Icterus

Also known as: Jaundice

Introduction

Image of a jaundiced cat, note the discoloured pinnae
(Image source Sabar 2007, Wikimedia Commons)

Icterus refers to the staining of tissues by bilirubin pigment or bilirubin complexes. Bile pigments such as bilirubin have particular affinity for elastic tissues and the typical yellow/orange colour of icterus is therefore evident in the slcera and mucous membranes in life and in the tunica intima of the aorta at post mortem examination.

The serum bilirubin concentration of an animal indicates the degree of icterus and the condition only becomes clinically evident at levels above 2 mg/100 ml (normal range below 0.5 mg/100 ml). Bilirubin should be measured by a technique which measures the large proportion which is bound to plasma albumin.

Causes of Icterus

Pre-hepatic Jaundice

This condition results from increased red blood cell destruction, overwhelming the capacity of the liver to conjugate and excrete the bilirubin which is released into the plasma. The majority of the bilirubin is therefore unconjugated and, unlike the conjugated form, this cannot be excreted by the kidney. Possible causes of haemolysis and prehepatic jaundice include:

• Haemolytic bacteria, including Clostridium haemolyticum in cattle and Leptospires in various species.
• Haemolytic parasites, including Babesiosis in cattle and dogs and Mycoplasma haemofelis in cats.
• Immune reactions to red blood cells, including:
  • Neonatal isoerthryolysis, resulting from the production of antibodies by the dam which are ingested by the neonate in colostrum and subsequently cause destruction of red blood cells. Bilirubin is able to cross the immature blood brain barrier and cause direct damage to the neurones of the brain, a phenomenon called kernicterus.
  • Autoimmune haemolytic anaemia or immune-mediated haemolytic anaemia.
  • Destruction of red blood cells of lambs fed with bovine colostrum.
• Hypophosphataemia, which may occur in cattle with post-parturient haemoglobinuria, in animals with diabetic ketoacidosis (DKA) which are rapidly stabilised with insulin and in refeeding syndrome.
• Inherited defects of red blood cell enzymes, including phosphofructokinase and pyruvate kinase.
• Microangiopathic damage to red blood cells as they pass through narrow or damaged blood vessels, as in haemangiosarcomata, disseminated intravascular coagulation (DIC) or vasculitis.
• Oxidative damage to red blood cells, caused by paracetamol in cats, onion poisoning in dogs and copper toxicity in many species. Ingestion of red maple leaves may also cause haemolysis in horses, as may brassicas (such as rape and kale) in cattle and sheep.

Haemolysis which is sufficiently severe to cause icterus is likely to be life-threatening due to the reduction in oxygen-carrying capacity of the blood. Animals affected acutely may require transfusions of whole blood, packed red blood cells or synthetic bovine haemoglobin and it may be advisable to provide oxygen by nasal catheter, flow-by or mask. In addition, the presence of large amounts of haemoglobin may cause acute intrinsic renal failure (in addition to the pre-renal failure caused by reduced oxygen delivery to the kidneys) and neonates may suffer from kernicterus, direct damage to the central nervous system caused by bilirubin.

Hepatic Jaundice

Liver cell damage may lead to jaundice by two main mechanisms:

• In acute hepatic necrosis and hepatic lipidosis, damaged cells swell to such a degree that flow of bile in the canaliculi is obstructed.
• In chronic liver failure, so much hepatic function is lost that the bilirubin produced by the constant turnover of red blood cells cannot be taken up and conjugated, leading to an accumulation of unconjugated bilirubin in the blood.

Post-hepatic Jaundice

This occurs due to an obstruction in the biliary tract which normally carriers bile from the liver and gall bladder to the duodenum. Conjugated bilirubin is found in the urine but, in complete obstruction, urobilinogen will be absent from the urine and stercobilin from the faeces. Possible causes of post-hepatic jaundice include:

• Intraluminal obstructions:
  • Choleliths ('gall stones') are much less common in animals than they are in humans. They are usually composed of bilirubin salts in dogs and calcium carbonate in cats, although they are very rare in the latter species.
  • Gall bladder mucocoeles produce a kiwi sign on radiographs and may be a sequel to cystic mucinous hyperplasia of the gall bladder mucosa.
  • Biliary neoplasia, most commonly cholangiocellular cystadenoma (in cats) or carcinoma (in dogs).
  • Aberrent migration of intestinal parasites, including Ascaris suum in pigs and Parascaris equorum in horses. This occur particularly when worms have been treated with an anthelmintic that causes spasticity of the muscles.
• Extraluminal obstructions:
  • Pancreatitis, pancreatic abcess or neoplasm
  • Biliary tract rupture
  • Pyloric or duodenal mass

Animals suffering from extra-hepatic biliary obstruction (EHBO) are often profoundly unwell. The reduced flow of bile salts into the gastro-intestinal (GI) tract allows GI bacteria to proliferate and eventually translocate across the intestinal wall. In addition, biliary stasis reduces the function of Kupffer cells within the liver, reducing their ability to remove and neutralise translocated bacteria from the portal blood. These animals should be stabilised adequately before any surgical repair is attempted.

Jaundice

• Jaundice is also known as icterus.
• Jaundice is a yellowish discoloration due to excessive levels of bilirubin in plasma.
  • Seen in tissues that are normally white, e.g.
    • Fat
    • Intima of blood vessels
    • Sclera
• Bilirubin stains brown with H&E, like both haemosiderin and lipofuscin.
  • Must be distinguished from each other by special stains.
    • Bilirubin stains bright green with a Fouchet stain.

Production of Bilirubin

• Red blood cells either undergo:
  • Phagocytosis, in the case of ageing cells.
  • Haemolysis, in haemolytic crises.
• Haemoglobin is freed from the red cells and is further broken down in the reticulo-endothelial system to haeme and globulin.
  • Haeme is a mixture of iron and porphyrin.
  • Both the iron and globulin are recycled for further use in erythropoiesis.
• The porphyrin from haemoglobin breakdown is converted to biliverdin.
  • A green pigment
    • May contribute to the greenish appearance seen in local bruising.
• Biliverdin is subsequently changed into bilirubin.
• The bilirubin is then bound to albumin, and transported in the blood to the liver.
  • In the hepatocyte, bilirubin is released from the albumin and conjugated with glucuronic acid.
    • Forms conjugated bilirubin.
      • Excreted into the intestine via the bile ducts.

Prehepatic (Haemolytic) Icterus

• Due to excessive production of bilirubin due to haemolysis, e.g.
  • Babesiosis
  • Leptospirosis
  • Copper poisoning in sheep.
• There is excessive unconjugated bilirubin in the blood.

Hepatic (Toxic) Icterus

• Due to liver cell damage.
  • In hepatocytic necrosis, the liver cannot conjugate bilirubin.
    • Results in increased levels of unconjugated bilirubin in the blood.
  • In less severe damage, the hepatocytes swell and bile caniculi are pressed closed.
    • There is therefore intrahepatic obstruction conjugated bilirubin accumulated in the blood.
• In reality, these situations occur together.
  • There is both excessive unconjugated and conjugated bilirubin in the blood.
• Examples:
  • Leptospira icterohaemorrhagica in the dog.
  • Rift Valley fever virus.
  • Some plant poisonings.
    • Lantana.
  • Some fungal infections.
    • Aflatoxicosis.

Post-Hepatic (Obstructive) Icterus

• Due to the flow of bile being obstructed, for example by:
  • Gallstones
  • Parasites
    • Ascaris suum in the bile ducts of pigs.
  • Tumours
    • Adenocarcinoma of pancreas presses upon and occludes the bile duct.
• Results in excessive conjugated bilirubin in the blood.
• Constructive icterus causes, out of the three types of icterus,
  • The most elevated levels of bilirubin in the blood
  • The greatest discoloration of the tissues of the body.

Van de Berg Test

• This test can distinguish between the different types of jaundice, based on whether the bilirubin is conjugated or not.
• Plasma from the jaundiced animal is treated with an aqueous solution of a reagent (diazotised sulphanilic acid).
  • Gives a red-purple colour.
    • The intensity of this colour is directly proportional to the amount of water-soluble (i.e. conjugated ) bilirubin in the sample.
  • Further addition of alcohol intensifies the colour if there is non-water-soluble (i.e. unconjugated) bilirubin also present.
    • The intensified colour is directly proportional to the total amount of bilirubin present in the sample.
  • The difference between the two readings gives the amount of unconjugated bilirubin in the sample.

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Literature Search

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Icterus publications

Icterus in dogs publications

Icterus in cats publications

Icterus in horses publications

Icterus in farm animals publications

References

Gorman N (1998) Canine Medicine and Therapeutics Blackwell Sciences