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<\/a>FIGURE 1. Icteric pinna of a cat in the critical care isolation unit; prehepatic hemolysis and anemia are a result of Cytauxzoon felis<\/em> infection.<\/p><\/div>\n The objective of this article is to briefly review differentials for hyperbilirubinemia in the cat, and present a diagnostic and therapeutic strategy that will help practitioners approach this problem in an efficient and effective manner.<\/p>\n Hyperbilirubinemia <\/strong>results when serum bilirubin concentrations reach 2 to 3 mg\/dL<\/strong> (35\u201350 mcmol\/L).<\/p>\n The differentials for hyperbilirubinemia should be organized by location: prehepatic<\/strong>, hepatic<\/strong>, and posthepatic<\/strong>. While, in cats, it is common to find concurrent disease processes, starting from this foundation is the first step toward an effective and efficient diagnostic workup of icteric cats.<\/p>\n Hemolysis releases hemoglobin, which is then metabolized through biliverdin to bilirubin in the liver. Hepatocytes in the healthy feline liver have a large capacity for uptake, conjugation, and excretion of bilirubin.<\/p>\n Prehepatic icterus is most likely due to the combination of a large increase in bilirubin from hemolysis and a degree of intrahepatic cholestasis secondary to hypoxia.2<\/sup> In dogs, the most common cause of prehepatic hyperbilirubinemia is immune-mediated hemolytic anemia (IMHA), but that condition appears to be quite rare in cats. The list of prehepatic causes of hyperbilirubinemia in cats is extensive (Table 1<\/strong>).<\/p>\n A significant decrease, or loss, of hepatocellular function effects bilirubin metabolism, and frequently results in intrahepatic cholestasis (Table 1<\/strong>). Unconjugated bilirubin from damaged hepatocytes is present, although the majority of bilirubin that appears in the cat\u2019s circulation is conjugated, having completed the metabolic step prior to encountering the cholestatic overflow into the vasculature.2<\/sup><\/p>\n Extrahepatic biliary disease interferes with the normal flow of bile and the final steps in bilirubin excretion, resulting in extrahepatic cholestasis (Table 1<\/strong>). As with intrahepatic disease, both unconjugated and conjugated bilirubin appear in the serum, rendering the biochemical distinction between conjugated and unconjugated serum bilirubin of minimal diagnostic importance.<\/p>\n Infectious disease is a relatively common cause of prehepatic hemolysis in cats.<\/p>\n Mycoplasma species<\/strong>, particularly Mycoplasma haemofelis<\/em>, can cause significant erythrocyte destruction, anemia, hyperbilirubinemia, and clinical disease. Outdoor, male, and\/or shelter cats appear to be at increased risk, and coinfection with feline immunodeficiency virus (FIV) is common.3-5<\/sup><\/p>\n Concurrent diseases, immunosuppression, and stress appear to impact the course and severity of disease and outcome of treatment. An eventual recurrence of disease is seen with some frequency in those cats that show a clinical response to treatment.<\/p>\n Feline leukemia virus<\/strong> (FeLV) infection can trigger a host immune response that results in immune-mediated prehepatic erythrocyte destruction. This may be the result of a virus-induced expression of antigens on the red blood cell (RBC) surface. Immune-mediated thrombocytopenia may accompany IMHA in cats with underlying FeLV infection.6<\/sup><\/strong><\/em><\/p>\n Cytauxzoon felis<\/em> is transmitted by ticks (Amblyomma americanum<\/em>) and appears to be increasing in prevalence and geographical distribution in the United States, expanding from the southeastern portion of the country. Risk for infection increases with increased exposure to the tick vector, and the progression of clinical disease is rapid and often fatal.<\/p>\n Babesia felis<\/em> can cause severe prehepatic hemolysis and anemia in cats, but appears to be rare outside of costal South Africa.7<\/sup><\/p>\n Primary IMHA appears to be quite rare in cats. It is difficult to characterize feline IMHA or determine risk factors because of the paucity of cases in the literature, but younger male cats may be overrepresented. The prognosis is guarded, with a mortality rate of 25%.8<\/sup><\/p>\n Erythrocyte pyruvate kinase (PK) deficiency is a very rare inherited disorder transmitted as an autosomal recessive trait, causing prehepatic hemolysis.<\/p>\n Cats usually present as young adults, and the severity of the anemia and clinical signs is variable and may change over time, ranging from asymptomatic to hemolytic crisis.<\/p>\n The disease is most frequently described in Abyssinian and Somali breeds but may also be present in a variety of other purebred and domestic shorthair cats.9<\/sup> Interestingly, Abyssinian and Somali breeds have also been shown to suffer from another inherited cause of prehepatic hemolysis: increased erythrocyte osmotic fragility. Genetic testing has been developed for screening cats for PK deficiency and is commercially available (vgl.ucdavis.edu\/services\/pkdeficiency.php)<\/p>\n Hemolysis secondary to hypophosphatemia<\/strong> has become rare due to heightened awareness, diligent monitoring, and proactive intervention during the treatment of diabetic ketoacidosis.<\/p>\n Disseminated intravascular coagulation<\/strong> is also a rare occurrence, seen predominantly in the critical care setting, but serving as a reminder that prehepatic hemolysis can occur as a secondary consequence in a variety of diseases.<\/p>\n Feline erythrocytes are susceptible to oxidative stress<\/strong>, and a large variety of toxins and drugs (including acetaminophen, benzocaine, methylene blue, phenazopyridine, onions\/onion powder, propylene glycol, and propylthiouracil) can cause Heinz body anemia or hemolytic destruction of RBC membranes.<\/p>\n Hepatic lipidosis appears to be a unique feline phenomenon, highlighting that hepatic metabolism in the cat is different from many other species.10<\/sup> Although feline hepatic lipidosis may be an idiopathic (Figure 2<\/strong>) and, therefore, primary problem, it quite frequently occurs secondary to another disease that caused the cat to stop eating.<\/p>\n FIGURE 2. The liver (seen laparoscopically) of a cat with idiopathic hepatic lipidosis.<\/p><\/div>\n In contrast to dogs\u2014in which hepatic disease is usually located in the liver parenchyma\u2014feline liver disease typically targets the biliary system, and is most commonly seen as cholangitis. The World Small Animal Veterinary Association Liver Standardization Group clarified the terminology, defining feline cholangitis as neutrophilic<\/em> (acute or chronic), lymphocytic<\/em>, or secondary to liver flukes<\/em>.11<\/sup><\/p>\n Cholelithiasis may be obstructive and is, thus, approached as a cause of extrahepatic bile duct obstruction (EHBO). Other causes of EHBO include tumors, nonneoplastic masses, cholecystitis, inspissated bile, cholangitis, and pancreatitis. The prognosis, even following successful surgery, is guarded.<\/p>\n Feline triaditis<\/em> describes the concurrent conditions of cholangitis, pancreatitis, and inflammatory bowel disease in cats.<\/p>\n There is a common outflow track for the feline pancreas and bile duct as they approach the major duodenal papilla. This anatomic association makes it likely that inflammatory disease or infection in one of these tissues impacts the health and function of the associated tissues.<\/p>\n At this time it is unclear if the underlying etiology of triaditis is immune-mediated process, infectious, or multifactorial, making treatment decisions difficult. Significant local inflammation may create a functional EHBO that is not amenable to surgical removal, but must be addressed medically.<\/p>\n Feline liver fluke infection is geographical and found in tropical environments, such as Florida, the Caribbean, and Hawaii, where land snails, lizards, and toads are the hosts. Infection is usually subclinical, although cats may present with nonspecific signs (Table 1<\/strong>).<\/p>\n As with any diagnostic approach, the clinical evaluation of an icteric cat begins with signalment, history, and physical examination.<\/p>\n The list of differentials for hyperbilirubinemia (Table 1<\/strong>) include breed-specific entries (eg, Abyssinian) and diseases that occur in certain age groups (eg, feline infectious peritonitis [FIP]). For many differentials the patient history is similar.<\/p>\n Anorexia is a key component in the presentation of cats with hepatic lipidosis and appears to be an early clinical manifestation of anemia in cats. Lethargy can be difficult to appreciate in sedentary cats, and sick cats often hide, further delaying the owner\u2019s observation of more obvious clinical signs.<\/p>\n Dog owners may notice changes in the color of urine or feces, but it is much less likely for cat owners to report pigmenturia or acholic feces in this fastidious species. It is also relatively unusual for cats to have dietary indiscretion of toxins, household products, medications, or human food, but certainly the potential for exposure should be investigated during the anamnesis.<\/p>\n The prevalence of multi-cat households also confounds the owner\u2019s ability to appreciate changes in appetite, water consumption, or elimination habits.<\/p>\n A complete physical examination, including body temperature, pulse, respiratory rate, fundic examination, cardiovascular auscultation, and abdominal palpation, is essential. Physical findings may indicate potential underlying etiologies, such as hepatomegaly with hepatic lipidosis, cranial abdominal discomfort with pancreatitis, and tachycardia with anemia.<\/p>\n The physical examination is often dominated by the color of the cat. Icterus is best appreciated as a discoloration of the mucous membranes, the sclera (Figure 3<\/strong>), and\/or the inner aspect of the pinnae (Figure 4<\/strong>). The intensity and actual color may be influenced by the normal tissue color, degree of anemia, and perfusion.<\/p>\n The clinical condition and color of the cat are influenced by both the degree of anemia\u2014mild to severe\u2014and the time course of RBC destruction\u2014acute or chronic.<\/p>\n FIGURE 3. The sclera of the feline immune-mediated hemolytic anemia patient.<\/p><\/div>\n FIGURE 4. The pinna of the feline immune-mediated hemolytic anemia patient.<\/p><\/div>\n Changes on the serum biochemical profile are nonspecific. The degree of elevation in total bilirubin is cited as a nonspecific but generally guides to the most likely location or etiology of the problem:<\/p>\n The laboratory diagnostic workup for the vast majority of icteric cats starts with determining whether prehepatic hemolysis is present.<\/p>\n Complete Blood Count<\/em><\/strong><\/p>\n Hemolysis can often be an extravascular antibody-mediated process in which the serum turns icteric. A simple hematocrit tube can be expected to identify a significant degree of anemia and a relatively normal serum total protein. Less frequently, the hemolysis occurs within the vasculature itself, in which case the serum may appear pink, while both the plasma (hemoglobinemia) and urine (hemoglobinuria) appear red.<\/p>\n A complete blood count (CBC) more accurately and completely characterizes the anemia as regenerative or nonregenerative; however, the regenerative process may take up to 5 days to manifest as an appropriate increase in the absolute reticulocyte count (> 40,000\u201360,000\/mcL, depending on the laboratory). A CBC also identifies other potentially important erythrocyte characteristics.<\/p>\n The degree of anemia is cited as a nonspecific but general indictor of the likelihood that feline icterus is the result of prehepatic hemolysis. As a rule of thumb, prehepatic hemolysis usually results in a packed cell volume (PCV) of less than 13% to 20%; however, the cat\u2019s baseline or normal PCV, hydration status, and the time frame over which the hemolysis occurred may all impact the clinical signs, measured PCV, and elevation in total bilirubin.<\/p>\n Blood Smear<\/em><\/strong><\/p>\n Careful examination of the blood smear is a critical step in any attempt to identify infectious organisms or indicators of immune-mediated agglutination.<\/p>\n Infectious disease testing is commonly used for prehepatic hyperbilirubinemia (Table 2<\/strong>).<\/p>\n Mycoplasmosis<\/em><\/strong><\/p>\n In addition to hyperbilirubinemia, cats with mycoplasmosis are frequently hyperglobulinemic as a result of chronic immune stimulation, and they may have mild to moderate elevations in liver enzyme activity as a result of anemic\u2014hypoxia-induced hepatocyte necrosis.<\/p>\n Feline Leukemia Virus<\/em><\/strong><\/p>\n There are a variety of technologies available to easily test for the FeLV p27 antigen, which is present in the majority of infected cats.<\/p>\n Cytauxzoonosis<\/em><\/strong><\/p>\n Biochemical changes with Cytauxzoon felis<\/em> are nonspecific, while anemia, pancytopenia, and thrombocytopenia may be seen on the CBC.<\/p>\n Diagnosing IMHA using persistent RBC agglutination, a positive Coombs\u2019 test, RBC characteristics, and reticulocytosis can be challenging in cats; other potential causes of prehepatic hemolysis must be carefully considered.<\/p>\n Agglutination can be difficult to distinguish from normal rouleaux formation in the cat, but true RBC autoagglutination can be identified by mixing one drop of potassium ethylenediaminetetraacetic acid (K-EDTA) whole blood with 1 to 4 drops of 0.9% sodium chloride on a microscope slide. Macroscopic slide erythrocyte agglutination is seen in all IMHA cats, although it rarely persists following RBC washing.<\/p>\n Biochemical abnormalities are varied and inconsistent, although the majority of cats have a positive direct Coombs\u2019 test, further supporting the diagnosis of IMHA. However, Coombs\u2019 testing should be interpreted with caution and related to other clinical and hematologic findings.12<\/sup><\/p>\n Biochemical and CBC parameters of cats with erythrocyte PK deficiency are nonspecific and inconsistent among patients, although hyperglobulinemia was frequently seen. Genetic testing and responsible breeding are clearly important considerations.<\/p>\n Hepatic hyperbilirubinemia is caused by significant primary hepatic disease. A minimum diagnostic database includes a CBC, serum biochemical profile, urinalysis, and FeLV\/FIV status.<\/p>\n Once the cat is icteric, and prehepatic causes have been ruled out, the serum bilirubin is elevated to the point where a bile acids test for liver function is redundant; the results will be abnormal. With mild hyperbilirubinemia (< 2 mg\/dL), a bile acids test may be warranted to assess liver function.<\/p>\n Ultrasonographic imaging of the entire abdomen by a board-certified specialist is an essential step in the assessment of the feline hepatobiliary system. Ultrasound is a powerful tool for assessing the liver parenchyma, visualizing the biliary system, and searching for EHBO.<\/p>\n Ultrasound-guided fine needle aspiration (FNA) is also a minimally invasive technique for acquiring samples of certain tissue, such as the liver, pancreas, and lymph nodes, and masses for cytology and culture. Coagulation parameters and clotting times should be determined prior to FNA.<\/p>\n In cats that present with hepatic lipidosis, it is critical to put diagnostic effort into identifying the disease that led to the cat\u2019s anorexia in the first place, whether that is as simple as dental disease or as complex as feline pancreatitis. Failure to identify and address the concurrent condition is very likely to result in the cat being presented to the hospital again with the same complaint.<\/p>\n The diagnostic effort of feline cholangitis is directed toward identification of the predominant inflammatory cell type present in the cat\u2019s hepatobiliary system: acute neutrophilic, chronic neutrophilic, or lymphocytic.<\/p>\n FNA of the liver is a relatively simple procedure that may produce a cytologic sample suggestive of cholangitis, but this technique has significant limitations. It may be of low yield, resulting in a nondiagnostic sample, the nonspecific report of hepatocellular vacuolization, or an interpretation that would be different than that obtained by histopathology.13<\/sup><\/p>\n Technically more challenging techniques, best performed by board-certified specialists with ample experience, are ultrasound-guided cholecystocentesis and laparoscopy-assisted gallbladder aspiration. For both procedures, samples are collected for cytology and culture, since bile has been shown to be the sample most likely to yield an informative bacterial culture result.14,15<\/sup><\/p>\n Liver biopsy is required for a definitive diagnosis of hepatic disease.1<\/sup><\/p>\n The most common infectious organisms found in patients with neutrophilic cholangitis are enteric bacteria (eg, E coli, Enterobacter, Clostridia<\/em>) and antibiotics for treatment should be selected based on sensitivity.<\/p>\n Abdominal ultrasound of cats with EHBO frequently identifies distension of the gallbladder, common bile duct, and intrahepatic ducts (Figure 5<\/strong>).<\/p>\n FIGURE 5. Abdominal ultrasound demonstrating a distended gallbladder and enlarged biliary outflow tract in a cat with EHBO.<\/p><\/div>\n Diagnosis of triaditis is based on identification of disease in each of the 3 tissues involved; the gold standard for diagnosis is histopathology. Less invasive diagnostics include the feline pancreatic lipase immunoreactivity (fPLI) blood test, abdominal ultrasound, liver FNA, cholecystocentesis, cytology, culture and sensitivity, and small intestinal endoscopic biopsy; however, these patients may have increased anesthetic risks.<\/p>\nHyperbilirubinemia: Organization By Location<\/h2>\n
Prehepatic Disease<\/strong><\/h3>\n
<\/a><\/p>\nHepatic Disease<\/strong><\/h3>\n
Posthepatic Disease<\/strong><\/h3>\n
Common Causes of Prehepatic Hyperbilirubinemia<\/h2>\n
Infectious Disease<\/strong><\/h3>\n
Immune-Mediated Hemolytic Anemia<\/strong><\/h3>\n
Inherited Erythrocyte Disorders<\/strong><\/h3>\n
Other Causes of Hemolysis<\/strong><\/h3>\n
Common Causes of Hepatic Hyperbilirubinemia<\/h2>\n
Feline Hepatic Lipidosis<\/strong><\/h3>\n
<\/a>Cholangitis<\/strong><\/h3>\n
Common Causes of Posthepatic Hyperbilirubinemia<\/h2>\n
Extrahepatic Bile Duct Obstruction<\/strong><\/h3>\n
Feline Triaditis Syndrome<\/strong><\/h3>\n
Liver Fluke<\/strong><\/h3>\n
Diagnostic Approach to an Icteric Cat<\/h2>\n
Signalment<\/strong><\/h3>\n
History & Clinical Signs<\/strong><\/h3>\n
Physical Examination<\/strong><\/h3>\n
<\/a><\/a>Laboratory Analysis<\/strong><\/h3>\n
\n
Prehepatic Hyperbilirubinemia Diagnostics<\/h2>\n
Blood Analysis<\/strong><\/h3>\n
Infectious Disease<\/strong><\/h3>\n
<\/a><\/p>\nImmune-Mediated Disease<\/strong><\/h3>\n
Inherited Erythrocyte Disorders<\/strong><\/h3>\n
Hepatic Hyperbilirubinemia Diagnostics<\/h2>\n
Laboratory Analysis<\/strong><\/h3>\n
Imaging<\/strong><\/h3>\n
Fine Needle Aspiration<\/strong><\/h3>\n
Hepatic Lipidosis<\/strong><\/h3>\n
Cholangitis<\/strong><\/h3>\n
Posthepatic Hyperbilirubinemia Diagnostics<\/h2>\n
Extrahepatic Bile Duct Obstruction<\/strong><\/h3>\n
<\/a>Triaditis<\/strong><\/h3>\n