Stuart Walton, BVSc (Hons), BScAgr (Hons), MANZCVS (SAIM), DACVIM

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Dr. Stuart Walton, BVSc (Hons), BScAgr (Hons), MANZCVS (SAIM), DACVIM

Jaundice/Icterus is a yellow discoloration of the skin, mucous membranes, sclera, and bodily fluids (plasma and urine) secondary to an increased concentration of bilirubin in serum and tissues. It poses a diagnostic challenge to the veterinary practitioner because it has several vastly different etiologies. In most instances, serum bilirubin > 1 mg/dl is considered abnormal with clinically detectable icterus occurring when the bilirubin is > 2 mg/dl (35 μmol/L) or greater than 5 – 10-fold above normal. It occurs either when the rate of bilirubin production exceeds the rate of bilirubin uptake by the hepatocytes (i.e., prehepatic e.g., hemolysis), when bilirubin cannot be handled by the liver (i.e., hepatic e.g., hepatic insufficiency), or bilirubin cannot be excreted by the biliary tract (i.e., post-hepatic e.g., biliary tract disease). Each designation may have a different or combined etiopathogenesis.

Approximately 80% of bilirubin is formed after red blood cells are recycled. Approximately 20% of bilirubin is formed from the breakdown of myoglobin, cytochromes and other hemecontaining proteins within the liver. Within macrophages of the liver and spleen, heme from phagocytized senescent erythrocytes is cleaved by the enzyme, heme oxygenase, to form biliverdin, a green pigment. Biliverdin is reduced to bilirubin by biliverdin reductase. Unconjugated bilirubin (free or direct), a yellow orange pigment, is then released into the circulation and is bound to albumin. Plasma bilirubin (unconjugated) is removed from the circulation by the liver (uptake) and converted to conjugated bilirubin by hepatocytes. From here, it is secreted from hepatocytes into the biliary system, and then excreted into the intestines with bile. Most conjugated bilirubin can be deconjugated in the duodenum by gut bacteria into urobilins (e.g., urobilinogen). A small amount of this is oxidized to form stercobilin, while the rest is reabsorbed via enterohepatic circulation and then re-excreted by the liver. A small portion of urobilins are excreted into the

urine by the kidneys. Bilirubin is not detectable in normal feline urine.

In cats, the presence of bilirubin in the urine is indicative of conjugated hyperbilirubinemia. The differentials for hyperbilirubinemia and jaundice should be organized by location;

1. Prehepatic – Increased bilirubin production from destruction of erythrocytes (hemolysis) 2. Hepatic – Decreased hepatocyte uptake, conjugation and secretion of bilirubin 3. Post-hepatic - Impaired biliary excretion

The first step toward an effective and efficient diagnostic workup of icteric cats is to determine whether jaundice falls into the category of prehepatic, hepatic or post-hepatic disease.

Essential to a diagnosis is a thorough history and detailed physical examination which incorporates the cat's signalment. History taking should question whether there are other cats in the household and whether they are clinically well. Indoor/Outdoor status should also be ascertained. A thorough medical and dietary history should be elucidated as well as parasitic prophylaxis.

The diagnostic workup should also be able to address and answer the following questions:

1. Is the source of the jaundice prehepatic, hepatic or posthepatic? Differentiating prehepatic disease from hepatic and post-hepatic disease is relatively simple and involves obtaining a small sample of blood to measure the packed cell volume (PCV) and total solids. Typical manifestations of anemia include: pale mucus membranes, lethargy, weakness/

Prehepatic

Hepatic

Post-hepatic

Cytauxzoon felis FeLV FIV Hemotropic Mycoplasma spp. Heinz body anemia Medications variety (cephalosporins, penicillins, potentiated sulfonamides) Hypophosphatemia

FIP FeLV FIV Histoplasma capsulatum Toxoplasma Cytauxzooan Hyperthyroidism Medications variety (acetaminophen/paracetamol, diazepam, ketoconazole, itraconazole, methimazole) End-stage chronic liver disease Hepatic lipidosis Hepatitis/cholangiohepatitis Neoplasia (carcinoma, lymphoma) Sepsis Liver flukes Platynosomum liver fluke Cholecystitis Cholelithiasis Gallbladder rupture Neoplasia (biliary adenocarcinoma) Pancreatitis

Table 1: Differentials for prehepatic, hepatic and post-hepatic disease in cats.

collapse, tachypnea, tachycardia, physiologic cardiac murmur and hepatosplenomegaly. If an anemia is identified, clinicians should then determine if there is any evidence of

RBC regeneration, and examine serum and a blood smear for evidence of hemolysis, Heinz bodies and red blood cell parasites. 2. Is there associated encephalopathy? This has a complex pathogenesis with an increase in blood ammonia concentration playing a significant role. Clinical signs are variable ranging from minor change in mentation/motor activity to depressed neurologic function (mental dullness/ coma). 3. Is there an associated coagulopathy? Liver disease is associated with coagulation abnormalities (82–98% of all cases) and can result in an increased risk of bleeding.

Coagulation abnormalities may include thrombocytopenia (due to decreased hepatic production of thrombopoietin or increased platelet consumption), alterations in prothrombin time/activated partial thromboplastic time (due to factor deficiencies) and increased D-dimer concentrations.

Cats without anemia should be evaluated for primary hepatobiliary disease or post-hepatic disease. Important diagnostics include a complete blood count, assessment for infectious diseases (e.g., FeLV antigen, FIV antibody) and serum biochemistry. Urinalysis, liver function tests (e.g. ammonia) and coagulation profiles are also important in the initial assessment as they provide essential information as to whether further diagnostic testing can and should be performed without complication. Hepatobiliary enzyme abnormalities should suggest certain diagnostic possibilities and be a guide for further investigation. It is important for clinicians to realize that the magnitude and duration of increase of hepatobiliary enzymes is dependent on the type, severity and duration of stimulus. It does not prognosticate the irreversibility of liver disease.

With hepatocellular injury, increased transaminase activity is expected with jaundice (i.e., ALT and AST). There is also expected to be some degree of cholestasis (i.e., increases in ALKP and GGT) due to cellular swelling and canaliculi occlusion. In general, there is usually a two to three time increase of primary hepatocellular enzymes (ALT, AST) above the reference range compared to cholestatic enzymes (ALP, GGT). In cats with biliary or post-hepatic disease, increases in liver enzymes usually reflect a decrease in bile canaliculi flow and regurgitation of conjugated bilirubin into plasma. Causes include intrahepatic biliary compression due to infection, inflammation or neoplasia (Table 1), and extrahepatic obstruction. Cats with cholestatic disease

are expected to have comparable levels of increased ALKP and GGT (i.e., ALKP = GGT). When there is discordance between ALKP and GGT (i.e., ALKP > GGT) hepatic lipidosis should be suspected. Hepatic lipidosis will occur as either a primary idiopathic disease or secondary due to other diseases like pancreatitis, inflammatory bowel disease, diabetes mellitus, etc.

Abdominal radiography and/or ultrasound examination are diagnostics that are routinely performed in the workup for hepatic and post-hepatic jaundice. Radiographs are important in the assessment of liver size, whereas abdominal ultrasound is useful in differentiating hepatic and extrahepatic disease. Abdominal ultrasound is a sensitive tool for evaluating the hepatic parenchyma, biliary system and hepatic vasculature. It is important to assess the cystic and bile ducts. Clinicians should be also aware that gallbladder wall thickening or the presence of echogenic material within the gallbladder is not normal and indicates inflammatory biliary disease (e.g., cholecystitis). Other readily detectable luminal abnormalities include nonmineralized and mineralized choleliths, an extrahepatic bile duct obstruction from pancreatitis (i.e., inflammation and edema surrounding the bile duct), duodenal strictures at major duodenal papilla, or biliary tumor.

Causes of hepatic disease are further decoded by fine needle aspirate and liver biopsy. Cytology is a useful diagnostic tool for hepatic lipidosis and infiltrative neoplasms. It is not useful in the diagnosis of inflammatory, dysplastic or hyperplastic changes to the liver. Complications are rare with bleeding being the most significant. Prior to performing cytology, it is important that clinicians warn owners of this potential complication.

As part of any diagnostic workup, cholecystocentesis should be considered. This has now become part of a routine diagnostic workup for hepatic disease. Cytology of bile should always be paired with culture. The procedure is considered safe with only a small number of complications being reported. Complications can include bile peritonitis, bleeding/hemorrhage, bacteremia/ sepsis and dissemination of neoplastic disease as well as others.

Biopsy should be considered if cytology is non-diagnostic, and cats have failed empiric medical therapy. Biopsy samples should be obtained for histopathology, aerobic and anaerobic culture, and heavy metal analysis. As well as biopsies of the liver, samples of bile should be collected for cytology and aerobic/anaerobic bacterial culture.

Dr. Stuart Walton, BVSc (Hons), BScAgr (Hons), MANZCVS (SAIM), DACVIM

Stuart Walton is a clinical assistant in small animal internal medicine at University of Florida Small Animal Hospital. He graduated from the University of Queensland in 1999 and gained experience in small animal practice, greyhound practice, and emergency medicine and critical care before undertaking advanced training in small animal internal medicine, initially in Australia and then at LSU. He was employed at University of Florida in 2016 at the completion of his residency. Dr. Walton has an interest in immune-mediated disease, infectious disease, toxicology and respiratory medicine. In his downtime, he enjoys photography, travelling and live music.