Liver Pathology

Liver Pathology

1. Functions

   • Portal Vein
     • Metabolic processing
       • Dietary carbohydrates
         • Lipids
           • Amino Acids
             • Vitamins
     • Detoxification, Degredation &/or Biliary Excretion
       • Endogenous wastes
         • Toxic molecules
           • Hormones
             • Xenobiotic compounds
               • Biotransformation of drugs
           • Detoxified chemical wastes
         • Bile salts, Bilirubin, cholesterol, HCO3-, H2O
     • Blood from Intestinal tract
     • Processing & Activation of some xenobiotic agents
       • Pro-drugs
         • Ex. Cytochrome p450
   • Synthesis of Plasma Proteins
     • Albumin
       • Globulins
         • Clotting factors
         • Complement proteins
       • Other serum transport/ binding proteins
   • Storage
     • Glycogen
       • Fats
         • Fe
           • Cu
             • Vitamins
               • Ex. Vitamin A (stored in Hepatic stellate cells)
   • Processing of Vitamin D
     • With Kidneys
   • Removal of Bacteria & Erythrocytes
     • Kupffer cells
     • Removal of Erythrocytes also occurs in the Spleen

2. Clinical Signs of Liver Disease

   • Jaundice/ Icterus
     • Accumulation of bilirubin in the body
     • Mechanism
       • Pre-Hepatic
         • Excessive breakdown of Erythrocytes
           • Liver is overwhelmed & cannot excrete the bilirubin fast enough
             • Ex. IMHA (Immune mediated Haemolytic Anaemia)
       • Post-Hepatic
         • Physical obstruction of bile outflow
           • Damage, disease, compression or obstruction of the gallbladder or common bile duct
             • Prevents Bile from being excreted into the small intestine (Cholestasis)
               • Ex. Gallstones, compressive tumor
       • Hepatic
         • Liver is diseased & cannot excrete even the normal bilirubin load
           • Ex. Cirrhosis
   • Oedema/Ascites/Anasarca
     • If the liver is unable to synthesize the normal plasma proteins, there will be a reduction in plasma oncotic pressure
       • Ex. Decrease in serum Albumin, Decrease in Oncotic pressure
       • Fluid moves out of circulation => Fluid accumulates in the body cavities & subcutaneous spaces
   • Coagulation (Clotting) Disorders
     • If liver is unable to produce sufficient clotting factors, fibrinolytic proteins, complement proteins & acute phase proteins:
       • => Poor or inappropriate Haemostasis & immune function
         • Risk of Haemorrhage after liver biopsy
         • Paradoxial balance
           • Liver products
             • Pro-coagulation
               • Lack of Anti-clotting factors
             • Anti-coagulation
               • Lack of clotting factors
   • Hepatic Encephalopathy
     • Liver usually converts ammonia into urea (excreted by the kidneys)
       • NH3 produced in intestine by bacteria
     • Liver disease:
       • Reduced ability to detoxify &/or remove nitrogenous compounds from the body
         • Increased [NH3] & other toxic substances (Mn?) in the blood
           • => Impairs brain function
             • =>Status spongiosus of white matter in CNS
               • Multiple fluid filled spaces of microscopic size in cerebral white matter
           • Toxicity
   • Metabolic disease & dysfunction
     • Liver disease (Reduced ability to):
       • Process dietary components delivered from the portal blood
       • Store Glycogen, fat & vitamins
       • Detoxify endogenous or exogenous toxins
       • Implications for drug selection, administration & dosage

3. Incidental Post-Mortem Changes

   • Prone to rapid PM change:
     • Composition
       • Vascularity
         • Proximity to the intestine
   • Softening & increased friability
   • Production of gas bubbles (Putrefactive bacterial fermentation)
   • Black discoloration (bacterial breakdown of Hb)
   • Green discoloration (Bile leakage)
     • Biliary Imbibition
   • Microscopically:
     • Dissociation of hepatocyte cords
       • Pyknosis of nuclei
         • Lysis of hepatocytes

4. Hepatic Degeneration

   • Hydrophobic Degeneration (Cloudy swelling)
     • Hepatocellular swelling
       • Early manifestation of cell injury (Hypoxia, toxins)
         • Hepatocytes unable to maintain normal homeostatsis
           • NRG production decreases => membrane pumps fail => lack of ATP
             • Intracellular accumulation of H2O
               • Swelling of mitochondria & other organelles
       • Cytoplasmic vacuoles may develop if severe
     • Reversible
       • Hepatocytes not damaged or destroyed
   • Fatty Change
     • Lipid accumulates in cytoplasm of injured hepatocytes
     • Inability to metabolize/function normally (Hypoxia, toxins)
       • I.e. Conversion of FFA => TAG
     • Often more severe damage than in hydropic degeneration/cloudy swelling
     • Reversible (If inciting cause is removed/corrected)
     • Fatty change (due to hypoxia/toxins) may eventually lead to lipidosis/steatosis when severe &/or chronic
     • Hepatic Lipidosis/Steatosis
       • Hepatocytes distended by discrete circular lipid vacuoles (displace nucleus to periphery of cell)
       • Due to massive uptake of fatty acids from the bloodstream following excessive mobilisation of adipose tissue reserves => Overloads metabolic capacity of hepatocytes & further inhibits their function
     • Pale, yellow, friable, "greasy" liver
     • Causes:
       • Starvation
         • Equine hyperlipaemia
           • Negative NRG balance in cattle
             • Feline hepatic lipidosis
               • Feline hyperlipaema
                 • Diabetes mellitus (Glycogen vs. lipid)
                   • Hypoxia/toxins => Lipidosis
   • Glycogen (Steroid Induced Hepatopathy)
     • Excessive accumulation of glycogen in the presence of high levels of corticosteroids
       • Exogenous corticosteroids
         • E.g. Dexamethasone (iatrogenic)
       • Endogenous corticosteroids
         • Hyperadrenocorticism
           • Diabetes mellitus
             • Glycgoen &/or fat accumulations
     • Hepatocytes distended by floccular ("feathery") cytoplasmic vacuoles (do not displace the nucleus)
     • Ballooning degeneration may occur
       • Irreversible
   • Amyloidosis
     • Primary
       • Can be familial
       • Shar pei dogs
       • Abyssinian, Siamese & other exotic cats
     • Secondary
       • Chronic inflammation
     • Gross pathology
       • Liver is enlarged
         • Pale & firm
           • Rounded borders
     • Histopathology
       • Amyloid is deposited extracellularly around portal tracts & along sinusoids in the space of Disse
         • Can also be deposited in kidneys, pancreas, blood vessels
     • Special stains
       • Congo red + Green birefringence
     • Types:
       • AA Type
         • Derived from the inflammatory acute phase protein serum amyloid A
       • AL Type
         • Derived from Ig light chains
       • ABeta type
         • Derived from amyloid precursor protein & islet amyloid polypeptide (IAPP: Hormone produced by Beta cells in pancreatic islets of cats)

5. Hepatic Necrosis

   • Mode of action of agent
     • Directly affects hepatocellular or biliary cells
     • Secondary to interference with blood supply or biliary tract damage
   • Severity & duration of action of agent
     • Mild &/or short duration => Reversible change
     • Severe, constant or repeated action => Irreversible change
   • Route of Access of Agent
     • Umbilical vein in foetus/neonate
       • Portal Vein
         • Hepatic Artery (O2)
           • Transcoelemic
             • Infections, neoplasms
             • Biliary system
               • Ascending infections
           • Toxins
   • Single-Cell Necrosis
     • Coagulative necrosis of individual cells & their immediate neighbors
     • Some forms of viral hepatitis e.g. Herpesvirus
   • Focal Necrosis
     • Usually a microscopic change in hepatocytes/biliary cells randomly distributed without obvious relationship to lobular pattern
     • Can be of minimal clinical significance
     • Viral & bacterial agents most common
   • Zonal Necrosis
     • Centrilobular (Periacinar) Necrosis
       • Hepatocytes are vulnerable to Hypoxic damage (Chronic venous congestion; Anaemia) b/c of relatively low gradient of O2 in center of the lobule
         • Also susceptible to toxic insult by toxins requiring hepatic biotransformation
     • Most common
     • Periportal Necrosis
       • Commonly seen in toxic damage where the toxin is preformed (closest to the incoming blood supply)
         • Portal vein or Hepatic artery
   • Massive Necrosis
     • Complete necrosis of individual lobules (cells & connective tissue scaffold)
     • May be isolated or multiple lobules
     • More Serious insult &/or longer duration insult
     • Does not neccessarily mean whole organ is affected
     • Followed by "Post-necrotic lobular collapse" & fibrosis (due to loss of reticulin scaffold
     • Ex. Hepatosis dietica (Vit. E deficiency - Pigs)

6. Response of Liver to Inflammation

   • Hypertrophy of Hepatocytes
     • Increase in size of surviving Hepatocytes: Increased amount of cytoplasm
   • Regenerative Hyperplasia
     • Nodular regeneration of existing mature hepatocytes in response to liver injury
       • Ability to regenerate varies w/ species & age
     • Hyperplasia may be diffuse, but often occurs as:
       • Microscopic nodules (Micronodular Hyperplasia)
       • Macroscopic nodules (Macronodular hyperplasia)
   • Nodular Hyperplasia
     • Common incidental finding in older dogs
     • Discrete, unencapsulated nodules of hepatocytes which retain good architecture of hepatic lobules & hepatocyte cords
       • Might be slightly vaculated
     • No evidence of concurrent hepatic disease
     • Not inflammatory
       • Needs to be differentiated from macronodular regeneration & neoplasia
   • Oval Cell Proliferation
     • Regeneration of new hepatocytes & bile ducts by proliferation of bipotential stem cells ("Oval cells") located in the terminal bile ductules (canals of Hering)
       • Oval cells = source of Hepatic Fibrosis
       • Often just see proliferation of bile duct type cells
         • i.e. more differentiated cells => biliary hyperplasia
   • Hepatic Atrophy
     • Atrophy of the whole liver, individual lobes or parts of lobes
     • Pressure on liver parenchyma, e.g. External or internal space occupying lesions
     • Anoxia/Hypoxia (Insidious O2 deprivation)
     • Impairment of bile flow: Chronic biliary disease
       • Fasciola hepatica infestation (Cattle & Sheep)
       • Cholestasis (Dogs & Cats)
   • Fibrosis
     • Localized or generalized deposition of extracellular connective tissue matrix (fibrous/scar tissue) as a healing response to hepatic injury
     • Centrilobular fibrosis
       • Prolonged hypoxia, cell death & fibrosis of centrilobular zones
       • Chronic venous congestion (Cardiac failure)
     • Biliary Fibrosis
       • Chronic periportal inflammation, cholangitis/cholangiohepatitis &/or biliary obstruction
       • Usually fibrosis in portal areas
     • Post-necrotic scarring
       • Following a single episode of widespread (massive) hepatocellular necrosis
       • Parenchyma & connective tissue scaffold (reticulin) are damaged
       • Post-necrotic collapse
       • Affected area cannot regenerate & is replaced by fibrous tissue
     • Diffuse Hepatic Fibrosis
       • On-going (Chronic) hepatocyte necrosis => Overwhelms the regenerative capacity
       • Chronic toxic injury => Phenobarbital, copper-associated, chronic inflammation
       • Widespread fibrous tissue deposition
       • Deposition of connective tissue in space of Disse =>Loss of fenestrations in sinusoidal endothelium (capillarisation) => Reduced permeability => Impaired blood-hepatocyte exchange
   • Cirrhosis
     • Diffuse, irreversible, end-stage hepatic disease
     • Combination of:
       • Hepatocyte destruction
         • Nodular regeneration
           • Biliary hyperplasia
             • Bridging fibrosis (across portal areas)
               • Portal-centrilobular vascular anastomoses
     • Mostly seen in Dogs
       • Hepatic insufficiency
         • Liver failure
           • Cause cannot always be established
     • Pathology:
       • Hypoproteinaemia:Ascites
       • Icterus: Hyperbilirubinaemia
       • Coagulopathy
       • Hepatic encephalopathy: NH3 retention
       • 2ndary photosensitisation: Herbivores (Phylloerythrin not excreted due to cholestasis)

7. Hepatic Mechanical Conditions (Trauma)

   • Displacement
     • Aquired displacement of Liver
     • RTA
       • Dogs, Cats
         • Liver lobe torsion
   • Rupture
     • Compression trauma
     • RTA (Dogs & Cats)
       • Abuse (Ex. kicks: Dogs & Cats)
         • Overlying (Piglets crushed by Sow)
           • "High rise syndrome" (Dogs & Cats)

8. Developmental Conditions

   • Congenital Cysts
     • Biliary cysts
       • Isolated or clusters
         • Formed from bile ductules
           • Concurrent polycystic kidney disease
       • Pigs, Calves,Lambs, Kittens, Dogs
   • Congenital vascular anomalies
     • Portosystemic Shunts
       • Anomalous development of portal vein
         • Extrahepatic: Prior to liver
           • Intrahepatic: Within liver
             • Persistent ductus venosus
           • Porto-caval; Porto-azygous
       • Sxs (Dogs, Cats):
         • Failure to gain weight, illthrift
         • Hepatic encephalopathy
       • Hypoplasia of liver & portal vein
       • Histopath:
         • Absence of portal venules (portal circulation diverted elsewhere)
         • Proliferation of Hepatic arterioles
     • Primary portal vein hypoplasia
       • Microvascular dysplasia
     • Intrahepatic arteriovenous fistulae
       • B/w Hepatic artery & portal vein
   • Hepatic Displacement
     • Congenital pericardial diaphragmatic hernia
       • Proplapse of one or more liver lobes into thorax (pericardial sec)
         • Persian cats
       • Opening in diaphragm to pericardial sac
   • Biliary atresia
     • Absence of bile ducts & ductules
   • Absence of gallbladder

9. Acquired Disturbances of Hepatic Circulation

   • Telangiectasis
     • Dilation (ectasia) of groups of sinusoids
       • Filled w/ blood
         • Incidental finding
           • Cattle, Cats
   • Vascular Obstruction
     • Portal Vein
       • Total rapid obstruction:
         • Death as a result of hypovolemic shock (sequestration of blood in splanchnic bed)
           • Medical Emergency
       • Partial or slowly progressive occlusion:
         • Atrophy of lobes of liver, depending on development of accessory portal circulation
           • When accessory circulation is inadequate, portal hypotension develops => Congestion & ascites
           • Aquired porto-systemic vascular shunting
             • Collateral blood vessels bypass the normal route of blood flow through the liver
               • Secondary to Portal Hypertension
                 • Severe hepatic disease (fibrosis/cirrhosis)
                 • Occlusion of the hepatic vein or portal vein
                   • Arteriovenous fistulae
                     • Primary portal vein hypoplasia
             • Dogs & Cats
             • Caval obstruction/chronic venous congestion of HEART FAILURE does NOT result in acquired shunts (No pressure gradient, caudal venacava & hepatic circulation are equally affected)

10. Hepatitis

    • Acute Hepatitis
      • Usually associated w/ hepatocellular necrosis
        • Suppurative necrotizing hepatitis (Bacterial infections)
          • Salmonellosis
        • Eosinophilic hepatitis (Parasitic infections)
          • Larval forms migrate through liver => Hepatitis
    • Chronic Hepatitis
      • Chronic inflammatory stimulus
      • Fibrovascular hyperplasia (Granulation tissue)
        • Nodular regeneration
          • Fibrosis
            • Cellular inflammatory infiltrates
              • Lymphocytes & plasma cells (portal areas)
              • Eosinophils (Portal areas)
              • Granulomatous inflammation
      • Copper-associated hepatopathy (Dogs)
        • Chronic copper toxicity (Sheep)
          • Ragwort toxicity (Due to pyrrolizidine alkaloids) (Horses, Cattle, Sheep)
            • Alfatoxins (aspergillus flavus) on stored grain (Pigs, Sheep)
              • Ascaris suum (pigs)
                • Milk spot liver
      • Chronic venous congestion w/ hepatocyte fatty degeneration & necrosis
    • Cholangiohepatitis
      • Inflammation of the biliary tree & hepatocellular parenchyma
        • Inflammation starts in the bile ducts & extends into parenchyma
      • Chronic fascioliasis in ruminants
        • Bacterial cholangiohepatitis from ascending infections from the intestine to the bile ducts
          • Cats: Chronic Cholangiohepatitis
            • In association w/ chronic pancreatitis &/or enteritis
              • => Triaditis (possibly due to common entry of bile & pancreatic ducts into the small intestine)

11. Biliary Disease

    • Cholangitis
      • Affects intra &/or extra Hepatic bile ducts
      • Usually an ascending infection
      • Chronic lymphocytic cholangitis (Cats)
        • Excessive aggregation of lymphocytes in portal tracts, bile duct proliferation & portal fibrosis
          • Possibly immune mediated
    • Cholecystitis
      • Inflammation of the gallbladder
      • Acute or Chronic
      • Ascending infection: Salmonella enterica
    • Cystic mucinous hyperplasia
      • Hyperplasia of the gallbladder & lining epithelium
      • Abundant production of mucous
        • Severe distension (mucocoele)
        • Obstruction (RARE)
    • Stenosis of the bile duct
      • External compression
        • Fibrosis, Inflammation, Tumors
    • Cholelithiasis
      • Gall stones (Choleliths)
        • Usually form in gallbladder
          • Mixture: Bilirubin, Ca carbonate, glycoprotein
      • Dogs, Cats
      • Cattle (Incidental finding)
      • Complete obstruction => Extrahepatic cholestasis => Jaundice
      • Leakage of bile into portal areas => inflammation & fibrosis

12. Hepatic Neoplasia

    • Hepatocellular carcinomas are more common than hepatocellular adenomas
    • Cholangiocarcinomas & Cholangioadenomas - Tumors of the gallbladder (Uncommon)
    • Vascular tumors - Haemangiosarcoma
    • Metastatic neoplasia (To Liver)
      • Ex. Pancreatic carcinoma, intestinal adenocarcinoma, splenic haemangiosarcoma
    • Multicentric neoplasia
      • Lymphoma or leukaemia

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