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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



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.



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.



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



Central Vein

Portal

track



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.



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



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



Sinusoids

Plates are one cell layer thick in a normal adult liver



• 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



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)



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



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



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



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.



Hepatocyte apoptosis: Councilman

bodies (arrow) represent apoptotic

hepatocytes. Common in chronic

Hepatitis C

Periportal chronic inflammation

Most common in chronic Hepatitis

C infection.



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.



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)



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



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



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.



Cirrhosis is a term used to describe diffuse fibrosis & nodular

regeneration resulting in severe scarring and disruption of the

hepatic architecture

Cirrhotic liver



•

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.



Gross findings: Diffusely nodularliver with micronodules ( <3 mm

diameter) or macronodules ( >3 mm

diameter).



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



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



CIRRHOSIS

Micronodular cirrhosis: This type of cirrhosis is often due to

metabolic insult, such as alcohol, hemochromatosis, Wilson’s.

Liver, sectioned



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 .



• 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



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)



CAUSES OF PORTAL

HYPERTENSION



TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC



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.



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



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.



VIRAL HEPATITIS



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



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.



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;



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



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



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



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





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)



• ~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.



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.



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




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



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



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



What diseases are depicted in each liver?



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 )



“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.



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.



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”



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



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



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.



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:



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.



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



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



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.



Micronodular cirrhosis due to chronic alchoholism. Note the pallor

of the hepatocytes due to extensive steatosis.

Bridgingfibrosis

Portal tract

“Nodule”

“Nodule”



Adapted from J. Glickman, BWH

HISTOLOGIC PATTERNS OF DRUG-INDUCED LIVER

DISEASE ARE EXCEEDINGLY DIVERSE

Non-alcoholic fatty liver disease (NAFLD)



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



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.



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.



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



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.



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.



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



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



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



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.



• 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)



CAUSE OF JAUNDICE OR

CHOLESTASIS LABS ASSOCIATED DISEASES



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



LABS for extrahepatic cholestasis

↑ conjugated bilirubin.

↑ urine bilirubin

↓ urine UBG

Causes?



PHYSIOLOGIC JAUNDICE OF THE NEWBORN (Unconjugated

hyperbilirubinemia of newborns)



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.



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



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



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)



( )

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



UGT = Uridine glucuronosyltransferase

Li H&E T 1 l t di



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

?



Alpha-1-antirypsin (AAT) is a serine protease inhibitor produced mainly in the liver One

Alpha-1-antitrypsin deficiency



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)



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).



(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)



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)

?



WILSON’S DISEASE (WD)Wilson's disease (hepatolenticular degeneration) is a genetic disorder of copper metabolism



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,



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



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)



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.



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)



• 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 .



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.



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



An MRCP of a patient with

primary sclerosing cholangitis

showing the classic pattern of

strictures and beading.



www.radiologyassistant

Autoimmune hepatitis.• Clinical: F>M, young-mid-age, abrupt or insidious onset, relapsing course;



• 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.



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



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



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



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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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



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



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



#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



INFECTIOUS CAUSES OF LIVER

ABSCESSES

Echinococcosis is caused by infection with tiny tapeworms of the genus Echinocococcus

ECHINOCOCCAL (HYDATID) CYSTS



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( 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



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



A 10 cm hydatid cyst wall with multiple daughter

cysts, most of them collapsed (~ 2 cm to 5 cm each)



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



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



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.



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



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



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



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.

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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)



The cause of portal hypertension

can be pre-hepatic, intrahepatic,

or post-hepatic, depending upon

the site of the pathology.

pdf liver pathology oct 2015

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