreted.
In cases of severe hyperbilirubinemia, neonates may require exchange transfusion.
Phototherapy blanket (for home treatment)
UpToDate
KERNICTERUS
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CAUSES OF KERNICTERUS:
One of the most common causes of kernicterus is
erythroblastosis fetalis, a severe, life-threatening
haemolytic disease caused by maternal
antibodies against fetal erythrocytes. This most
often happens in a setting of Rh incompatibility
(i.e. Rh+ infant, and Rh- mother) Current
methods have significantly reduced the incidence
of erythroblastosis fetalis & kernicterus.
Genetic diseases in which there is complete
absence of such as Type I Crigler Najjar can also
cause kernicterus in infants.
In some cases of neonatal jaundice, there are abnormally high or sustained levels of
unconjugated hyperbilirubinemia. The main danger associated with a high bilirubin level is
Kernicterus, also called bilirubin encephalopathy. This is a defined as a neurologic condition
associated with severe jaundice. resulting from damage to the basal ganglia of the brain.Cases of severe kernicterus are often fatal and most surviving infants have severe
choreoathetosis and mental retardation. This condition is essentially confined to newborns
with severe unconjugated hyperbilirubinemia
Excess unconjugated bilirubin
deposits in tissues:
Conjugated bilirubin is water soluble, can
therefore be filtered by the kidneys &
excreted in urine if present in excess.
Unconjugated bilirubin is highly
insoluble in water and thus cannot berenally excreted. excreted. Instead, it gets
deposited in various tissues, including the
skin and brain, where it may cause tissue
injury (possibly by by interfering with
mitochondrial function).
GILBERT SYNDROME
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GILBERT SYNDROME
A benign liver disorder that results in an unconjugated hyperbilirubinemia
due to a gene mutation causing partial deficiency inglucuronosyltransferase (UGT), and therefore a decreased ability of
hepatocytes to conjugate bilirubin with glucuronic acid. It ccurs in > 5% of
the population and is male predominant.
Clinical presentation: Jaundice triggered by stress (e.g., illness, exercise).
Jaundice usually resolves within a week and generally, no intervention isneeded.
Labs: Unconjugated hyperbilirubinemia. Decreased levels of conjugated
bilirubin relative to total bilirubin. No bilirubin in urine
CRIGLER-NAJJAR SYNDROME (TYPES I & II)
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( )
Inheritance pattern: Both types I and II are autosomal recessive.
Mechanism: Type I has a complete lack of enzyme needed for the conjugation
of glucuronic acid to bilirubin. Type II has partial lack of the enzyme.
Clinical presentation: Type I is usually fatal in infants due to kernicterus. Levels
of unconjugated bilirubin are on 20-25 mg/dL on average, but may rise up to 50
gm/dL. Type II is less severe and infants may present with jaundice.
DUBIN-JOHNSON SYNDROME
Mechanism: Absence of canalicular proteinmultidrug-resistant protein 2 (MRP2), which
transports bilirubin glucuronides.
Gross morphology: Black liver.
ROTOR SYNDROME
An autosomal recessiveconjugated hyperbilirubinemia
clinically similar to Dubin-
Johnson syndrome
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UGT = Uridine glucuronosyltransferase
Li H&E T 1 l t di
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Deficiency of glucose-6-phosphatase results
in accumulation of glycogen in hepatocytes.
The liver is enlarged and pale, and the
hepatocytes are swollen and compress thesinusoids.
Steatosis can be present too. Note the pale
cytoplasm of hepatocytes (due to excess
glycogen) Compare to the hepatocytes in the
adjacent image of normal liver.
http://commons.wikimedia.org/wiki
Liver H&E : Type 1 glycogen storage disease
Liver H&E : Normal liver
Pale hepatocytes due to excess glycogen in cytoplasm
?
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Alpha-1-antirypsin (AAT) is a serine protease inhibitor produced mainly in the liver One
Alpha-1-antitrypsin deficiency
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Alpha-1-antirypsin (AAT) is a serine protease inhibitor produced mainly in the liver. One
of its functions involves deactivation of the neutrophil elastase . Patients with low
serum levels of AAT are at increased risk of developing emphysema. A variety of
mutant alleles causing low serum AAT levels have been identified. In one of the most
common types of AAT, the mutant allele produces a defectively folded protein that gets
retained in the endoplasmic reticulum of the hepatocyte instead of being secreted into
the circulation. This results in low serum levels of AAT, and abnormal accumulation of
the defectively folded protein in the cytoplasm of hepatocytes. Therefore, in addition
to emphysema, these patients are also prone to developing varying degrees of liver
disease, due to accumulation of the abnormal protein. In a few cases, cirrhosis mayalso develop.
Low & high power H&E
images of a liver biopsyfrom a patient with AAT
deficiency, showing large
globules (arrows) of the
abnormally-folded
protein within the
hepatocyte cytoplasm.
HEREDITARY HEMOCHROMATOSIS (HHC)
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CLINICAL FINDINGS AND MANAGEMENT:
Excess iron deposition can lead to liver disease, skin pigmentation, diabetes mellitus,
arthropathy, impotence in males, cardiac enlargement and cardiac conduction defects.
In advanced hereditary hemochromatosis, the classic triad is
• Cirrhosis
• Diabetes (so-called “bronze diabetes”)
• Hyperpigmentation: Due primarily to increases in melanin.
Treatment: Phlebotomy 1-2x/week until ferritin is < 20-50 micrograms/L, then 3-6
times/year. With early treatment, life expectancy is normal
HHC results from a recessive mutation involving (most commonly) the hemochromatosis
gene (HFE) on chromosome 6, that leads to increased iron absorption from the gut.
The mutations result in iron overload and deposition of hemosiderin in tissues such as the
liver, pancreas, skin, joints and pituitary. The excess iron deposition can be toxic to thetissues. The accumulation occurs over decades and usually manifests during the 5th or 6th
decade of life. Although both men and women can inherit the mutation, men are much
more likely to be diagnosed with the effects of hemochromatosis than women (Why?)
About 1 in 10 persons of northern European ancestry are carriers of the abnormal Hfe gene
(the most common mutation is C282Y).
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(Iron mainly in hepatocytes)Iron within hepatocytes. Note the heavy
periportal iron deposition within hepatocytes
with sparing of Kupffer cells. In early-mid stages
of HH, the retained iron is primarily depositedin parenchymal cells, with kupffer cell
accumulation occurring very late in the disease.
This is in contrast to transfusional iron overload
in which iron deposition occurs first in the
Kupffer cells and then in parenchymal cells
Liver from a middle-aged male with
hereditary hemochromatosis.The dark brown colour of the liver, as well
as the pancreas (bottom centre) andlymph nodes (bottom right) on sectioning
is due to extensive iron deposition in a
middle-aged man with hereditary
hemochromatosis.
Iron deposition in the liver due to secondary iron overload.
LIVER: Iron stain (Prussian blue) LIVER: Iron stain (Prussian blue)
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MECHANISM OF IRON ACCUMULATION: Each unit of blood contains about 250 mg of iron. Thebody has no mechanism for getting rid of excess iron. About 10 to 20 mg of iron per day is lost with
normal desquamation of epithelia; menstruating women lose slightly more. Any excess iron
becomes storage iron, or hemosiderin. Over time, hemosiderosis involves more and more tissues of
the body, particularly the liver. Initially, hemosiderin deposits are found in Kupffer cells and other
mononuclear phagocytes in the bone marrow, spleen, and lymph nodes. With great excess of iron,
liver cells also accumulate iron.
As the iron burden increases, iron deposits can be seen
in both the hepatocytes (red arrows) & Kupffer cells
(brown arrows)
In early stages or mild cases of iron overload,
iron deposits primarily in the Kupffer cells,
with sparing of the hepatocytes.
LIVER: Iron stain (Prussian blue) LIVER: Iron stain (Prussian blue)
?
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WILSON’S DISEASE (WD)Wilson's disease (hepatolenticular degeneration) is a genetic disorder of copper metabolism
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Wilson s disease (hepatolenticular degeneration) is a genetic disorder of copper metabolism
resulting in accumulation of toxic levels of copper in various organs.
GENETICS: Autosomal recessive; caused by a mutation in the ATP7B gene encoding a hepatocyte
canalicular copper-transporting ATPase. This leads to decreased biliary excretion of copper. The
worldwide prevalence is ~1 in 30,000, but varies by population
CLINICAL PRESENTATION: usually manifests in childhood or adolescence as liver disease. Typical
presentations include neuropsychiatric and hepatic dysfunction
DIAGNOSIS: ↓↓ serum levels of the copper-carrying protein ceruloplasmin, tissue copper levels
(usually by liver bx), 24-hr urinary copper excretion or direct molecular testing for the mutation
(the most decisive tool).TREATMENT: Copper chelators (remove extra Cu from the body by releasing it from organs into
the bloodstream), zinc (prevents gut absorption of copper), avoidance of copper-containing foods
(shellfish, liver, nuts, mushrooms, chocolate) Liver transplantation is curative.
Affected tissues:
• Liver: Fatty change, chronic hepatitis,
fulminant hepatitis and micronodular cirrhosis
• Cornea: Kayser-Fleischer rings [copper
deposition in Descemet's membrane]
• Brain: Neurological and psychiatric
manifestation and movement disorders Micronodular cirrhosis in a patient with WD
Kayser-Fleischer rings are brownish or gray-
Kayser-Fleisher ring (arrow) in a patient
with advanced Wilson disease,
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green rings that are due to fine pigmented
granular deposits of copper in the cornea.
Kayser-Fleischer rings are a characteristic
feature of Wilson disease and are seen in about
98% of patients with neurologic manifestations
and about 50% of patients with hepatic
manifestations.
compared to a normal individual (below) Note
the dense brown Cu deposits encircling the iris.In earlier stages of disease, these rings are less
prominent and require the use of a slit lamp for
visualization.
The neurologic manifestations of Wilson disease
are numerous and can mimic other neurologicdisorders, especially any type of movement
disorder (eg. Essential tremors, Parkinson’s dz,
Huntington’s disease (rare), The presence of
Kayser-Fleischer rings can help differentiate
Wilson disease from these other disorders.
Normal iris
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Summary of autoimmune liver diseasesDisease Key Feature Screening test Confirming test
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Primarybiliarycirrhosis
Middle aged women;
Serum Alk Phos;
Often associated withautoimmune dz likerheumatoid arthritis, &Sjogren’s.
Cholestasis-related sxs, butmany are asymptomatic.
Anti-mitochondrialantibody (AMA) isthe serologic
hallmark of PBC.
Biopsy: (Granulomotouscholangitis with bile ductdesctruction)
Primary
sclerosingcholangitis
Young to middle aged men
most often affectedInsidious onset.
Serum Alk Phos;
Increased risk of concurrentIBD (esp. Ulcerative colitis
Risk of cholangiocarcinoma
Cholestasis-relatedsymptoms, but MOST areasymptomatic.
Anti neutrophil
cytoplasmicantibodies (p-Anca); ASMA, ANAmay be positive
Bile duct imaging is the MOST
important test and showsmultifocal stricturing & dilation ofintrahepatic and/or extrahepaticbile ducts on cholangiography.
A biopsy will show peri-ductalonion skinning fibrosis, withfibrous obliteration of small bile
ducts.**Biopsies can support thediagnosis but are generally notdiagnostic on their own.
Autoimmunehepatitis
~18% of non-viral hepatitis;
Mainly young women
ANA and ASMA+
False positive anti-HCV common
Serologic tests +/- Biopsy: Bx showsa non-specific Lymphoplasmacyticinflammation.
PBC is an inflammatory autoimmune disease mainly affecting the intrahepatic bile ducts
PRIMARY BILIARY CIRRHOSIS (PBC)
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PBC is an inflammatory autoimmune disease mainly affecting the intrahepatic bile ducts,
characterized by a nonsuppurative, inflammatory destruction of medium-sized intrahepatic
bile ducts. Also accompanied by portal inflammation & scarring, with gradual progression
cirrhosis & liver failure. Usually affects middle aged females (90% of cases) are females.Clinical features: Insidious onset. Pts. Usually
present with fatigue and pruritus. Hepatomegaly is
a typical finding, and eyelid xanthelasmas arise
from infiltration of the eyelid by cholesterol-rich
macrophages. Hyperpigmentation due to melanin
deposition & an inflammatory arthropathy are seenin 25% to 40% of cases. Other features include
steatorrhea, vit D malabsorption.
Labs: Elevated IgG AMA (anti-mitochondrial
antibody) in at more than 90% of cases which
targets part of the pyruvate dehydrogenase
complex in the mitorchondria of bile duct epithelial
cells.
Other findings: Alk Phos and cholesterol early
in disease. Hyperbilirubinemia usually occurs later.
PBC is ssociated with other autoimmune dz, like
Sjogren’s, scleroderma, RA, & thyroid disease.
Micronodular cirrhosis due to PBC
Liver, cut surface: Note the greenish
appearance of the liver due to bile
stasis.
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Granulomatous cholangitis with bileduct injury, is the classic histologic
finding in PBC. As usual, other diseasescan mimic these findings (e.g. infection,sarcoid, drug reactions, etc), therefore themicroscopic findings should always becorrelated with the clinical findings.
J. Glickman
Periportal Granulomatous chronic
inflammation, causing bile duct destruction.
PBC: Stages of histologic progressionto cirrhosis:
– I. bile duct damage, granulomas
– II. Ductular proliferation, periportalhepatitis
– III. Scarring and fibrosis
– IV. Cirrhosis
P i l i h l iti (PSC) i h i h l t ti li di f k
Primary Sclerosing Cholangitis (PSC)
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• Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown
etiology characterised by inflammation, fibrosis and stricturing of the biliary tree. The
mean age at diagnosis is 40 years and men are affected twice as often as women.
• PSC is thought to be immune-mediated and is often associated with inflammatory bowel
disease, especially ulcerative colitis
• Most patients have no symptoms and may remain asymptomatic even with advanced
disease. Many identified by abnormal LFTs on routine testing. Otherwise, patients have
mild symptoms such as fatigue, abdominal discomfort and pruritus and later may develop,splenomegaly and jaundice. The disease usually progresses to cirrhosis and liver failure.
• Cholangiocarcinoma develops in 8-30% of patients.
• Autoantibodies are frequently present, with titers in the range associated with autoimmune
hepatitis. Most common are anti-smooth muscle antibodies (ASMA) and antinuclearantibodies (ANA), found in approximately 75 percent of patients (Including p-Anca)
• Liver transplantation remains the only effective therapeutic option for patients with end-
stage liver disease from PSC, although high dose ursodeoxycholic acid may have a
beneficial effect.
The characteristic histologic finding of PSC is of concentric "onion-skin" fibrosis surrounding the bile ducts .
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The classic microscopic finding in PSC is periductal fibrosis in an “onion skinning”
pattern. Other bile duct abnormalities may include necrosis of epithelial cells,
inflammatory infiltrates and fibrosis. There may be intrahepatic bile duct
proliferation with ductopenia or edema in some portal tracts. In advanced cases,
loss of bile ducts can be a feature.
Bile duct
Primary Sclerosing Cholangitis can be diagnosed
with an ERCP or MRCP.
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An ERCP will usually reveal
multiple irregular areas of
stricturing and dilatation(beading). Due to the risk of
cholangitis and/or
pancreatitis after ERCP,
MRCPs are now preferred.
with an ERCP or MRCP.
MRCPs for Primary Sclerosing Cholangitis
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An MRCP of a patient with
primary sclerosing cholangitis
showing the classic pattern of
strictures and beading.
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www.radiologyassistant
Autoimmune hepatitis.• Clinical: F>M, young-mid-age, abrupt or insidious onset, relapsing course;
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• Sometimes only involves the liver or may also be associated with other systemicautoimmune diseases.
•Labs: transaminases; +ANA +anti-LKM (liver/kidney/anti-microsomal antibody)
Prominent periportal lymphoplasmacytic infiltrate
Bile duct
Classic microscopic findings: A
prominent periportal
lymphoplasmacytic (lymphocytes +
plasma cells) infiltrate. A milderlobular inflammation is usually
present.
Other causes (e.g. drugs, systemic
autoimmune disease, infection,
etc) should be clinically ruled out.
Autoimmune hepatitis.
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Cirrhosis due to autoimmune hepatitis: The microscoipic findings in this figure arenonspecific regarding the etiology of the cirrhosis; however, the presence of a
periportal lymphoplasmacytic inflammatory infiltrate (see high power image on
previous page) are compatible with an underlying autoimmune hepatitis. Other
causes of chronic hepatitis (e.g., viral infection, drug reaction) must be excluded
clinically or histologically.
Trichrome StainLiver core needle biopsy
H&E stain, low magnification
Common Benign and Malignant lesions
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of the Liver
Malignant lesions
• Hepatocellular carcinoma
• Cholangiocarcinoma• Angiosarcoma
• Metastatic disease
Benign lesions
• Hepatic hemangioma
• Focal nodular hyperplasia
• Hepatic adenoma
• Nodular regenerative
hyperplasia
• Bile duct hamartomas
FNH is now generally accepted to be a benign hyperplastic (regenerative) response related to
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CLINICAL: FNH is more common in young women (~70%).
Unlike hepatic adenomas, the association with OCPs is not
entirely certain. However, patients taking OCPs tend to have
larger tumors with increased vasculature.
These lesions are often managed conservatively.
GROSS AND MICROSCOPIC FINDINGS:
The nodule is often found near the capsule and looks lighter
than the surrounding parenchyma. Grossly, there is a
characteristic central scar.
HISTOLOGY: Note the prominent muscular vessel with
irregular wall thickness. Usually there is a prominent bileductular reaction that is typically present at the junction of the
stroma and parenchymal nodules.
They can be distinguished microscopically from hepatic
adenomas usually by the presence of bile ducts, which should
be absent in adenomas.
FNH is now generally accepted to be a benign hyperplastic (regenerative) response related to
the hyperperfusion of abnormal vasculature found in the center of these nodules (Previously
it was considered to be either a hamartoma or a neoplasm) . It is often an incidental finding.
Central
stellate scar Rim ofnormal liver
Hepatic adenomas• Hepatic adenomas are strongly associated with the use of oral contraceptives, anabolic
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The tumor cells have cytologic features similar to those of normal liver. The cell platearchitecture is preserved, and cell plates are usually two cells thick. Note absence of bileducts. These tumors most commonly occur on the right lobe of the liver
androgens, and glycogen storage disease. They are less commonly associated with pregnancy
and diabetes mellitus. However, many show significant size increase in pregnancy.
• Usually present as a solitary mass and sometimes can be difficult to distinguish from FNH.
• The natural history and prognosis of hepatic adenomas is not well established. Management
depends upon symptoms, size, number, location, and certainty of the diagnosis. OCPs should
generally be discontinued. Lesions > 5 cm are normally resected.
• Multiple adenomas in the liver have been associated with glycogen storage disease type I.
HEPATOCELLULAR CARCINOMA (HCC)HCC is the most common primary malignant tumor of the liver in adults.
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p y g
Its incidence is increased in the following settings:
• Chronic Hepatitis B and C infection.
• Wilson’s disease
• Hemochromatosis
• A1-antitrypsin deficiency
• Alcoholic cirrhosis
•
Exposure to carcinogens (e.g. aflatoxin from Aspergillus)
HCC arising in a patient with HCV cirrhosisClinical presentation and course:
• Jaundice, tender hepatomegaly, ascities,
polycythemia, hypoglycaemia.
• It can also lead to Budd Chiari syndrome(thrombosis of the hepaic vein)
• It usually spreads hematogenously.
Lab detection tests: Associated with
increased
-fetoprotein in the serum.
Hepatocellular Carcinoma
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The tumor trabeculae are separated by relatively thin fibrous bands The
Reticulin stain shows increased staining along the thin fibrous septa that
separate tumor trabeculae. The tumor cell plates tend to line up in a side-
by-side (ribbon-like) pattern and are usually more than 4 cell layers thick.
CHOLANGIOCARCINOMA
Ch l i i d i d f i h i lif i f li
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Massive neoplasm in the right lobe with
widespread intrahepatic metastases.
Tumor cells forming glandular structures
surrounded by dense sclerotic stroma.
Cholangiocarcinomas are derived from an intrahepatic proliferation of malignant
bile duct epithelium. It affects older adults, with no gender preference. Patients
typically have non-cirrhotic livers and present with obstructive symptoms or pain
Associations: Primary Sclerosing Cholangitis, Thorotrast, parasitic infection
(Chlonorchis)
HEPATOBLASTOMA
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#Hepatoblastomas are the most common liver tumours in children (90% <5 y/o
and 70% <2 y/o) Patients present with an enlarging abdomen. Paraneoplastic
syndromes such as anemia and thrombocytopenia may be present. Prognosis is
dependeNt on tumour stage. 90% of hepatoblastomas are associated with
elevated alpha-fetoprotein (AFP). AFP negative tumours are more aggressive.
TREATMENT: Surgical excision with adjuvant chemotherapy is the treatment of
choice. Liver transplantation is another option
Gross: Single/multiple heterogeneous
mass(es) most commonly involving the
right or both lobes
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INFECTIOUS CAUSES OF LIVER
ABSCESSES
Echinococcosis is caused by infection with tiny tapeworms of the genus Echinocococcus
ECHINOCOCCAL (HYDATID) CYSTS
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y y p g
( Echinococcus granulosus or Echinococcus multilocularis). It is classified as either 1. cystic
echinococcosis (i.e. hydatid disease) or 2. alveolar echinococcosis. Dogs and foxes are
definitive hosts. Sheep, goats, pigs and small rodents are intermediate hosts and humansare accidental intermediate hosts.
Following accidental ingestion, embryos penetrate the wall of the intestine in humans, enter
the bloodstream and then travel to the liver (most common), lung, brain, long bones, etc. As
the cysts enlarge, they cause symptoms due to compression of adjacent structures.
CLINICAL PRESENTATION: Patients with hydatid
cysts in the liver usually have symptoms of
abdominal fullness or pain. Jaundice or portal
hypertension can also develop from pressure
effects. Complications include cyst rupture and
infection. The most common site of rupture is into
the bile ducts within the liver causing symptoms ofbile duct obstruction & infection. Some patients
present with an allergic reaction after cyst rupture.
Treatment ranges from pharmacologic agents
(mebendazole or albendazole) to surgery (drainage
or entire cyst removal).
Summary of the life cycle of E. multilocularis
• The adult echinococcus tapeworm can be found in the
intestines of the definitive host (dogs) It is composed of
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intestines of the definitive host (dogs). It is composed of
proglottid segments that have both male and female
sexual organs and produces eggs containing embryos,
called oncospheres. Eggs are highly resistant and canremain infective for a year in a moist environment.
• The eggs are expelled in the dog’s faeces and may be accidentally
ingested by humans or an intermediate host. Following egg ingestion
by the intermediate host, the oncospheres hatch from the eggs,
penetrate the intestinal mucosa, enter the blood and/or lymphaticsystem, and migrate to the liver or other visceral organs
• A few days later, a fluid-filled cyst begins to develop in the target
organ. The cyst develops multiple layers to become a hydatid cyst
(metacestode). As it grows, it produces protoscolices and daughter
cysts. Cysts are usually visible 3 weeks after ingestion and continue
to secrete fluid causing compression of the liver
• Dogs become infected by ingesting organs of infected intermediate
hosts or ingesting protoscolices shed in the faeces of intermediate
hosts.
• The ingested protoscolices attach to dog’s small intestine and
develop into adult worms
The adult echinococcus
is usually < 1cm long
Proctoscolex
Numerous protoscoloices
within daughter cysts
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A 10 cm hydatid cyst wall with multiple daughter
cysts, most of them collapsed (~ 2 cm to 5 cm each)
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The wall of the echinoccocal hydatid cyst is
laminated and composed of multiple daughter
cysts (each ~ a few cm in diameter) containing
the inact organisms (protoscolices/hooklets)
Calcification in the cystic wall is common. Cysts
less than 5 cm are usually asymptomatic and no
specific treatment is required.
Laminated
Cyst Wall
Webpathology
LIVER
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Laminated
Cyst Wall
Cyst Wall
Protoscolices
AMEBIAISISAmebic infection or amebiasis is a common infection in the tropics. The organism responsible
f th di i E t b Hi t l ti
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Patients usually present with acute abdominalpain and fevers. Up to 8% of patients present
with mild jaundice. Tests to detect antibodies
in the blood (which are positive in up to 95%
of patients) should be performed.
Various radiologic studies can be used to help
in the diagnosis. Treatment is primarily with
antimicrobials such as metronidazole.
Aspiration of the abscess is rarely indicated. An
operation is indicated if worsening infection is
noted despite adequate medical therapy.
for the disease process is Entamoeba Histolytica.
Transmission usually occurs via ingestion of infected water. Amebiasis is seen most frequently
in the cecum and ascending colon, although the sigmoid colon, rectum, and appendix can alsobe involved. Liver abscess formation occurs when the ameba penetrates through the intestines
and into local veins that drain into the liver. Liver abscesses are more common in patients who
are immunocompromised, malnourished or have a malignancy. Less than one-third of the
patients have intestinal symptoms prior to the diagnosis of liver abscess.
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LIVER: SUPPLEMENTARY MATERIAL
Hepatic failure is the most severe clinical consequence of liver injury. It occurs when 80-90%
of the hepatic functional capacity is lost Hepatic failure occurs in one of three situations:
HEPATIC FAILURE
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of the hepatic functional capacity is lost. Hepatic failure occurs in one of three situations:
Massive hepatic necrosis, chronic liver disease, or widespread but non-fatal injury to the
hepatocytes.
1. Hepatic failure as a result of chronic liver disease: Most commonly due to the end stage
of cirrhosis
2. Hepatic failure due to widespread injury to the hepatocytes: Acute fatty liver of
pregnancy,
3. Massive hepatic necrosis is often the result of fulminant hepatitis or toxic injury.
Fulminant hepatic failure is characterized by the onset of encephalopathy within 8weeks of the onset of jaundice in a patient with hepatic injury and no history of prior
liver disease.
Signs/symptoms of hepatic failure
• Hepatic encephalopathy,
• Hepatorenal syndrome,
• Jaundice,
• Hyperammonemia
• Coagulopathy: Due to deficiency of vitamin K –dependent factors II, VII, IX & X.
• Hypoglycemia: Due to impaired gluconeogenesis
• Infections: A leading cause of death in these patients.
Ascites is defined as the accumulation of fluid in the peritoneal
ASCITES
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Local causes of ascites
• Peritoneal exudation, e.g.
tuberculous, peritonitis.
• Malignancies: Peritoneal
mesothelioma, Ovarian cancer,
Metastatic tumors, etc.
Ascites is defined as the accumulation of fluid in the peritoneal
cavity. It occurs by one or more of the following mechanisms:
1. Local exudation from the peritoneum
2. Hypoproteinemia (e.g. in liver failure and renal failure)
3. High pressure in the portal or systemic venous systems
Other factors contributing to ascites is the increase in hepatic lymph flow that occurs in
cirrhosis and the increase in aldosterone secretion. Ascites is detectable on physical
examination (shifting dullness and fluid wave) at amounts of 500 mL. In persons who
suffer from cirrhosis,
Systemic causes of ascites:
• Liver failure: The most common cause of ascites.
Associated with high mortality within 2 years.• Cardiac failure, including constrictive pericarditis:
Associated with peripheral edema and elevated
jugular venous pressure.
• Renal failure: Marked protein loss.
• Malnutrition: e.g. Kwashiorkor.
A diagnostic paracenteses can be very useful in determining the cause of ascites.
Analysing a Diagnostic Parancentesis
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Interpreting the serum-albumin gradient:
High serum albumin ascites gradient ( > 1.1 g/dl)
• Cirrhosis
• Alcoholic hepatitis
• Cardiac ascites• Fulminant hepatic failure
• Budd-Chiari syndrome
• Veno-occlusive disease
• Myxedema
• Fatty liver
Low serum albumin-ascites gradient
ascites: < 1.1 g/dl
• Peritoneal carcinomatosis
• Tuberculous peritonitis• Pancreatic ascites
• Biliary ascites
• Nephrotic syndrome (kidney
disease resulting in protein loss)
• Serositis.
g p y g
1. Appearance: e.g. blood in the ascites is more consistent with a malignant neoplastic
process.
2. Protein concentration: Higher protein ascites concentrations are more suggestive ofinfection than cirrhosis. Use the albumin serum ascites albumin gradient (the difference
between serum albumin and ascitic fluid albumin concentrations) to determine whether the
fluid is transudative gradient (>1.1 g/dL) or exudative (gradient < 1.1 g/dL). This gradient
is a useful means of accurately evaluating protein concentrations, especially in liver disease
where the serum albumin concentration is low.
3. Cytology and culture – A neutrophil/band count exceeding 250 x 106 / l in the ascitic fluid
suggests infection (normal peripheral blood counts: 4,000 - 9,000 x 106 / l.4. Amylase levels (if thought to be pancreatic-related)
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The cause of portal hypertension
can be pre-hepatic, intrahepatic,
or post-hepatic, depending upon
the site of the pathology.
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