Category:Liver - Toxic Pathology

As well as playing a central role in detoxification in the body, the liver itself is very susceptible to intoxication. A vast number of hepatoxic agents are known, and it is impossible to describe and list all of them. Drugs, plant and fungal products, metals and other chemicals are all absorbed from the gut and passed to the liver for detoxification. In the course of this process, new products may be formed, and it can be these metabolites rather than the original compound which is hepatotoxic.

Hepatoxicity, Acute

Chronic hepatoxicity

Is associated with the continual ingestion of toxic compounds at low doses over a period of time

There will be evidence of regeneration and repair of the damaged tissue ie fibrosis and biliary hyperplasia

Ragwort

• Senecio jacobaea
• plant toxin ingested over a long period of time
• livestock
  • cattle and horses are more susceptible than sheep
  • livestock will not normally eat the fresh plant
  • most cases arise in horses and cattle consuming ragwort in hay or silage
• pyrrolizidine alkaloids
  • toxic principle converted in the body to the toxic intermediate pyrroles and their esters
  • cause intitial and continued damage to hepatocytes
  • have an anti-mitotic effect whilst allowing continued synthesis within the cell and its nucleus
    • causes a marked increase in the size of parenchymal cells, a phenomenon termed 'megalocytosis'
    • these very enlarged hepatocytes can be up to 20 times bigger
    • the enlarged cells are closely apposed so that the sinusoids may not be evident
• it is likely that the vascular component of the attempted repair of the chronic damage by fibrosis (really a type of granulation tissue) aids the shunting from the portal triads to the central vein and thereby bypassing the hepatocytes
• other plant and fungal toxins perform in the same way

Gross

• slightly enlarged liver
• pale in colour
• very firm to section

Microscopically

• necrosis
• haemorrhage
• diffuse fibrosis

Mycotoxins

• metabolites of fungi
• Alfatoxins produced by Aspergillus flavus and other species
• main expression
  • chronic intoxication in livestock following fungal growth on badly stored (moisture) grain
• isolated toxins
  • B1 - the most potent
  • B2
  • G1
  • G2
• toxic intermediates bind to cellular nuclei acids and proteins
  • potent toxins, carcinogens, and teratogens (the last two are less important in domestic animals)
• lesions similar to ragwort poisoning, including the hepatocytic cytomegaly

Copper

• sheep are very susceptible
  • they have poor ability to excrete copper in the bile
• copper accumulates in hepatocytes until it reaches a critical level
  • the hepatocytes die and release the copper into the blood
  • causes haemolysis of the red blood cells
• this haemolysis further damages the hepatocytes
  • releases even more copper

Predisposing factors

• contamination of foodstuffs and pasture with copper
• any damage to the biliary system as in ragwort poisoning
• pastures low in molybdenum
  • increases the availability of dietary copper
  • molybdenum combines with copper to form insoluble complexes in the gut

Gross

• carcass
  • jaundiced
  • reddish
• liver
  • swollen
  • soft
  • orange in colour
• kidneys
  • deep red
  • red urine due to haemoglobinuria

Microscopically

• periacinar hepatic necrosis and profuse bile due to haemolysis and cholestasis
• copper can be demonstrated with special stain - rhodanine

Genetic inheritance

• Bedlington and West Highland White Terriers
• copper toxicosis susceptibility
• inherited as autosomal defect
• copper levels can be very high in the livers of these animals
• there is no haemolytic crisis

Clinical

• ill thrift
• progressive neurological signs due to liver failure

Gross

• liver is small and fibrosed
• jaundice is not a consistent feature

Hepatic toxicity due to drugs

Primidone

• an anticonvulsant will cause periacinar necrosis in dogs
• prolonged thereapy will result in a small cirrhotic liver

Sulphonamides

• some of these casue hepatic necrosis in susceptible animals
• has been associated with a reduced capability of detoxifying the metabolites
• Doberman Pincher breed appear to be susceptible

Paracetamol

• cats are very susceptible to this drug
• causes periacinar necrosis

Copper and liver disease

• Copper – cofactor for enzymes (lysyl oxidase), electron transport proteins (cytochrome c oxidase) and antioxidant molecules (superoxide dismutase).
• Primarily absorbed through the small intestine and stomach (upper small intestine in the dog).
• Enterocyte regulation of absorption – metallothionein and a copper transport protein – ATPase7A.
• Metallothionein is a low molecular wt cytoplasmic protein, in all tissues; expression in response to heavy metals, various hormones and stress. metallothionein in cytoplasm of enterocytes leads to absorption of copper.
• ATPase7A – transmembrane copper transporter in a number of cell types.
• Defective in people with Menke’s disease – the animal model is the mottled mouse – results in faulty transport of copper out of the cell –leads to copper accumulation in enterocytes. Liver and brain that have little of the transporter experience copper deficiency.
• Chronic diet XS of copper leads to accumulation in the liver .
• Serum copper – in 2 pools
  • Exchangeable pool – loosely bound to carrier molecules; 80% of it bound to transcuperin, the rest bound to albumin.
  • Other pool – tightly bound to carrier molecules.