Peer Reviewed THE YELLOW : DIAGNOSTIC & THERAPEUTIC STRATEGIES

The Yellow Cat: Diagnostic & Therapeutic Strategies

Craig B. Webb, PhD, DVM, Diplomate ACVIM (Small Animal Internal Medicine) Colorado State University

There is no mystery when it comes to a “yellow” cat. Icterus and jaundice—both of which describe a yellowish pigmentation of the skin—indicate hyperbilirubinemia, a 5- to 10-fold elevation in serum bilirubin concentration. However, this is where the certainty ends and the diagnostic challenge begins. The icteric cat presentation is not a sensitive or specific marker of disease, despite the visually obvious and impressive clinical sign (Figure 1).1 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. FIGURE 1. Icteric pinna of a cat in the critical HYPERBILIRUBINEMIA: ORGANIZATION care isolation unit; prehepatic hemolysis BY LOCATION and anemia are a result of Cytauxzoon felis infection. Hyperbilirubinemia The differentials for hyperbilirubinemia should be results when organized by location: prehepatic, hepatic, and serum bilirubin posthepatic. While, in , it is common to find Hepatic Disease concentrations concurrent disease processes, starting from this A significant decrease, or loss, of hepatocellular reach 2 to 3 mg/dL foundation is the first step toward an effective and function effects bilirubin metabolism, and (35–50 mcmol/L). efficient diagnostic workup of icteric cats. frequently results in intrahepatic cholestasis (Table 1, page 40). Unconjugated bilirubin from damaged Prehepatic Disease hepatocytes is present, although the majority of Hemolysis releases hemoglobin, which is then bilirubin that appears in the cat’s circulation is metabolized through biliverdin to bilirubin in the conjugated, having completed the metabolic step . Hepatocytes in the healthy feline liver have a prior to encountering the cholestatic overflow into large capacity for uptake, conjugation, and excretion the vasculature.2 of bilirubin. Prehepatic icterus is most likely due to the Posthepatic Disease combination of a large increase in bilirubin from Extrahepatic biliary disease interferes with the hemolysis and a degree of intrahepatic cholestasis normal flow of bile and the final steps in bilirubin secondary to hypoxia.2 In dogs, the most common excretion, resulting in extrahepatic cholestasis cause of prehepatic hyperbilirubinemia is immune- (Table 1, page 40). As with intrahepatic disease, mediated hemolytic anemia (IMHA), but that both unconjugated and conjugated bilirubin appear CE condition appears to be quite rare in cats. The list in the serum, rendering the biochemical distinction ARTICLE of prehepatic causes of hyperbilirubinemia in cats is between conjugated and unconjugated serum extensive (Table 1, page 40). bilirubin of minimal diagnostic importance.

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COMMON CAUSES OF PREHEPATIC present in a variety of other purebred and domestic HYPERBILIRUBINEMIA shorthair cats.9 Interestingly, Abyssinian and Somali Infectious Disease breeds have also been shown to suffer from another Infectious disease is a relatively common cause of inherited cause of prehepatic hemolysis: increased prehepatic hemolysis in cats. erythrocyte osmotic fragility. Genetic testing has Mycoplasma species, particularly Mycoplasma been developed for screening cats for PK deficiency haemofelis, can cause significant erythrocyte and is commercially available (vgl.ucdavis.edu/ destruction, anemia, hyperbilirubinemia, and clinical services/pkdeficiency.php) disease. Outdoor, male, and/or shelter cats appear to be at increased risk, and coinfection with feline Other Causes of Hemolysis immunodeficiency virus (FIV) is common.3-5 Hemolysis secondary to hypophosphatemia has Concurrent diseases, immunosuppression, become rare due to heightened awareness, diligent and stress appear to impact the course and severity monitoring, and proactive intervention during the of disease and outcome of treatment. An eventual treatment of diabetic ketoacidosis. recurrence of disease is seen with some frequency in Disseminated intravascular coagulation is also those cats that show a clinical response to treatment. a rare occurrence, seen predominantly in the critical (FeLV) infection care setting, but serving as a reminder that prehepatic can trigger a host immune response that results hemolysis can occur as a secondary consequence in a in immune-mediated prehepatic erythrocyte variety of diseases. destruction. This may be the result of a virus-induced Feline erythrocytes are susceptible to oxidative expression of antigens on the red blood cell (RBC) stress, and a large variety of toxins and drugs surface. Immune-mediated thrombocytopenia may (including acetaminophen, benzocaine, methylene accompany IMHA in cats with underlying FeLV blue, phenazopyridine, onions/onion powder, infection.6 propylene glycol, and propylthiouracil) can cause Cytauxzoon felis is transmitted by ticks (Am- Heinz body anemia or hemolytic destruction of RBC blyomma americanum) and appears to be increasing membranes. in prevalence and geographical distribution in the United States, expanding from the southeastern COMMON CAUSES OF HEPATIC portion of the country. Risk for infection increases HYPERBILIRUBINEMIA with increased exposure to the tick vector, and the progression of clinical disease is rapid and often fatal. Hepatic lipidosis appears to be a unique feline Babesia felis can cause severe prehepatic phenomenon, highlighting that hepatic metabolism hemolysis and anemia in cats, but appears to be rare in the cat is different from many other species.10 outside of costal South Africa.7 Although feline hepatic lipidosis may be an idiopathic (Figure 2) and, therefore, primary problem, it quite Immune-Mediated Hemolytic Anemia frequently occurs secondary to another disease that Primary IMHA appears to be quite rare in cats. caused the cat to stop eating. 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

Inherited Erythrocyte Disorders Erythrocyte pyruvate kinase (PK) deficiency is a very rare inherited disorder transmitted as an autosomal recessive trait, causing prehepatic hemolysis. 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. FIGURE 2. The liver (seen laparoscopically) of a The disease is most frequently described in cat with idiopathic hepatic lipidosis. Abyssinian and Somali breeds but may also be

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TABLE 1. Hyperbilirubinemia in Cats: Differential Diagnoses & Clinical Signs pain

diarrhea

/ OTHER CLINICAL SIGNS Anorexia Lethargy Fever Lymphadenopathy Vomiting loss Weight Anemia Abdominal

PREHEPATIC HYPERBILIRUBINEMIA Mycoplasma species23 Hypothermia x x x Physiologic murmur Increased heart rate/respiratory effort secondary to anemia Cytauxzoon felis24 Dehydration x x x Evidence of shock Progression to moribund dyspnea and hypothermia Feline infectious peritonitis Effusive/wet FIP: Ascites, pleural effusion x x x x Dry FIP: Ocular and neurologic signs Babesia species x x x x Feline leukemia virus Immune suppression x Secondary infection Feline immunodeficiency virus Oral inflammation x x x Secondary infection and lymphoma Immune-mediated hemolytic Signs of primary IMHA, excluding identifiable causes x x x anemia8,25 Pica Erythrocyte PK deficiency26 Pica Increased erythrocyte osmotic x x x x fragility27 Neonatal isoerythrolysis28 Cessation of nursing, failure to thrive Acute kidney injury x Disseminated intravascular coagulation Death Pigmenturia Transfusion reaction29 Erythema or pruritus Tremor, convulsion Vocalization Shock x x Dyspnea or tachypnea Cardiopulmonary arrest Tachycardia or bradycardia Hypophosphatemia30,31,a Clinical signs usually consistent with acute hemolysis x x x Weakness Tachypnea, tachycardia Microangiopathic hemolytic Clinical signs vary with condition and severity anemia32,b Hyperthermia x x x x Obtundation Cardiopulmonary arrest Drugs, toxins, envenomation, Clinical signs nonspecific and depend on underlying etiology; may include oxidative stress c clinical signs associated with Microangiopathic hemolytic anemia (above) and allergic reaction (eg, swelling, pain, redness, focal inflammation)

Cholangitis COMMON CAUSES OF POSTHEPATIC In contrast to dogs—in which hepatic disease is HYPERBILIRUBINEMIA usually located in the liver parenchyma—feline liver Extrahepatic Bile Duct Obstruction disease typically targets the biliary system, and is Cholelithiasis may be obstructive and is, thus, most commonly seen as cholangitis. The World Small approached as a cause of extrahepatic bile duct ob- Animal Veterinary Association Liver Standardization struction (EHBO). Other causes of EHBO include Group clarified the terminology, defining feline tumors, nonneoplastic masses, cholecystitis, inspissat- cholangitis as neutrophilic (acute or chronic), ed bile, cholangitis, and pancreatitis. The prognosis, lymphocytic, or secondary to liver flukes.11 even following successful surgery, is guarded.

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TABLE 1. (continued) Hyperbilirubinemia in Cats: Differential Diagnoses & Clinical Signs pain

diarrhea

/ OTHER CLINICAL SIGNS loss

Anorexia Lethargy Fever Lymphadenopathy Vomiting Weight Anemia Abdominal

HEPATIC HYPERBILIRUBINEMIA Hepatic lipidosis33,34 Idiopathic or secondary hepatic lipidosis x x x Clinical signs vary with underlying etiology Hiding, decreased interaction Cholangitis35,36 Bacterial, acute or chronic neutrophilic, lymphocytic x x x x x Dehydration Hepatomegaly Feline infectious peritonitis37 See clinical signs of FIP (previous page) Virulent systemic Oral ulceration Upper respiratory signs x Edema Ulcerative dermatitis Conjunctivitis Francisella tularensis38 x x x Tachypnea and tachycardia Drugs, toxins39,40,d Nonspecific signs of intoxication Acute hepatic failure Death Amyloidosis41 Familial, Siamese, and other types of amyloidosis x Sudden death Acute abdominal bleeding Sepsis Clinical signs associated with specific underlying etiology Systemic inflammatory response x x x Collapse syndrome42,e Bradycardia and hypotension POSTHEPATIC HYPERBILIRUBINEMIA Cholelithiasis43,44 See clinical signs associated with EHBO (below) Extrahepatic biliary obstruction45 Coagulopathy x x x x x Hypotension and shock Triaditis46 Clinical signs may progress in cases of EHBO x x x x x x Hepatomegaly Liver flukes47 x x x x (Platynosomum concinnum) a. As a result of enteral alimentation, diabetes mellitus, diabetic ketoacidosis treatment b. As a result of disseminated intravascular coagulation, neoplasia, pancreatitis, sepsis, systemic lupus erythematosus, heat stroke c. As a result of exposure to zinc, onion, garlic, propylene glycol, naphthalene, benzocaine, methimazole, bees, spiders d. Such as oral benzodiazepines, acetaminophen, amanitin mushrooms e. Due to septic peritonitis, hepatic abscess, pyothorax, pyometra EHBO = extrahepatic bile duct obstruction; FIP = feline infectious peritonitis; IMHA = immune-mediated hemolytic anemia

Feline Triaditis Syndrome At this time it is unclear if the underlying etiology Feline triaditis describes the concurrent conditions of triaditis is immune-mediated process, infectious, or of cholangitis, pancreatitis, and inflammatory bowel multifactorial, making treatment decisions difficult. disease in cats. Significant local inflammation may create a functional There is a common outflow track for the feline EHBO that is not amenable to surgical removal, but pancreas and bile duct as they approach the major must be addressed medically. duodenal papilla. This anatomic association makes it likely that inflammatory disease or infection in one of Liver Fluke these tissues impacts the health and function of the Feline liver fluke infection is geographical and associated tissues. found in tropical environments, such as Florida,

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TABLE 2. Hyperbilirubinemia in Cats: Differential Diagnoses, Diagnostics, & Treatment

DIFFERENTIAL DIAGNOSES DIAGNOSTICS TREATMENT OPTIONS

PREHEPATIC HYPERBILIRUBINEMIA Mycoplasma species23 Complete blood count (CBC) Doxycycline, 5 mg/kg PO Q 12 H for 14 d Blood smear Pradofloxacin, 5 mg/kg PO Q 24 H for 14 d Serum biochemical profile Enrofloxacin, 5 mg/kg PO Q 24 H for 14 d Polymerase chain reaction (PCR) Cytauxzoon felis24 CBC Atovaquone, 15 mg/kg PO Q 8 H Blood smear Azithromycin, 10 mg/kg PO Q 24 H PCR Feline infectious peritonitis CBC FIP: Supportive care Babesia species Blood smear Polyprenyl Immunostimulant (sassandsass.com) PCR Pentoxifylline, 10 mg/kg PO Q 12 H Prednisolone, 2–4 mg/kg PO Q 24 H Babesiosis: Imidocarb diproprionate, 2.5 mg/kg IM Doxycycline, 10 mg/kg/day PO for 21 d Feline leukemia virus FeLV: p27 antigen test Blood transfusion Feline immunodeficiency virus FIV: Antibody test Supportive care Antiviral treatment Medical therapy: • Prednisolone, 2.2 mg/kg Q 12 H • Cyclosporine, 5 mg/kg Q 24 H • Chlorambucil, 2 mg/cat Q 3 days • Mycophenolate mofetil, 10 mg/kg Q 12 H Immune-mediated hemolytic Saline agglutination Prednisolone, 2.2 mg/kg PO Q 12 H anemia8,25 (primary, excluding Coombs’ test Mycophenolate mofetil, 10 mg/kg Q 12 H identifiable causes) In one report:8 Anemia was severe, with median packed cell volume of 12% Erythrocyte PK deficiency26 Genetic testing Breeding practices Increased erythrocyte osmotic Supportive care fragility27 Ursodeoxycholic acid, 5−15 mg/kg Q 24 H Neonatal isoerythrolysis28 Appropriate blood typing prior to Supportive care breeding Cardiovascular support Transfusion reaction29 Pretesting donors Supportive care Blood-typing Cardiovascular support Crossmatching Hypophosphatemia30,31 Electrolyte monitoring Supportive care Treatment of underlying conditions Microangiopathic hemolytic CBC with platelets Intensive monitoring anemia32 Clotting times Cardiovascular support Treatment of underlying conditions Drugs, toxins, envenomation, Various toxin assays Remove exposure oxidative stress Blood smear Reduce remaining burden (eg, emesis) Support of target organs Plasmapharesis

the Caribbean, and Hawaii, where land snails, Signalment lizards, and toads are the hosts. Infection is The list of differentials for hyperbilirubinemia usually subclinical, although cats may present with (Table 1) include breed-specific entries (eg, nonspecific signs Table( 1). Abyssinian) and diseases that occur in certain age groups (eg, feline infectious peritonitis [FIP]). For DIAGNOSTIC APPROACH TO AN many differentials the patient history is similar. ICTERIC CAT As with any diagnostic approach, the clinical History & Clinical Signs evaluation of an icteric cat begins with signalment, Anorexia is a key component in the presentation of history, and physical examination. cats with hepatic lipidosis and appears to be an early clinical manifestation of anemia in cats. Lethargy

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TABLE 2. (continued) Hyperbilirubinemia in Cats: Differential Diagnoses, Diagnostics, & Treatment

DIFFERENTIAL DIAGNOSES DIAGNOSTICS TREATMENT OPTIONS

HEPATIC HYPERBILIRUBINEMIA Hepatic lipidosis33,34 CBC Vitamin K1, 1 mg SC Q 12 H (idiopathic or secondary) Serum biochemical profile Nutrition via E-tube Urinalysis FeLV/FIV testing Bile acids fPLI blood test Ultrasound-guided liver FNA Cholangitis35,36 Ultrasound-guided or laparoscopy- Amoxicillin and clavulanic acid, 62.5 mg/cat Q 12 H (bacterial, acute or chronic neutrophilic, assisted cholecystocentesis and liver Enrofloxacin, 5 mg/kg Q 24 H lymphocytic) FNA Metronidazole, 7.5 mg/kg Q 12 H Cytology Prednisolone, 2 mg/kg Q 24 H, taper to 0.5−1 mg/kg Q 24 H Culture and sensitivity Cyclosporine, 5 mg/kg PO Q 24 H Ursodeoxycholic acid, 10–15 mg/kg Q 24 H Infectious disease Infectious disease testing Supportive care (FIP37, virulent systemic feline Treatment of underlying infection calicivirus, Francisella tularensis38) Drugs, toxins39,40 Various toxin assays S-adenosyl-methionine, 90 mg/cat Q 24 H Silimarin, 2−5 mg/kg Q 24 H Vitamin E, 50 IU Q 24 H Amyloidosis41 FNA of liver Supportive care (familial, Siamese, others) Cytology Sepsis Various diagnostics Supportive care Systemic inflammatory response Treatment of underlying condition syndrome42 POSTHEPATIC HYPERBILIRUBINEMIA Cholelithiasis43,44 Abdominal ultrasound Ursodeoxycholic acid, 5−15 mg/kg Q 24 H Surgery Extrahepatic biliary obstruction45 Abdominal ultrasound Ursodeoxycholic acid, 5−15 mg/kg Q 24 H FNA of affected tissue Treatment of underlying condition surgically or medically Triaditis46 fPLI blood test Supportive care: hydration, perfusion, acid–base balance Abdominal ultrasound Buprenorphine, 0.01 mg/kg sublingual Q 8 H FNA of liver Maropitant, 1 mg/kg SC Q 24 H Cholecystocentesis Antibiotics Cytology Nutrition via E-tube Culture and sensitivity Single anti-inflammatory dose of glucocorticoid Small intestinal endoscopic biopsy Liver flukes47 Fecal examination Praziquantel, 10−30 mg/kg Q 24 H for 3 days (Platynosomum concinnum) Ultrasound-guided cholecystocentesis Surgery if EHBO and bile cytology Abdominal ultrasound EHBO = extrahepatic biliary obstruction; FeLV = feline leukemia virus; FIP = feline infectious peritonitis; FIV = feline immunodeficiency virus; FNA = fine needle aspiration; fPLI = feline pancreatic lipase immunoreactivity; PCR = polymerase chain reaction can be difficult to appreciate in sedentary cats, and The prevalence of multi-cat households also sick cats often hide, further delaying the owner’s confounds the owner’s ability to appreciate changes observation of more obvious clinical signs. in appetite, water consumption, or elimination Dog owners may notice changes in the color habits. of urine or feces, but it is much less likely for cat owners to report pigmenturia or acholic feces in this Physical Examination fastidious species. It is also relatively unusual for cats A complete physical examination, including to have dietary indiscretion of toxins, household body temperature, pulse, respiratory rate, fundic products, medications, or human food, but certainly examination, cardiovascular auscultation, and the potential for exposure should be investigated abdominal palpation, is essential. Physical findings during the anamnesis. may indicate potential underlying etiologies, such

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as hepatomegaly with hepatic lipidosis, cranial • 3 to 6 mg/dL is associated with prehepatic abdominal discomfort with pancreatitis, and hemolysis, FIP, pancreatitis, and sepsis tachycardia with anemia. • Greater than 12 mg/dL is associated with hepatic The physical examination is often dominated by lipidosis and EHBO. the color of the cat. Icterus is best appreciated as a discoloration of the mucous membranes, the sclera PREHEPATIC HYPERBILIRUBINEMIA DIAGNOSTICS (Figure 3), and/or the inner aspect of the pinnae Blood Analysis (Figure 4). The intensity and actual color may be The laboratory diagnostic workup for the vast influenced by the normal tissue color, degree of majority of icteric cats starts with determining anemia, and perfusion. whether prehepatic hemolysis is present. The clinical condition and color of the cat are influenced by both the degree of anemia—mild to Complete Blood Count severe—and the time course of RBC destruction— Hemolysis can often be an extravascular antibody- acute or chronic. mediated process in which the serum turns icteric. A simple hematocrit tube can be expected to identify a Laboratory Analysis significant degree of anemia and a relatively normal Changes on the serum biochemical profile are serum total protein. Less frequently, the hemolysis nonspecific. The degree of elevation in total bilirubin occurs within the vasculature itself, in which case is cited as a nonspecific but generally guides to the the serum may appear pink, while both the plasma most likely location or etiology of the problem: (hemoglobinemia) and urine (hemoglobinuria) appear red. 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 (> 40,000–60,000/ mcL, depending on the laboratory). A CBC also identifies other potentially important erythrocyte characteristics. 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 FIGURE 3. The sclera of the feline immune- mediated hemolytic anemia patient. in a packed cell volume (PCV) of less than 13% to 20%; however, the cat’s 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.

Blood Smear Careful examination of the blood smear is a critical step in any attempt to identify infectious organisms or indicators of immune-mediated agglutination.

Infectious Disease Infectious disease testing is commonly used for prehepatic hyperbilirubinemia (Table 2, page 42).

Mycoplasmosis FIGURE 4. The pinna of the feline immune- mediated hemolytic anemia patient. In addition to hyperbilirubinemia, cats with mycoplasmosis are frequently hyperglobulinemic as a

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result of chronic immune stimulation, and they may Once the cat is icteric, and prehepatic causes have have mild to moderate elevations in liver enzyme been ruled out, the serum bilirubin is elevated to activity as a result of anemic—hypoxia-induced the point where a bile acids test for liver function is hepatocyte necrosis. redundant; the results will be abnormal. With mild hyperbilirubinemia (< 2 mg/dL), a bile acids test Feline Leukemia Virus may be warranted to assess liver function. There are a variety of technologies available to easily test for the FeLV p27 antigen, which is present in the Imaging majority of infected cats. Ultrasonographic imaging of the entire abdomen by a board-certified specialist is an essential step in Cytauxzoonosis the assessment of the feline hepatobiliary system. Biochemical changes with Cytauxzoon felis are Ultrasound is a powerful tool for assessing the liver nonspecific, while anemia, pancytopenia, and parenchyma, visualizing the biliary system, and thrombocytopenia may be seen on the CBC. searching for EHBO.

Immune-Mediated Disease Fine Needle Aspiration Diagnosing IMHA using persistent RBC Ultrasound-guided fine needle aspiration (FNA) is agglutination, a positive Coombs’ test, RBC also a minimally invasive technique for acquiring characteristics, and reticulocytosis can be samples of certain tissue, such as the liver, pancreas, challenging in cats; other potential causes of and lymph nodes, and masses for cytology and prehepatic hemolysis must be carefully considered. culture. Coagulation parameters and clotting times Agglutination can be difficult to distinguish from should be determined prior to FNA. normal rouleaux formation in the cat, but true RBC autoagglutination can be identified by mixing one Hepatic Lipidosis drop of potassium ethylenediaminetetraacetic acid In cats that present with hepatic lipidosis, it is (K-EDTA) whole blood with 1 to 4 drops of 0.9% critical to put diagnostic effort into identifying the sodium chloride on a microscope slide. Macroscopic disease that led to the cat’s anorexia in the first slide erythrocyte agglutination is seen in all IMHA place, whether that is as simple as dental disease or cats, although it rarely persists following RBC as complex as feline pancreatitis. Failure to identify washing. and address the concurrent condition is very likely to Biochemical abnormalities are varied and result in the cat being presented to the hospital again inconsistent, although the majority of cats have a with the same complaint. positive direct Coombs’ test, further supporting the diagnosis of IMHA. However, Coombs’ testing Cholangitis should be interpreted with caution and related to The diagnostic effort of feline cholangitis is other clinical and hematologic findings.12 directed toward identification of the predominant inflammatory cell type present in the cat’s Inherited Erythrocyte Disorders hepatobiliary system: acute neutrophilic, chronic Biochemical and CBC parameters of cats with neutrophilic, or lymphocytic. erythrocyte PK deficiency are nonspecific FNA of the liver is a relatively simple procedure and inconsistent among patients, although that may produce a cytologic sample suggestive hyperglobulinemia was frequently seen. Genetic of cholangitis, but this technique has significant testing and responsible breeding are clearly limitations. It may be of low yield, resulting in a important considerations. nondiagnostic sample, the nonspecific report of hepatocellular vacuolization, or an interpretation HEPATIC HYPERBILIRUBINEMIA that would be different than that obtained by DIAGNOSTICS histopathology.13 Laboratory Analysis Technically more challenging techniques, best Hepatic hyperbilirubinemia is caused by significant performed by board-certified specialists with ample primary hepatic disease. A minimum diagnostic experience, are ultrasound-guided cholecystocentesis database includes a CBC, serum biochemical profile, and laparoscopy-assisted gallbladder aspiration. For urinalysis, and FeLV/FIV status. both procedures, samples are collected for cytology

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Liver Fluke Liver fluke eggs can sometimes be found in the feces or by bile cytology. A recent study assessing the use of percutaneous ultrasound-guided cholecystocentesis in cats known to be infected with Platynosomum species flukes found the technique to be technically feasible and safe in cats with cholangitis.17

THERAPEUTIC APPROACH Detailed treatment protocols for specific differentials are beyond the scope of this article. However, some selected therapies are described. Hydration status, pain (buprenorphine, 0.01 mg/ kg sublingual Q 8 H), and vomiting (maropitant, FIGURE 5. Abdominal ultrasound demonstrating 1 mg/kg SC Q 24 H) can all be addressed in a a distended gallbladder and enlarged biliary relatively effective manner and can significantly outflow tract in a cat with EHBO. impact the clinical outcome. Ursodeoxycholic acid (5−15 mg/kg Q 24 H) is an and culture, since bile has been shown to be the adjunct therapy that has been used in the successful sample most likely to yield an informative bacterial treatment of bilirubin cholelithiasis, EHBO, and culture result.14,15 a with PK deficiency, but it should not Liver biopsy is required for a definitive diagnosis of be used in place of antibiotics or prednisolone for hepatic disease.16 lymphocytic cholangitis and neutrophilic cholangitis, The most common infectious organisms found respectively.18 in patients with neutrophilic cholangitis are enteric Adjunct therapy may include S-adenosyl- bacteria (eg, E coli, Enterobacter, Clostridia) and methionine (90 mg/cat Q 24 H), silimarin (2−5 antibiotics for treatment should be selected based on mg/kg Q 24 H), and/or vitamin E (50 IU Q 24 sensitivity. H); however, there may be a limit to the number of medications an owner can administer to a cat. POSTHEPATIC HYPERBILIRUBINEMIA DIAGNOSTICS Selected Prehepatic Hyperbilirubinemia Extrahepatic Bile Duct Obstruction Treatment Options Abdominal ultrasound of cats with EHBO frequently Immune-Mediated Hemolytic Anemia identifies distension of the gallbladder, common bile In addition to supportive care, including blood products, cats with IMHA appeared to respond duct, and intrahepatic ducts (Figure 5).

Triaditis 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 immu- noreactivity (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. Although not widely available in private practice, feline abdominal laparoscopy can be performed with equipment sized for pediatrics and allows the collection of tissue for histopathology (liver FIGURE 6. Laparoscopic-assisted aspiration of and pancreas) as well as direct aspiration of the the gallbladder in an icteric cat. gallbladder (Figure 6).

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Nutrition is critical; therefore, placement of an E-tube should be encouraged early in the disease process if the cat is anorectic. Vitamin K1 (1 mg SC Q 12 H) should be administered prior to E-tube placement if evidence of a coagulopathy is present.

Cholangitis Degenerative neutrophils with pleomorphic bacteria from the bile of an acutely ill cat is consistent with acute neutrophilic cholangitis (Figure 8), and treatment is initiated with 2 months of antibiotics aimed at enteric bacteria: cephalosporins, amoxicillin and clavulanic acid (62.5 mg/cat Q 12 H), FIGURE 7. Icteric cat with IMHA ready for enrofloxacin (5 mg/kg Q 24 H), and metronidazole hospital discharge after placement of an (7.5 mg/kg Q 12 H). esophagostomy feeding tube. A mixed population of inflammatory cells or cytology dominated by lymphocytes in a cat to prednisolone therapy, although additional presenting with a more chronic history of illness, immunosuppressive drugs have also been used. or failure of initial antibiotic therapy, is consistent Anecdotal and case reports discuss the addition with chronic neutrophilic cholangitis or lymphocytic of cyclosporine (5 mg/kg Q 24 H), chlorambucil cholangitis, and prednisolone (2 mg/kg Q 24 H (2 mg/cat every 3 days), and mycophenolate initially; taper to 0.5−1 mg/kg Q 48 H) is the mofetil (10 mg/kg Q 12 H) to treatment protocols, foundation of treatment.22 especially if prednisolone fails to improve the cat’s Lymphocytic cholangitis is believed to be immune- 19,20 anemia. mediated, and treatment includes prednisolone with or without a period of concurrent antibiotics, Feline Leukemia Virus although other immunosuppressive medications, such Although immunosuppression in FeLV positive as cyclosporine, have been used in these patients. cats is best avoided, in those patients with clear evidence of IMHA secondary to FeLV infection, Selected Posthepatic Hyperbilirubinemia blood transfusions are indicated and, if those fail, Treatment Options prednisolone (2.2 mg/kg Q 12 H) may be used as Extrahepatic Biliary Obstruction with primary IMHA patients.8,21 Posthepatic causes, such as EHBO, often require surgical intervention—laparotomy may be the Erythrocyte PK Deficiency only viable therapeutic option—and carry a poor Therapy for erythrocyte PK deficiency is supportive and nonspecific, and outcome depends, in large part, on the severity of presentation and use of transfusions to stabilize critical patients.

Selected Hepatic Hyperbilirubinemia Treatment Options Treatment of hepatic causes of hyperbilirubinemia is best guided by histopathology, when possible, or cytology and culture.

Hepatic Lipidosis The foundation of treatment for hepatic lipidosis is relatively simple: provide nutrition to the cat. The logistics may be challenging but the advent of FIGURE 8. Ultrasound-guided FNA of the liver of an icteric cat reveals suppurative inflammation. esophagostomy tubes (E-tube) makes both nutrition Courtesy Dr. David Twedt and medication administration easier (Figure 7).

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prognosis. Nonsurgical causes, such as pancreatitis CBC = complete blood count; EBHO = extrahepatic and cholangitis, are medically managed and the biliary obstruction; E-tube = esophagostomy tube; prognosis is impacted by the severity of disease, FeLV = feline leukemia virus; FIP = feline infectious response to treatment, and owner commitment. peritonitis; FIV = feline immunodeficiency virus; FNA = fine needle aspiration; IMHA = immune- mediated hemolytic anemia; PCV = packed cell Triaditis volume; PK = pyruvate kinase; RBC = red blood cell The effective treatment of triaditis is complicated, but is initiated with supportive care targeting hydration, References perfusion, electrolyte and acid–base balance, pain, 1. Sherding RG. Feline jaundice. J Fel Med Surg 2000; 2(3):165- and vomiting; then targets the aspect of the disease 169. 2. Sherding RG. Icterus. In Washabau RJ, Day MJ (eds): Canine constellation that appears to be having the greatest and Feline Gastroenterology. St. Louis: Elsevier, 2013, pp impact on the patient. 140-147. Antibiotics are administered in patients in which 3. Jenkins KS, Dittmer KE, Marschall JC, et al. Prevalence and risk factor analysis of feline haemoplasma infection in New there is the potential for sepsis, gastrointestinal Zealand domestic cats using a real-time PCR assay. J Feline translocation, positive bacterial cultures, or a left shift Med Surg 2013; 15:1063-1069. with band neutrophils on the CBC. 4. Duarte A, Marques V, Correia JH, et al. Molecular detection of haemotropic Mycoplasma species in urban and rural cats Corticosteroids are usually avoided in the face of a from Portugal. J Feline Med Surg 2015;17:516-522. positively identified bacterial component, although a 5. Walker VR, Morera GF, Gómez JM, et al. Prevalence, risk single anti-inflammatory dose of glucocorticoid may factor analysis, and hematological findings of hemoplasma infection in domestic cats from Valdivia, Southern Chile. Comp be used to counter the inflammatory mediators. With- Immunol Microbiol Infect Dis 2016; 46:20-26. out strong evidence of a bacterial infection, corticoste- 6. Hartmann K. Clinical aspects of feline retroviruses: A review. roids are often used to treat each separate component Viruses 2012; 4:2684-2710. 7. Hartmann K, Addie D, Belák S, et al. Babesiosis in cats: of feline triaditis: inflammatory bowel disease, pancre- ABCD guidelines on prevention and management. J Feline atitis, and lymphocytic-plasmacytic cholangitis. Med Surg 2013; 15(7):643-646. Nutritional support in the form of E-tube 8. Kohn B, Weingart C, Eckmann V, et al. Primary immune- mediated hemolytic anemia in 19 cats: Diagnosis, therapy, and placement is often implemented. outcome (1998-2004). J Vet Intern Med 2006; 20(1):159- 166. Liver Fluke 9. Grahn RA, Grahn JC, Penedo MC, et al. Erythrocyte pyruvate kinase deficiency mutation identified in multiple breeds of Medical treatment for liver fluke infection may be domestic cats. BMC Vet Res 2012; 8:207-217. attempted with praziquantel (20−30 mg/kg Q 24 10. Verbrugghe A, Bakovic M. Peculiarities of one-carbon H for 3 days), but rare, severe cases may require metabolism in the strict carnivorous cat and the role in feline hepatic lipidosis. Nutrients 2013; 5:2811-2835. surgery to remove a posthepatic biliary obstruction as 11. Van den Ingh TS, Van Winkle T, Cullen JM, et al. identified with abdominal ultrasound. Morphological classification of parenchymal disorders of the canine and feline liver: 2. Hepatocellular death, hepatitis and cirrhosis. In Rothuizen J, Bunch SE, Charles JE, et al: WSAVA IN SUMMARY Standards for Clinical and Histological Diagnosis of Canine A thoughtful approach to hyperbilirubinemia, starting and Feline Liver Diseases. Philadelphia: Elsevier, 2006, pp with localization of the disease and including the 85-101. 12. Wardrop KJ. Coombs’ testing and its diagnostic significance in calculated consideration of differentials unique to that dogs and cats. Vet Clin North Am Small Animal Pract 2012; location, greatly enhances the efficient and effective 42:43-51. diagnosis and treatment of the “yellow cat.” Orga- 13. Wang KY, Panciera DL, Al Rukivat RK, et al. Accuracy of nizing the effort in terms of pre-hepatic, hepatic, and ultrasound-guided fine-needle aspiration of the liver and cytologic findings in dogs and cats: 97 cases (1990-2000). post-hepatic conditions is a logical and time-tested JAVMA 2004; 224(1):75-78. approach that has been successfully applied to many 14. Wagner KA, Hartmann FA, Trepanier LA. Bacterial culture icteric cats. results from liver, gallbladder, or bile in 248 dogs and cats evaluated for hepatobiliary disease: 1998-2003. J Vet Intern Med 2007; 21:417-424. CRAIG B. WEBB 15. Peters LM, Glanemann B, Garden OA, et al. Cytological Craig B. Webb, PhD, DVM, Diplomate ACVIM (Small Animal Internal findings of 140 bile samples from dogs and cats and associated Medicine), is a professor in the clinical sciences department at clinical pathological data. J Vet Intern Med 2016; 30:123-131. Colorado State University (CSU) and head of the small animal 16. Rothuizen J, Twedt DC. Liver biopsy techniques. Vet Clin medicine section. Dr. Webb specializes in gastroenterology and North Am Sm Anim Pract 2009; 39:469-480.8. hepatology and, along with Drs. David Twedt and Eric Monnet, 17. Koster L, Shell L, Illanes O, et al. Percutaneous ultrasound- teaches the CSU CE Endoscopy & Laparoscopy course as well as the guided cholecystocentesis and bile analysis for detection of Platynosomum spp.-induced cholangitis in cats. J Vet Intern ACVIM Dry-Lab Laparoscopy course. Dr. Webb’s research interests Med 2016; 30(3):787-793. include chronic enteropathies, oxidative stress, nutraceuticals, and 18. Harvey AM, Holt PE, Barr FJ, et al. Treatment and long-term the use of stem cell therapy in small animal patients. He received his follow-up of extrahepatic biliary obstruction with bilirubin DVM from the University of Wisconsin–Madison. cholelithiasis in a Somali cat with pyruvate kinase deficiency.J Feline Med Surg 2007; 9(5):424-431.

48 TODAY’S VETERINARY PRACTICE | September/October 2016 | tvpjournal.com THETHE YELLOWYELLOW CAT:CAT DIAGNOSTIC & THERAPEUTIC STRATEGIES Peer Reviewed

19. Black V, Adamantos S, Barfield D, et al. Feline non-regenerative immune-mediated anaemia: Features and outcome in 15 cases. J Feline Med Surg 2015; 26:1-6. 20. Bacek LM, Macintire DK. Treatment of primary immune-mediated hemolytic anemia with mycophenolate mofetil in two cats. J Vet Emerg Crit Care 2011; 21:45-49. 21. Hartmann K. Feline leukemia virus infection. In Greene CE. Infectious Diseases of the Dog and Cat, 3rd ed. Philadelphia: Saunders Elsevier, 2006, p 124. 22. Otte CM, Penning LC, Rothuizen J, Favier RP. Retrospective comparison of prednisolone and ursodeoxycholic acid for the treatment of feline lymphocytic cholangitis. Vet J 2013; 195(2):205-209. 23. Weingart C, Tasker S, Kohn B. Infection with haemoplasma species in 22 cats with anaemia. J Feline Med Surg 2016; 18(2):129-136. 24. Sherrill MK, Cohn LA. Cytauxzoonosis: Diagnosis and treatment of an emerging disease. J Feline Med Surg 2015; 17(11):940-948. 25. Bacek LM, Macintire DK. Treatment of primary immune-mediated hemolytic anemia with mycophenolate mofetil in two cats. J Vet Emerg Crit Care 2011; 21(1):45-49. 26. Kohn B, Fumi C. Clinical course of pyruvate kinase deficiency in Abyssinian and Somali cats. J Feline Med Surg 2008; 10(2):145-153. 27. Tritschler C, Mizukami K, Raj K, Giger U. Increased erythrocyte osmotic fragility in anemic domestic shorthair and purebred cats. J Feline Med Surg 2016; 18(6):462-470. 28. Silvestre-Ferreira AC, Pastor J. Feline neonatal isoerythrolysis and the importance of feline blood types. Vet Med Int 2010; 2010:1-8. 29. Tocci LJ. Transfusion medicine in small animal practice. Vet Clin North Am Small Anim Pract 2010; 40(30):485-494. 30. Justin RB, Hohenhaus AE. Hypophosphatemia associated with enteral alimentation in cats. J Vet Intern Med 1995; 9(4):228-233. 31. Adams LG, Hardy RM, Weiss DJ, Bartges JW. Hypophosphatemia and hemolytic anemia associated with diabetes mellitus and hepatic lipidosis in cats. J Vet Intern Med 1993; 7(5):266-271. 32. Estrin MA, Wehausen CE, Jessen CR, Lee JA. Disseminated intravascular coagulation in cats. J Vet Intern Med 2006; 20(6):1334- 1339. 33. Armstrong PJ, Blanchard G. Hepatic lipidosis in cats. Vet Clin North Am Small Anim Pract 2009; 39(3):599-616. 34. Center SA. Feline hepatic lipidosis. Vet Clin North Am Small Anim Pract 2005; 35(1):225-269. 35. Brain PH, Barrs VR, Martin P, et al. Feline cholecystitis and acute neutrophilic cholangitis: Clinical findings, bacterial isolates and response to treatment in six cases. J Feline Med Surg 2006; 8(2):91- 103. 36. Callahan Clark JE, Haddad JL, Brown DC, et al. Feline cholangitis: A necropsy study of 44 cats (1986-2008). J Feline Med Surg 2011; 13(8):570-576. 37. Pedersen NC. An update on feline infectious peritonitis: Diagnostics and therapeutics. Vet J 2014; 201(2):133-141. 38. Pennisi MG, Egberink H, Hartmann K, et al. Francisella tularensis infection in cats: ABCD guidelines on prevention and management. J Feline Med Surg 2013; 15(7):585-587. 39. Weingarten MA, Sande AA. Acute liver failure in dogs and cats. J Vet Emerg Crit Care 2015; 25(4):455-473. 40. Park FM. Successful treatment of hepatic failure secondary to diazepam administration in a cat. J Feline Med Surg 2012; 14(2):158-160. 41. Beatty JA, Barrs VR, Martin PA, et al. Spontaneous hepatic rupture in six cats with systemic amyloidosis. J Small Anim Pract 2002; 43(8):355-363. 42. Cooper J, Webster CRL. Acute liver failure. Compend Contin Educ Pract Vet 2006; 28(7):498-515. 43. Center SA. Diseases of the gallbladder and biliary tree. Vet Clin North Am Small Anim Pract 2009; 39(3):543-598. 44. Eich CS, Ludwig LL. The surgical treatment of cholelithiasis in cats: a study of nine cases. JAAHA 2002; 38(3):290-296. 45. Mayhew PD, Holt DE, McLear RC, Washabau RJ. Pathogenesis and outcome of extrahepatic biliary obstruction in cats. J Small Anim Pract 2002; 43(6):247-253. 46. Simpson KW. Pancreatitis and triaditis in cats: Causes and treatment. J Small Anim Pract 2015; 56(1):40-49. 47. Haney DR, Christiansen JS, Toll J. Severe cholestatic liver disease secondary to liver fluke Platynosomum( concinnum) infection in three cats. JAAHA 2006; 42(3):234-237.

tvpjournal.com | September/Octobertvpjournal.com | September/October 2016 49 2016 | TODAY’S VETERINARY PRACTICE 49 Peer Reviewed THE YELLOW CAT: DIAGNOSTIC & THERAPEUTIC STRATEGIES

CE TEST. THE YELLOW CAT: DIAGNOSTIC & THERAPEUTIC STRATEGIES

This article is RACE-approved for 1 hour of continuing education credit. To receive credit, take the approved test online at vetmedteam.com/tvp.aspx (CE fee of $5/article).

Learning Objectives After reading this article clinicians should be able to differentiate the disease processes in cats with hyperbilirubinemia, formulate an efficient diagnostic path, and prepare an effective treatment protocol for these patients.

Overview This article provides an overview of the differentials for feline hyperbilirubinemia, a diagnostic plan for identifying the underlying etiology of the condition, and a number of therapeutic options for these patients.

1. True/False: Icterus is a sensitive marker of 6. Which of the following is not one of the WSAVA the cause of hyperbilirubinemia in cats. classifications of feline cholangitis? a. True a. Acute neutrophilic b. False b. Chronic neutrophilic c. Lymphocytic 2. Locating the source of hyperbilirubin- d. Acute eosinophilic emia is an important diagnostic step. 7. Cytology can be used to guide treatment in cases Which of the following is not normally a of feline cholangitis. If ultrasound-guided FNA of component of this localizing step? the liver revealed degenerative neutrophils with a. Prehepatic intracellular bacteria, the foundation of treatment b. Hepatic would be which of the following? c. Intrahepatic a. Interferon Note d. Posthepatic b. Amoxicillin and clavulanic acid Questions online c. Prednisolone may differ from 3. Which of the following is the first and d. Ursodeoxycholic acid those here; answers most cost-effective step toward the are available once diagnosis of prehepatic hemolysis? 8. Which of the following is not considered a CE test is taken at component of feline triaditis? a. Hematocrit tube (PCV/TP) vetmedteam.com/ a. Kidney b. Complete blood count tvp.aspx. Tests are b. Liver valid for 2 years from c. Serum biochemical profile c. Pancreas date of approval. d. Coombs’ test d. Intestines

4. Which of the following is not considered 9. Which of the following is the treatment of choice a cause of hemolytic anemia in cats? in a cat in which biliary choleliths are causing an a. FeLV extrahepatic biliary obstruction? b. Cytauxzoon felis a. Ursodeoxycholic acid c. Toxoplasmosis b. Prednisolone d. Mycoplasma hemofelis c. Surgery d. Antibiotics 5. Which of the following is the single most 10. Placement of an esophagostomy feeding tube important component of the treatment allows the owner to administer which of the plan for idiopathic hepatic lipidosis? following to an icteric cat at home? a. Antibiotics a. Fluids b. Nutrition b. Nutrition c. Glucocorticoids c. Medications d. Vitamin E d. All of the above

50 TODAY’S VETERINARY PRACTICE | September/October 2016 | tvpjournal.com