Jaundice in the Dog
Patrick Lecoindre, DVM, Dipl. ECVIM-CA
Colette Arpaillange, DVM
Jaundice (or icterus) is a syndrome characterized by a yellow discoloration of the mucosae and teguments, caused by an increase in the serum concentration of bilirubin (hyperbilirubinaemia). Although often indicative of hepatic disease, extrahepatic conditions can also result in icterus. Detection of jaundice in the dog is relatively easy, but determining the exact aetiology can prove more challenging and a rigorous diagnostic work-up is essential. Given the complexity of the mechanisms behind icterus, it is important to follow a clear and consistent diagnostic approach; this article describes the authors’ preferred method of approaching a dog with icterus.
Pathophysiology of Icterus
Icterus can be classified into three pathophysiological and aetiological types (1,2). Pre-hepatic or “haemolytic” icterus (as it is a consequence of haemolysis) occurs when the increase in bilirubin production exceeds the capacities of the hepatocytes to conjugate and excrete it. Hepatic icterus results from intrahepatic cholestasis, associated with diffuse disease of the bile ducts or hepatocytes, principally in the periportal zone (the so-called zone 1). Post-hepatic icterus results from extrahepatic cholestasis due to impaired or obstructed flow of bile downstream from the liver.
The normal total bilirubin concentration in the blood is less than 0.4 mg/dL. The tissues start to discolor when the concentration exceeds 2 mg/dL, and icterus becomes frank at 4 mg/dL and above. Biochemical icterus therefore always precedes clinical icterus. The presence of massive bilirubinuria, which may occur long before icterus, should prompt the clinician to test the bilirubin concentration in the blood.
However, it is important to note that over the course of the disease several pathological components can be identified in cases of icterus and these often become mixed: with significant haemolysis, oxygen deprivation of the hepatocytes may lead to oedema then hepatocytic necrosis due to the accumulation of certain degradation products from the red blood cells and this results in a hepatic icterus. Similarly, extra-hepatic cholestasis progressively leads to the development of intrahepatic cholestasis and the onset of a mixed hepatic and post-hepatic icterus.
When presented with a case of icterus in a dog, it is important for the clinician to assess the intensity of the icterus and to try and correlate it with other symptoms that could help narrow down the differential diagnosias (see Table 1 and Figure 1). Pale yellow mucosae (sub-icterus) and/or orange-brown or even dark brown urine (“coffee granules”) are suggestive of a pre-hepatic icterus with the proviso that anaemia is confirmed on haematology. In the absence of anaemia and signs of haemolysis, the clinician should focus on diseases of the liver or biliary tract.
A precise and detailed history is essential when working-up an icteric patient as it is a significant source of information. It is particularly important to ascertain the time and mode of onset of the icterus from the owner. In general, a pre-hepatic icterus (haemolytic) has an acute onset and is accompanied by depression, anorexia, and discoloration of the urine in the event of intravascular haemolysis. Posthepatic icterus associated with obstruction of the main bile duct can be chronic in onset, progressing over a period of several weeks (3,4). It may be well tolerated with the only clinical signs being a drop in appetite, a few non-specific gastrointestinal signs, and mild weight loss. However, extra-luminal biliary obstruction caused by pancreatitis or rupture of the extra-hepatic bile ducts may cause more severe clinical signs and be acute to subacute in nature (4). Nausea and vomiting are common in inflammatory disease of the biliary tract, and more specifically of the gallbladder and common bile duct (5). This is probably related to their highly developed autonomic innervation. The high concentration of emetic receptors at this level leads to enhanced sensitivity to distension, inflammation, or neoplastic infiltration. Hepatic icterus may be acute in onset (6). Leptospirosis is the most common cause of acute hepatitis in the dog, the ictero-hemorrhagic form of which causes marked icterus and is accompanied by severe clinical signs (depression, gastrointestinal disorders, dehydration, and hemorrhagic diathesis). However, some forms of leptospirosis can be subclinical and chronic. Chronic hepatitis, irrespective of the aetiology (infectious, toxic, immune-mediated, or breed related), has a more insidious nature and icterus is often the sign of very advanced disease (7-11).
Acute or chronic in onset, hepatic icterus is the result of a very severe deterioration in hepatic function, usually associated with systemic signs reflecting the severity of the disease and its repercussions. The possibility of toxic processes should be explored if the animal has been exposed to certain toxins (lead, copper), has been on medication (NSAIDs, phenobarbital), or has recently undergone gaseous anaesthesia (12). It is very important to take the breed of dog into consideration since numerous causes of chronic hepatitis are breed-related and are associated with the onset of icterus (8-11). Many breeds of dog are predisposed to the development of chronic idiopathic hepatitis (Springer spaniel, Labrador, Doberman, etc.) (10,13) or are associated with metabolic anomalies such as copper overload (Bedlington terrier, Labrador, West Highland white terrier, etc.) (8,9,11), or an accumulation of alpha 1- antitrypsin (cocker spaniel) (14). Similarly the Shetland sheepdog and Scottish terrier are predisposed to the development of biliary mucocele, which can generate a severe extra-hepatic cholestasis (15). The dog’s environment and vaccination status are obviously important factors. Hunting dogs, or those that live outside, are more exposed to piroplasmosis or leptospirosis. With the latter, several infective strains may not be covered by vaccination (L. icterohemorrhagiae and L. canicola) and can be responsible for the onset of clinical leptospirosis.
The clinical examination should first and foremost concentrate on the detection of signs of haemolysis and any symptoms associated with the icterus such as ascites, abdominal pain, and neurological disorders (1,2). The yellow coloration may be subtle, notably in cases with haemolytic syndrome, especially given that the mucosae are often pale at the time of examination; this is often referred to as sub-icterus (see clinical case report later in the article). However, this coloration may be very intense if it is accompanied by mucosal congestion.
Particular attention should be paid to the liver during abdominal palpation. The size, shape, firmness, and presence of any surface irregularities should be assessed. Palpation may reveal localized cranial abdominal pain in cases of gallbladder or pancreatic disease. Splenomegaly may indicate haemolytic anaemia. In the event of icterus, the urine becomes discoloured (orange-brown or even dark brown - “coffee grounds”) if intravascular haemolysis is present (haemoglobinuria). Pigmenturia is identified on examination of a urine dip stick, revealing bilirubinuria and urobilinuria in cases of prehepatic icterus. The presence of haemoglobin is indicative of haemolytic icterus, but the latter cannot be ruled out in its absence. Polyuriapolydipsia (PUPD), common in cases of chronic hepatic disease, leads to a reduction in urine density and dilution of the bilirubin: bilirubinuria, even moderate, should be considered as significant when the urine is of low density. Faeces are usually dark coloured with hepatic icterus, and pale in cases of extra-hepatic bile duct obstruction; complete bleaching occurs around one week after complete obstruction. Other clinical signs may also be present, such as purpura, respiratory signs (due to intoxication with agents that cause methaemoglobinemia), and abdominal effusion.
Further Diagnostic Tests
Further diagnostic tests should make it possible to quantify the icterus, and to determine its type and etiology. These include laboratory tests and imaging.
Haematology is an essential part of the diagnostic work up in icterus as it can determine the presence of anaemia. The haematocrit will reveal an anaemia which should then by objectivised with a complete differential count. Cases of haemolytic anaemia that result in icterus are severe and regenerative, even if the regeneration only becomes maximal after two to four days, which may delay the onset of reticulocytosis. Anaemia associated with hepatic disease is associated with chronic inflammatory reactions (defective iron utilization) and is usually moderate, nonregenerative, normocytic, and normochromic (2). If haemolysis is suspected, other examinations (blood smear, Coombs’ test, serology for infectious diseases) should be considered. The examination of a blood smear will provide a definitive diagnosis of babesiosis. Other morphological anomalies of red blood cells may help to orientate the diagnosis: spherocytes are suggestive of an autoimmune haemolytic anaemia, and Heinz bodies are observed following the ingestion of certain toxins (zinc, onions, benzocaine). A Coombs’ test provides confirmation of the immunological character of anaemia. It is then advisable to look for any possible primary infectious or parasitic aetiology (babesiosis, ehrlichiosis, bartonella, leishmaniasis, dirofilariasis), neoplastic, iatrogenic, or toxic.
These simple diagnostic tests are primarily oriented towards hepatic function (16) and usually make it possible to quantify and classify the icterus as pre-hepatic, hepatic, or posthepatic (Figure 1).
Detecting cytolysis... Transaminases (ALT and AST) are markers of hepatic cytolysis. The magnitude of the increase in transaminase activity indicates the number of hepatocytes that have been injured, but not the reversibility of the phenomenon and therefore the prognosis. AST in dogs is also found in other organs and is not specific to the liver. An ALT assay is sufficient and simultaneous assay of both transaminases, common in human medicine, is not justified.
Investigating cholestasis... The ALPs (alkaline phosphatases) are enzymes that are excreted in the bile. Their activity increases in the event of cholestasis, but also under the effect of certain drugs, such as corticosteroids or anticonvulsants. ALP is also present in numerous tissues, in particular bone. An increase in ALP is observed in growing dogs or in the event of bony disease (osteomyelitis, neoplasia, etc.). GGTs are also present in numerous tissues but the majority of their activity is hepatic. GGT assay is more specific but less sensitive; a combined GGT/ALP assay has a specificity of 94% in the diagnosis of hepatobiliary disease, whilst when ALP is tested alone the specificity drops to 50%.
Detecting hepatocellular insufficiency... Tests for hepatocellular insufficiency rely on the demonstration of a reduction in the synthetic capacities of the hepatocytes due to a reduction in serum proteins (in particular albumin) and clotting factors. Total proteins are usually normal as the frequent increase in inflammatory proteins masks the reduction in albumin levels. A reduction in the blood urea nitrogen may be indicative of an alteration in the liver’s synthetic capacities.
Confirm the presence of inflammation... Serum protein electrophoresis will reveal inflammation and enables the evaluation of the synthetic capacities of the liver. An acute inflammatory condition provokes the synthesis of proteins that migrate in the α2 zone of the electrophoresis, whilst chronic disease causes an elevation in the γ‚ and β zones, and may even result in a βγ block in the event of cirrhosis.
Bilirubin assay... When icterus is clinically perceptible, the only advantage of performing a bilirubin assay is to monitor the progression of the disease and the efficacy of any treatment. Indeed icterus persists clinically even after a reduction in serum bilirubin levels. However, the distinction between conjugated and non-conjugated bilirubin is of no interest.
Other laboratory tests
Other tests may prove necessary to pinpoint the aetiology of the icterus, in particular when considering infectious disease. In cases of haemolytic anaemia, ehrlichiosis should be ruled out using PCR or serology. A detailed examination of a blood smear should enable the identification of babesiosis; this can be simplified by concentrating the blood to improve sensitivity. In cases of acute hepatic disease, leptospirosis should be ruled out using serology or PCR. The antibody response is only detectable after one week and the dog’s vaccination status should be taken into account when interpreting serology results.
Radiography... can provide valuable information in animals with suspected biliary tract disease. Up to 50% of choleliths (gallstones) are radiopaque because of their mineral content. The presence of gas around biliary structures is very indicative and compatible with emphysematous cholecystitis, abscessation, or severe cholangitis.
Ultrasonography... is the examination of choice for differentiating intrahepatic cholestasis from extra-hepatic cholestasis. The sensitivity of this examination is significant in the confirmation of extra-hepatic cholestasis and in the diagnosis of the aetiology of this obstruction. It is not unusual to diagnose an extra-hepatic obstruction of the bile ducts on ultrasonography before the onset of icterus. In the event of obstruction of the extra-hepatic biliary tract, dilation of the gallbladder is common but not systematic and in some cases it may even appear normal or reduced in size secondary to chronic inflammation. Dilation of the common bile duct is characteristic of extra-hepatic cholestasis. Certain diseases of the gallbladder or biliary tract have a characteristic appearance on ultrasonography (cholangiocarcinoma, biliary mucocele). Cholecystocentesis can be performed under ultrasonographic guidance using a fine needle (20 - 22 G); although this is a relatively low-risk procedure it should not be performed if the extra-hepatic biliary tract is obstructed. Cytology and bacteriology can then be performed on the sample.
Laparoscopy... enables assessment of the hepatic lobes to confirm any changes in colour or appearance, visualization of the extra-hepatic biliary tract, gallbladder, cystic duct and common bile duct, and biopsies from specific sites.
Liver Biopsy and histology... is the final examination in the diagnostic tree and provides a diagnosis of the lesions, a prognosis, and the selection of appropriate treatment (17,18).
Icterus in the dog is usually easily identifiable on clinical examination, but determining the cause requires a reasoned, step-by-step diagnostic work-up. Further diagnostic tests often provide an indication of the aetiology of the hyperbilirubinemia and will allow the veterinarian to pursue objective treatment strategies.
This article was kindly provided by Royal Canin, makers of both wet and dry Hepatic diets for dogs and cats. For the full range please visit www.RoyalCanin.co.uk or speak to your Veterinary Business Manager:
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This article was first published in 2011.