Liver Pathology

Liver Pathology

Functions
1. Portal Vein
  1. Metabolic processing
    1. Dietary carbohydrates
      1. Lipids
        Amino Acids
        Vitamins
  2. Detoxification, Degredation &/or Biliary Excretion
    1. Endogenous wastes
      1. Toxic molecules
        Hormones
        Xenobiotic compounds
        Biotransformation of drugs
        Detoxified chemical wastes
      2. Bile salts, Bilirubin, cholesterol, HCO3-, H2O
  3. Blood from Intestinal tract
  4. Processing & Activation of some xenobiotic agents
    1. Pro-drugs
      1. Ex. Cytochrome p450
2. Synthesis of Plasma Proteins
  1. Albumin
    1. Globulins
      1. Clotting factors
      2. Complement proteins
    2. Other serum transport/ binding proteins
3. Storage
  1. Glycogen
    1. Fats
      1. Fe
        Cu
        Vitamins
        Ex. Vitamin A (stored in Hepatic stellate cells)
4. Processing of Vitamin D
  1. With Kidneys
5. Removal of Bacteria & Erythrocytes
  1. Kupffer cells
  2. Removal of Erythrocytes also occurs in the Spleen
Clinical Signs of Liver Disease
1. Jaundice/ Icterus
  1. Accumulation of bilirubin in the body
  2. Mechanism
    1. Pre-Hepatic
      1. Excessive breakdown of Erythrocytes
        Liver is overwhelmed & cannot excrete the bilirubin fast enough
        Ex. IMHA (Immune mediated Haemolytic Anaemia)
    2. Post-Hepatic
      1. 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
    3. Hepatic
      1. Liver is diseased & cannot excrete even the normal bilirubin load
        Ex. Cirrhosis
2. Oedema/Ascites/Anasarca
  1. If the liver is unable to synthesize the normal plasma proteins, there will be a reduction in plasma oncotic pressure
    1. Ex. Decrease in serum Albumin, Decrease in Oncotic pressure
    2. Fluid moves out of circulation => Fluid accumulates in the body cavities & subcutaneous spaces
3. Coagulation (Clotting) Disorders
  1. If liver is unable to produce sufficient clotting factors, fibrinolytic proteins, complement proteins & acute phase proteins:
    1. => Poor or inappropriate Haemostasis & immune function
      1. Risk of Haemorrhage after liver biopsy
      2. Paradoxial balance
        Liver products
        Pro-coagulation
        Lack of Anti-clotting factors
        Anti-coagulation
        Lack of clotting factors
4. Hepatic Encephalopathy
  1. Liver usually converts ammonia into urea (excreted by the kidneys)
    1. NH3 produced in intestine by bacteria
  2. Liver disease:
    1. Reduced ability to detoxify &/or remove nitrogenous compounds from the body
      1. 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
5. Metabolic disease & dysfunction
  1. Liver disease (Reduced ability to):
    1. Process dietary components delivered from the portal blood
    2. Store Glycogen, fat & vitamins
    3. Detoxify endogenous or exogenous toxins
    4. Implications for drug selection, administration & dosage
Incidental Post-Mortem Changes
1. Prone to rapid PM change:
  1. Composition
    1. Vascularity
      1. Proximity to the intestine
2. Softening & increased friability
3. Production of gas bubbles (Putrefactive bacterial fermentation)
4. Black discoloration (bacterial breakdown of Hb)
5. Green discoloration (Bile leakage)
  1. Biliary Imbibition
6. Microscopically:
  1. Dissociation of hepatocyte cords
    1. Pyknosis of nuclei
      1. Lysis of hepatocytes
Hepatic Degeneration
1. Hydrophobic Degeneration (Cloudy swelling)
  1. Hepatocellular swelling
    1. Early manifestation of cell injury (Hypoxia, toxins)
      1. Hepatocytes unable to maintain normal homeostatsis
        NRG production decreases => membrane pumps fail => lack of ATP
        Intracellular accumulation of H2O
        Swelling of mitochondria & other organelles
    2. Cytoplasmic vacuoles may develop if severe
  2. Reversible
    1. Hepatocytes not damaged or destroyed
2. Fatty Change
  1. Lipid accumulates in cytoplasm of injured hepatocytes
  2. Inability to metabolize/function normally (Hypoxia, toxins)
    1. I.e. Conversion of FFA => TAG
  3. Often more severe damage than in hydropic degeneration/cloudy swelling
  4. Reversible (If inciting cause is removed/corrected)
  5. Fatty change (due to hypoxia/toxins) may eventually lead to lipidosis/steatosis when severe &/or chronic
  6. Hepatic Lipidosis/Steatosis
    1. Hepatocytes distended by discrete circular lipid vacuoles (displace nucleus to periphery of cell)
    2. 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
  7. Pale, yellow, friable, "greasy" liver
  8. Causes:
    1. Starvation
      1. Equine hyperlipaemia
        Negative NRG balance in cattle
        Feline hepatic lipidosis
        Feline hyperlipaema
        Diabetes mellitus (Glycogen vs. lipid)
        Hypoxia/toxins => Lipidosis
3. Glycogen (Steroid Induced Hepatopathy)
  1. Excessive accumulation of glycogen in the presence of high levels of corticosteroids
    1. Exogenous corticosteroids
      1. E.g. Dexamethasone (iatrogenic)
    2. Endogenous corticosteroids
      1. Hyperadrenocorticism
        Diabetes mellitus
        Glycgoen &/or fat accumulations
  2. Hepatocytes distended by floccular ("feathery") cytoplasmic vacuoles (do not displace the nucleus)
  3. Ballooning degeneration may occur
    1. Irreversible
4. Amyloidosis
  1. Primary
    1. Can be familial
    2. Shar pei dogs
    3. Abyssinian, Siamese & other exotic cats
  2. Secondary
    1. Chronic inflammation
  3. Gross pathology
    1. Liver is enlarged
      1. Pale & firm
        Rounded borders
  4. Histopathology
    1. Amyloid is deposited extracellularly around portal tracts & along sinusoids in the space of Disse
      1. Can also be deposited in kidneys, pancreas, blood vessels
  5. Special stains
    1. Congo red + Green birefringence
  6. Types:
    1. AA Type
      1. Derived from the inflammatory acute phase protein serum amyloid A
    2. AL Type
      1. Derived from Ig light chains
    3. ABeta type
      1. Derived from amyloid precursor protein & islet amyloid polypeptide (IAPP: Hormone produced by Beta cells in pancreatic islets of cats)
Hepatic Necrosis
1. Mode of action of agent
  1. Directly affects hepatocellular or biliary cells
  2. Secondary to interference with blood supply or biliary tract damage
2. Severity & duration of action of agent
  1. Mild &/or short duration => Reversible change
  2. Severe, constant or repeated action => Irreversible change
3. Route of Access of Agent
  1. Umbilical vein in foetus/neonate
    1. Portal Vein
      1. Hepatic Artery (O2)
        Transcoelemic
        Infections, neoplasms
        Biliary system
        Ascending infections
        Toxins
4. Single-Cell Necrosis
  1. Coagulative necrosis of individual cells & their immediate neighbors
  2. Some forms of viral hepatitis e.g. Herpesvirus
5. Focal Necrosis
  1. Usually a microscopic change in hepatocytes/biliary cells randomly distributed without obvious relationship to lobular pattern
  2. Can be of minimal clinical significance
  3. Viral & bacterial agents most common
6. Zonal Necrosis
  1. Centrilobular (Periacinar) Necrosis
    1. Hepatocytes are vulnerable to Hypoxic damage (Chronic venous congestion; Anaemia) b/c of relatively low gradient of O2 in center of the lobule
      1. Also susceptible to toxic insult by toxins requiring hepatic biotransformation
  2. Most common
  3. Periportal Necrosis
    1. Commonly seen in toxic damage where the toxin is preformed (closest to the incoming blood supply)
      1. Portal vein or Hepatic artery
7. Massive Necrosis
  1. Complete necrosis of individual lobules (cells & connective tissue scaffold)
  2. May be isolated or multiple lobules
  3. More Serious insult &/or longer duration insult
  4. Does not neccessarily mean whole organ is affected
  5. Followed by "Post-necrotic lobular collapse" & fibrosis (due to loss of reticulin scaffold
  6. Ex. Hepatosis dietica (Vit. E deficiency - Pigs)
Response of Liver to Inflammation
1. Hypertrophy of Hepatocytes
  1. Increase in size of surviving Hepatocytes: Increased amount of cytoplasm
2. Regenerative Hyperplasia
  1. Nodular regeneration of existing mature hepatocytes in response to liver injury
    1. Ability to regenerate varies w/ species & age
  2. Hyperplasia may be diffuse, but often occurs as:
    1. Microscopic nodules (Micronodular Hyperplasia)
    2. Macroscopic nodules (Macronodular hyperplasia)
3. Nodular Hyperplasia
  1. Common incidental finding in older dogs
  2. Discrete, unencapsulated nodules of hepatocytes which retain good architecture of hepatic lobules & hepatocyte cords
    1. Might be slightly vaculated
  3. No evidence of concurrent hepatic disease
  4. Not inflammatory
    1. Needs to be differentiated from macronodular regeneration & neoplasia
4. Oval Cell Proliferation
  1. Regeneration of new hepatocytes & bile ducts by proliferation of bipotential stem cells ("Oval cells") located in the terminal bile ductules (canals of Hering)
    1. Oval cells = source of Hepatic Fibrosis
    2. Often just see proliferation of bile duct type cells
      1. i.e. more differentiated cells => biliary hyperplasia
5. Hepatic Atrophy
  1. Atrophy of the whole liver, individual lobes or parts of lobes
  2. Pressure on liver parenchyma, e.g. External or internal space occupying lesions
  3. Anoxia/Hypoxia (Insidious O2 deprivation)
  4. Impairment of bile flow: Chronic biliary disease
    1. Fasciola hepatica infestation (Cattle & Sheep)
    2. Cholestasis (Dogs & Cats)
6. Fibrosis
  1. Localized or generalized deposition of extracellular connective tissue matrix (fibrous/scar tissue) as a healing response to hepatic injury
  2. Centrilobular fibrosis
    1. Prolonged hypoxia, cell death & fibrosis of centrilobular zones
    2. Chronic venous congestion (Cardiac failure)
  3. Biliary Fibrosis
    1. Chronic periportal inflammation, cholangitis/cholangiohepatitis &/or biliary obstruction
    2. Usually fibrosis in portal areas
  4. Post-necrotic scarring
    1. Following a single episode of widespread (massive) hepatocellular necrosis
    2. Parenchyma & connective tissue scaffold (reticulin) are damaged
    3. Post-necrotic collapse
    4. Affected area cannot regenerate & is replaced by fibrous tissue
  5. Diffuse Hepatic Fibrosis
    1. On-going (Chronic) hepatocyte necrosis => Overwhelms the regenerative capacity
    2. Chronic toxic injury => Phenobarbital, copper-associated, chronic inflammation
    3. Widespread fibrous tissue deposition
    4. Deposition of connective tissue in space of Disse =>Loss of fenestrations in sinusoidal endothelium (capillarisation) => Reduced permeability => Impaired blood-hepatocyte exchange
7. Cirrhosis
  1. Diffuse, irreversible, end-stage hepatic disease
  2. Combination of:
    1. Hepatocyte destruction
      1. Nodular regeneration
        Biliary hyperplasia
        Bridging fibrosis (across portal areas)
        Portal-centrilobular vascular anastomoses
  3. Mostly seen in Dogs
    1. Hepatic insufficiency
      1. Liver failure
        Cause cannot always be established
  4. Pathology:
    1. Hypoproteinaemia:Ascites
    2. Icterus: Hyperbilirubinaemia
    3. Coagulopathy
    4. Hepatic encephalopathy: NH3 retention
    5. 2ndary photosensitisation: Herbivores (Phylloerythrin not excreted due to cholestasis)
Hepatic Mechanical Conditions (Trauma)
1. Displacement
  1. Aquired displacement of Liver
  2. RTA
    1. Dogs, Cats
      1. Liver lobe torsion
2. Rupture
  1. Compression trauma
  2. RTA (Dogs & Cats)
    1. Abuse (Ex. kicks: Dogs & Cats)
      1. Overlying (Piglets crushed by Sow)
        "High rise syndrome" (Dogs & Cats)
Developmental Conditions
1. Congenital Cysts
  1. Biliary cysts
    1. Isolated or clusters
      1. Formed from bile ductules
        Concurrent polycystic kidney disease
    2. Pigs, Calves,Lambs, Kittens, Dogs
2. Congenital vascular anomalies
  1. Portosystemic Shunts
    1. Anomalous development of portal vein
      1. Extrahepatic: Prior to liver
        Intrahepatic: Within liver
        Persistent ductus venosus
        Porto-caval; Porto-azygous
    2. Sxs (Dogs, Cats):
      1. Failure to gain weight, illthrift
      2. Hepatic encephalopathy
    3. Hypoplasia of liver & portal vein
    4. Histopath:
      1. Absence of portal venules (portal circulation diverted elsewhere)
      2. Proliferation of Hepatic arterioles
  2. Primary portal vein hypoplasia
    1. Microvascular dysplasia
  3. Intrahepatic arteriovenous fistulae
    1. B/w Hepatic artery & portal vein
3. Hepatic Displacement
  1. Congenital pericardial diaphragmatic hernia
    1. Proplapse of one or more liver lobes into thorax (pericardial sec)
      1. Persian cats
    2. Opening in diaphragm to pericardial sac
4. Biliary atresia
  1. Absence of bile ducts & ductules
5. Absence of gallbladder
Acquired Disturbances of Hepatic Circulation
1. Telangiectasis
  1. Dilation (ectasia) of groups of sinusoids
    1. Filled w/ blood
      1. Incidental finding
        Cattle, Cats
2. Vascular Obstruction
  1. Portal Vein
    1. Total rapid obstruction:
      1. Death as a result of hypovolemic shock (sequestration of blood in splanchnic bed)
        Medical Emergency
    2. Partial or slowly progressive occlusion:
      1. 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)
Hepatitis
1. Acute Hepatitis
  1. Usually associated w/ hepatocellular necrosis
    1. Suppurative necrotizing hepatitis (Bacterial infections)
      1. Salmonellosis
    2. Eosinophilic hepatitis (Parasitic infections)
      1. Larval forms migrate through liver => Hepatitis
2. Chronic Hepatitis
  1. Chronic inflammatory stimulus
  2. Fibrovascular hyperplasia (Granulation tissue)
    1. Nodular regeneration
      1. Fibrosis
        Cellular inflammatory infiltrates
        Lymphocytes & plasma cells (portal areas)
        Eosinophils (Portal areas)
        Granulomatous inflammation
  3. Copper-associated hepatopathy (Dogs)
    1. Chronic copper toxicity (Sheep)
      1. Ragwort toxicity (Due to pyrrolizidine alkaloids) (Horses, Cattle, Sheep)
        Alfatoxins (aspergillus flavus) on stored grain (Pigs, Sheep)
        Ascaris suum (pigs)
        Milk spot liver
  4. Chronic venous congestion w/ hepatocyte fatty degeneration & necrosis
3. Cholangiohepatitis
  1. Inflammation of the biliary tree & hepatocellular parenchyma
    1. Inflammation starts in the bile ducts & extends into parenchyma
  2. Chronic fascioliasis in ruminants
    1. Bacterial cholangiohepatitis from ascending infections from the intestine to the bile ducts
      1. Cats: Chronic Cholangiohepatitis
        In association w/ chronic pancreatitis &/or enteritis
        => Triaditis (possibly due to common entry of bile & pancreatic ducts into the small intestine)
Biliary Disease
1. Cholangitis
  1. Affects intra &/or extra Hepatic bile ducts
  2. Usually an ascending infection
  3. Chronic lymphocytic cholangitis (Cats)
    1. Excessive aggregation of lymphocytes in portal tracts, bile duct proliferation & portal fibrosis
      1. Possibly immune mediated
2. Cholecystitis
  1. Inflammation of the gallbladder
  2. Acute or Chronic
  3. Ascending infection: Salmonella enterica
3. Cystic mucinous hyperplasia
  1. Hyperplasia of the gallbladder & lining epithelium
  2. Abundant production of mucous
    1. Severe distension (mucocoele)
    2. Obstruction (RARE)
4. Stenosis of the bile duct
  1. External compression
    1. Fibrosis, Inflammation, Tumors
5. Cholelithiasis
  1. Gall stones (Choleliths)
    1. Usually form in gallbladder
      1. Mixture: Bilirubin, Ca carbonate, glycoprotein
  2. Dogs, Cats
  3. Cattle (Incidental finding)
  4. Complete obstruction => Extrahepatic cholestasis => Jaundice
  5. Leakage of bile into portal areas => inflammation & fibrosis
Hepatic Neoplasia
1. Hepatocellular carcinomas are more common than hepatocellular adenomas
2. Cholangiocarcinomas & Cholangioadenomas - Tumors of the gallbladder (Uncommon)
3. Vascular tumors - Haemangiosarcoma
4. Metastatic neoplasia (To Liver)
  1. Ex. Pancreatic carcinoma, intestinal adenocarcinoma, splenic haemangiosarcoma
5. Multicentric neoplasia
  1. Lymphoma or leukaemia

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	Created by melian.yates over 10 years ago