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LIVER - Normal histology - Cirrhosis

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Title: LIVER DISEASE Author: Andrew McDonald Last modified by: Cynthia Created Date: 11/26/2005 12:43:38 PM Document presentation format: On-screen Show – PowerPoint PPT presentation

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Title: LIVER - Normal histology - Cirrhosis


1
LIVER - Normal histology - Cirrhosis
  • 8th November 2007
  • Dr. Cynthia Heffron
  • Clinical Lecturer in Histopathology

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INTRODUCTION
  • Normal liver weight 1400 - 1600g.
  • Architecture of liver
  • Divided into lobules oriented around the terminal
    tributaries of the hepatic vein.
  • Sheets of hepatocytes with portal triads at the
    corner of each lobule.
  • Portal triad/tract
  • Bile duct
  • Portal vein
  • Hepatic artery
  • The functional unit of the liver parenchyma is
    the hepatic acinus with zones 1,2 3. Zone 1 is
    periportal, zone 3 is perivenular, zone 2
    intermediate.

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1. Parenchyma
  • Liver cells (hepatocytes) trabeculae 1 cell thick
    in adults
  • Kupffer cells in sinusoids are phagocytes
  • Hepatic stellate cells (also called Ito cells) in
    space of Disse (an extrasinusoidal space)
  • Cells of mesenchymal origin
  • Store vitamin A
  • Transform into collagen-producing myofibroblasts
    when there is inflammation and fibrosis of the
    liver
  • Regulate blood flow in sinusoids
  • Liver-associated lymphocytes.

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2. Biliary drainage system
  • Canaliculi (between abutting hepatocytes)
  • 1-2um in diameter
  • Canals of Hering cholangioles
  • Canaliculi join to form these larger structures
  • Intra-hepatic bile ducts
  • Extra-hepatic bile ducts

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3. Vasculature
  • Incoming blood to the liver at the porta hepatis
  • Portal vein supplies 70 of the blood flow.
  • Hepatic artery supplies 30 of the blood flow.
  • Within the liver
  • Sinusoids lined by fenestrated endothelium.
  • Blood leaving the liver
  • Hepatic venules
  • Hepatic veins drain into the IVC.

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Functions of liver
  • The liver is important for
  • Metabolism of carbohydrate, protein, lipids.
  • Protein synthesis, albumin, coagulation factors,
    complement factors etc.
  • Storage of iron, copper, vitamins A, D, B12.
  • Detoxification/drug metabolism.
  • Bile production.

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Investigation of liver diseases
  • Biochemical - enzymes, proteins, bilirubin.
  • Haematological - coagulation factors among
    others.
  • Immunological - antibodies (viruses, autoimmune).
  • Imaging - ultrasound, CT, MRI, ERCP, MRCP.
  • Liver biopsy
  • percutaneous needle biopsy, transjugular biopsy,
    wedge biopsy at laparoscopy or open surgery.
  • Useful in providing information as to the
    aetiology and severity of the liver disease,
    ruling out the presence of other concomitant
    disease, monitoring response to therapy.
  • Focal lesions require US or CT guidance.

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Morphological patterns of liver injury
  • Degeneration
  • Ballooning degeneration (hydropic change)
  • Feathery degeneration (bile-induced damage).
  • Intracellular accumulations
  • Fat (steatosis)
  • Iron
  • Copper
  • Bile
  • Mallorys hyaline

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Haemosiderosis
Mallorys hyaline
Bile
Steatosis
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Morphological patterns of liver injury
  • Degeneration
  • Ballooning degeneration (hydropic change)
  • Feathery degeneration (bile-induced damage).
  • Intracellular accumulations
  • Fat (steatosis)
  • Iron
  • Copper
  • Bile
  • Mallorys hyaline
  • Necrosis
  • Coagulative or lytic and apoptosis.
  • Necrosis may be
  • randomly focal (spotty necrosis),
  • zonal eg zone 3
  • bridging (bridging hepatic necrosis, eg portal to
    venular), involve most or almost all of the liver
    (submassive and massive respectively).
  • Zone 3 is most prone to injury as it is farthest
    from the blood supply and is the area containing
    most drug-metabolising enzymes.

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Morphological patterns of liver injury
  • 4. Inflammation
  • Acute, chronic or granulomatous.
  • May be portal, periportal (interface hepatitis)
    or acinar (focal, or panacinar)

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  • Chronic inflammation
  • Viral hepatitis
  • Granulomatous inflammation
  • Foreign material
  • Organisms
  • Drugs

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Morphological patterns of liver injury
  • 5. Regeneration
  • Hepatocytes have great ability to regenerate.
  • Regeneration occurs in many diseases.
  • Bile duct proliferation is seen in the portal
    tracts in cirrhosis.

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  • 6. Fibrosis
  • Forms in response to inflammation or direct
    toxic injury.
  • Irreversible form of liver injury.
  • Can be portal, perivenular, form bridging
    fibrosis, finally cirrhosis.

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The great variety of liver diseases and the
livers limited patterns of response means that
close clinicopathological correlation is required
for their diagnosis.
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CIRRHOSIS
  • Definition
  • Degenerative disease in an organ of the body,
    esp. the liver, marked by excess formation of
    connective tissue and, usually, subsequent
    painful swelling
  • Etymology ModL lt Gr kirrhos, tawny -osis so
    named by R. T. H. Laënnec (1781-1826), Fr
    physician, because of the orange-yellow
    appearance of the diseased liver
  • Among the top 10 causes of death in the Western
    world.
  • End stage of liver disease.
  • Characterised by
  • Bridging fibrous septa
  • Parenchymal nodules
  • Disruption of the architecture of the entire
    liver

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  • Characterised by
  • Bridging fibrous septa
  • Fibrosis is usually irreversible.
  • Regression observed rarely.
  • Parenchymal nodules
  • Regenerative nodules surrounded by fibrosis are
    necessary for diagnosis.
  • lt 3mm Micronodular cirrhosis
  • Bile duct obstruction or alcohol
  • gt 3mm Macronodular cirrhosis
  • Other causes
  • Disruption of the architecture of the entire
    liver
  • Vasculature affected in particular with formation
    of abnormal interconnections between vascular
    inflow and hepatic vein outflow

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Classification of Cirrhosis?
Generally classified by Aetiology
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Aetiology of Cirrhosis
  • Infections
  • Viral hepatitis (10).
  • Toxins and drugs
  • Alcohol (60-70)
  • Therapeutic drugs.
  • Autoimmune
  • Hepatitis
  • Primary biliary cirrhosis.
  • Metabolic
  • Haemochromatosis (5).
  • Wilson disease.
  • Alpha-1-antitrypsin deficiency.
  • Glycogen storage disease and many others.
  • Biliary diseases (5-10)
  • Congenital atresia.
  • Sclerosing cholangitis.
  • Hepatic outflow obstruction.
  • Cryptogenic (10-15).

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Aetiology of cirrhosis
  • The aetiology of cirrhosis varies throughout the
    world.
  • In the Western world, alcohol is the most common
    factor at 60 and viral hepatitis 10.
  • Viral hepatitis is the most common factor in Asia
    and Africa.
  • Cryptogenic cirrhosis (cause unknown) forms 10.
  • Once cirrhosis has developed and become
    established, it is usually not possible to
    determine the aetiology by morphology alone and
    results of other investigations are required.

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Biopsy
  • Used for primary diagnosis and monitoring
    disease.
  • Percutaneous, transjugular, wedge biopsies.
  • One study has shown that biopsy was a significant
    aid in establishing the diagnosis in approx 75
    of cases.
  • Accurate interpretation of the biopsy requires
    clinical and laboratory data.

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Mallory bodies
  • Characteristic of alcoholic hepatitis but not
    specific
  • Composed of tangled cytokeratin intermediate
    filaments and other proteins

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Alcoholic liver disease
  • Fatty liver
  • Alcoholic hepatitis
  • Cirrhosis (10-20 of alcoholics develop cirrhosis)
  • Gross
  • Enlarged fatty liver
  • Microscopic
  • Hepatocyte swelling and necrosis
  • Mallory bodies
  • Neutrophilic reaction
  • Fibrosis

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  • Individual hepatocytes are affected by viral
    hepatitis.
  • Viral hepatitis A rarely leads to signficant
    necrosis, but hepatitis B can result in a
    fulminant hepatitis with extensive necrosis.
  • A large pink cell undergoing "ballooning
    degeneration" is seen below the right arrow.
  • At a later stage, a dying hepatocyte is seen
    shrinking down to form an eosinophilic
    "councilman body" below the arrow on the left.

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Histological features of viral hepatitis
  • Acute
  • Ground-glass hepatocytes (HBV)
  • Balloon degeneration of hepatocytes
  • Fatty change (HCV)
  • Macrophage aggregates
  • Apoptosis (councilman bodies, spotty necrosis)
  • Bridging necrosis
  • Portal tract inflammation
  • Chronic
  • Lymphoid aggregates
  • Interface hepatitis
  • Fibrosis
  • Periportal
  • Bridging
  • Cirrhosis

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  • Hereditary Haemochromatosis autosomal
    recessive, chromosome 6
  • Defect in intestinal absorption of iron leading
    to excessive absorption
  • Normal amount of Iron in liver 0.5g, in
    haemochromatosis up to 50g
  • Men gt women

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  • Secondary haemochromatosis
  • Most common cause Haemolytic anaemias
  • Others transfusions, alcohol
  • Clinically
  • Main manifestations are hepatomegaly, abdominal
    pain, skin pigmentation, deranged glucose
    homeostasis or frank diabetes mellitus, cardiac
    dysfunction and atypical arthritis.
  • High risk of developing hepatocellular carcinoma.

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The periportal red hyaline globules seen here
with periodic acid-Schiff (PAS) stain are
characteristic for alpha-1-antitrypsin (AAT)
deficiency.
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a1- antitrypsin (AAT) deficiency
  • AAT deficiency is an autosomal recessive disorder
    (chromosome 14) marked by abnormally low serum
    levels of this major protease inhibitor.
  • Most people with AAT deficiency are likely to
    develop chronic obstructive pulmonary disease
    with panlobular emphysema.
  • The globules are collections of
    alpha-1-antitrypsin not being excreted from
    hepatocytes.
  • This may eventually lead to chronic hepatitis and
    cirrhosis.
  • Liver disease is more likely to occur in children
    with AAT deficiency, while lung disease occurs in
    adults.

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  • This is a case of primary biliary cirrhosis, a
    rare autoimmune disease.
  • Seen here in a portal tract is an intense
    chronic inflammatory infiltrate with loss of bile
    ductules.

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Primary biliary cirrhosis
  • Autoimmune cholestatic liver disease mostly of
    middle-aged women.
  • Characterized by destruction of bile ductules
    within the triads of the liver.
  • This destruction is granulomatous and destroys
    medium sized intrahepatic bile ducts.
  • Antimitochondrial antibody can be detected in
    serum.
  • Micronodular cirrhosis ensues.

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Pathogenesis of Cirrhosis
  • Liver injury results in chronic inflammation and
    activation of Kupffer cell, and other endogenous
    liver cells with the production of cytokines.
  • These, together with disruption of the
    extracellular matrix activates hepatic stellate
    cells (HSC). Toxins may activate HSCs. These
    transform into myofibroblasts which produce
    collagen and constrict sinusoids.
  • Collagen in the space of Disse leads to
    capillarisation of the sinusoids and loss of
    endothelial fenestrations, hindering exchange of
    solutes.
  • New vascular channels in fibrous bands link
    inflow of blood (venous arterial) with outflow
    (hepatic venules) thus by- passing parenchyma.
  • Existing vascular channels and biliary channels
    may be obliterated.
  • The results are internal vascular shunts and
    portal hypertension.
  • The hepatocytes in the regenerative nodules may
    appear normal microscopically but are unable to
    adequately fulfill their functions.
  • Function will be further reduced if there is
    continuing liver cell damage.

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CLINICAL FEATURES
  • Cirrhosis may be asymptomatic.
  • When symptomatic
  • Non specific symptoms weakness, fatigue, weight
    loss, anorexia, nausea, gaseous abdominal
    distension, upper abdominal discomfort.
  • Symptoms and signs secondary to liver failure
    encephalopathy, hypoglycaemia, bleeding, ascites,
    overwhelming infection
  • Symptoms and signs secondary to portal
    hypertension ascites, portosystemic venous
    shunts (varices), congestive splenomegaly,
    hepatic encephalopathy.
  • The liver may be enlarged, hard and irregular or
    smaller than normal.
  • Decompensated cirrhosis manifests as signs of
    liver failure or complications of portal
    hypertension.
  • Deterioration in liver function can be an
    indication of the development of hepatocellular
    carcinoma.

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Complications of Cirrhosis
  1. Hepatic failure
  2. Hepatic encephalopathy
  3. Hepatorenal syndrome
  4. Hepatocellular carcinoma

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Complications of cirrhosis (continued)
  • 5. Portal hypertension
  • Portal venous pressure gt 10mmHg
  • Causes
  • Prehepatic obstructive thrombosis
  • Hepatic - cirrhosis
  • Posthepatic right sided heart failure,
    constrictive pericarditis, hepatic vein outflow
    obstruction
  • Manifestations
  • Ascites
  • Transudate (lt3gm/dL protein),straw coloured or
    pale green, a few mononuclear cells.
  • Risk of spontaneous infection when polymorphs
    predominate.
  • Is due to aldosterone-induced retention of Na
    water, low oncotic pressure (low albumin), and
    portal hypertension.
  • Excess hepatic lymph and intestinal fluid leakage
    also contributes to ascites.
  • Portosystemic shunts
  • oesophageal varices
  • periumbilical caput medusae
  • haemorrhoids
  • Congestive splenomegaly
  • Hepatic encepaholopathy

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  • Other complications due to impaired parenchymal
    function
  • Disturbed glucose homeostasis
  • Impaired bile salt prodcution
  • Malabsortpion
  • Decreased albumin
  • Unbound drugs and metatbolites in plasma
  • Jaundice
  • Clotting factors
  • Oestrogen metabolism impaired
  • Spider naevi
  • Finger clubbing
  • Renal failure
  • Infections

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  • The ultimate mechanism of most cirrhotic deaths
    is
  • Progressive liver failure.
  • Complication related to portal hypertension.
  • Development of hepatocellular carcinoma.

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