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Icteric Cats: More Than Just Hepatic Lipidosis
from FVMA Advocate Issue 4, 2023
by FVMA
Adam Honeckman | DVM, DACVIM (Small Animal Internal Medicine) | Veterinary Specialty Solutions
Icterus can be defined as increased bilirubin in the serum, urine, or tissues. Bilirubinuria can be detected earlier than hyperbilirubinemia. Often, serum total bilirubin concentration must exceed 3 mg/dl before it can be detected on physical exam, whereas a serum bilirubin of >1mg/dl can cause the serum to be grossly icteric.
Bilirubin is a product of hemoglobin metabolism. Increased levels can occur due to prehepatic (hemolysis), hepatic, or post-hepatic causes. With the exception of Mycoplasma haemofelis (formerly known as Hemobartonella felis), hemolytic anemias are relatively uncommon in cats. Most causes of icterus in cats are hepatic or post-hepatic in origin.
Although hepatic lipidosis is reported to be one of the most common causes of icterus in cats, several other differentials need to be considered. A review of 50 icteric cats seen in the author's practice revealed that only 30% had hepatic lipidosis. Cholangitis was responsible for 20%, and lymphoma was diagnosed in another 20%. Pancreatitis (15%), extrahepatic bile duct obstruction (10%), and other miscellaneous diseases (5%) were responsible for the remaining icteric cats. The disease could also have more than one identifiable cause (i.e., hepatic lipidosis + cholangitis and/or pancreatitis, pancreatitis + cholangitis +/- inflammatory bowel disease).
DIAGNOSTIC EVALUATION
When evaluating an icteric cat, the PCV should be assessed. If the PCV <20%, then pre-hepatic causes are most likely. The exception would be in cats with anemia, and icterus due to simultaneous involvement of the bone marrow and liver (i.e., lymphoma or other myeloproliferative disease). If the PCV >20%, then hemolytic anemia is unlikely, and the diagnostics should focus on hepatic and post-hepatic causes of icterus.
If hemolytic diseases are ruled out, abdominal ultrasonography is the next diagnostic step to help differentiate between hepatic and post-hepatic icterus. If the common bile duct is >5mm, extrahepatic biliary duct obstruction (EHBDO) is likely. Causes of EHBDO include choleliths, neoplasia, flukes, cholangitis, and pancreatitis.
In cases of pancreatitis, abdominal ultrasonography may reveal an enlarged hypoechoic pancreas surrounded by hyperechoic fat, pancreatic duct dilation, and/or localized peritoneal effusion. A normal ultrasound doesn’t rule out pancreatitis since the sensitivity is only about 11-84%. A fasted spec fPL (run by Texas A&M GI laboratory or Idexx) is the most sensitive and specific test for feline pancreatitis. Alternatively, the PSL assay by Antech has been shown to have a fair correlation with the spec fPL in some studies. The author prefers to use both abdominal ultrasound and the spec fPL (or PSL) to diagnose pancreatitis. The snap fPL test is a screening test (a negative test makes pancreatitis less likely), but a positive test is nonspecific and needs to be confirmed by abdominal ultrasound and/or spec fPL determination.
If abdominal ultrasound does not demonstrate changes consistent with pancreatitis or EHBDO, hepatic icterus is most likely. A diffusely hyperechoic liver is highly suggestive of hepatic lipidosis but can also be seen in diabetic or healthy obese cats. The ultrasound appearance of lymphoma or cholangitis can be variable, sometimes with no abnormalities being found.
LIVER FINE NEEDLE ASPIRATE VS. BIOPSY
Cytology or histopathology is needed for a definitive diagnosis of hepatic icterus because ultrasound changes of hepatic parenchyma are often nonspecific. Cytologic evaluation of liver fine needle aspirates may be useful in diagnosing hepatic lipidosis or lymphoma, but often misses necroinflammatory disorders such as cholangitis. Therefore, histopathologic evaluation of a liver biopsy may be superior to a fine needle aspirate.
Since coagulation abnormalities are common in cats with hepatobiliary disease, a coagulation profile (PT, PTT, and platelet count) should be performed prior to performing a liver biopsy. Coagulopathies may be caused by decreased clotting factor synthesis, vitamin K malabsorption, DIC, or decreased platelet function. Vitamin K deficiency has been noted in 5075% of cats with hepatobiliary disease. The author routinely administers Vitamin K1 0.5-1.5mg/kg SQ q 12 hrs for three doses prior to performing a liver biopsy in icteric cats.
Liver biopsies can be obtained either surgically, laparascopically, or ultrasound-guided. Some cases of EHBDO, such as those due to pancreatitis, may respond to medical management and do not require surgery. Surgical biopsies are indicated in cases with EHBDO that require biliary diversion (i.e. cholecystoduodenostomy or cholecystojejunostomy). In most other instances, less invasive methods of obtaining biopsies are preferred. In the author's practice, ultrasound-guided liver biopsies are most common.
Prior to placing the biopsy sample in formalin, the author generally makes impression smears for cytologic evaluation. This may make it possible to provide a preliminary diagnosis of hepatic lipidosis or lymphoma. Samples of liver tissue and/or bile are submitted for aerobic and anaerobic culture, especially if cholangitis is suspected. A recent study showed that 14% of liver biopsy cultures and 36% of bile cultures were positive in cats with hepatobiliary disease. Cytologic evaluation of bile may also be useful. In a recent study, microorganisms were detected on bile cytology in 22% of feline bile specimens and inflammation was evident in 19% of cats. While the cat is sedated for the liver biopsy, the author routinely places a feeding tube if hepatic lipidosis is suspected or if the cat has been anorectic for > three days.
Pending the results of the biopsy and culture, icteric cats are treated with nutritional support, if indicated, and fluid therapy (usually non-lactate, non-dextrose-containing fluids) as needed to correct dehydration or electrolyte imbalances (such as hypokalemia and/or hypophosphatemia). In the absence of hypoglycemia, dextrose supplementation is avoided since it may increase hepatic triglyceride accumulation, inhibit fatty acid oxidation, and worsen electrolyte depletion. Empirical antibiotic therapy can be used if cholangitis is suspected. If liver flukes are possible, a therapeutic trial of praziquantel 20mg/kg SQ (or PO) SID x three days is administered. The rest of the treatment regimen depends on the results of the biopsy.
TREATMENT OF SPECIFIC DISEASES
Hepatic Lipidosis
Hepatic lipidosis may be idiopathic or secondary. The diagnosis of idiopathic hepatic lipidosis is a diagnosis of exclusion. Up to 40-90% of hepatic lipidosis cases are secondary to other diseases –such as cholangitis, lymphoma, pancreatitis, inflammatory bowel disease, cardiomyopathy, diabetic ketoacidosis, or pyelonephritis. A thorough diagnostic evaluation is necessary to diagnose and treat any potentially underlying cause.
Nutritional support with a feeding tube is the cornerstone of treating cats with hepatic lipidosis. Syringe/force-feeding is stressful for both cats and their owners. Appetite stimulants are not a substitute for a feeding tube and are rarely prescribed in the author's practice. For long-term enteral nutritional support, esophagostomy or gastrostomy tubes are used. A percutaneous endoscopic gastrostomy tube may be used in cats that require gastrointestinal biopsies to rule out GI disease (i.e., inflammatory bowel disease or GI lymphoma) as the cause of anorexia. PEG tubes, rather than esophagostomy tubes, should also be used if esophageal disease is present. In most other cases, an esophagostomy tube works just as well as a gastrostomy tube. An esophagostomy tube is the most frequently used feeding tube in the author’s practice.
If the cat is not stable enough for sedation/anesthesia at initial presentation, stabilization with fluid therapy and a nasoesophageal feeding tube is performed for the first few days. A five or eight French nasoesophageal feeding tube can be inserted with just topical anesthesia in most cats.
In addition to tube feeding 60 kcal/kg/day, cats with hepatic lipidosis are treated with SAMe 20mg/kg/day for its antioxidant effects and its ability to replenish hepatic glutathione. Many clinicians advocate administering L-carnitine 250mg BID, taurine 250mg BID, and thiamine. Subcutaneous cobalamin supplementation should be considered since subnormal levels are present in 57% of cases. Vomiting can be controlled by using maropitant (use 0.5mg/kg SID instead of 1mg/kg SID), metoclopramide, or 5-HT3 antagonists (such as ondansetron or dolasetron). If hepatic lipidosis is secondary to another underlying disease, treatment of the primary disease is also important.
Most (80-85%) cats with hepatic lipidosis can be successfully treated with bilirubin decreasing by 50% within seven to 10 days. Failure to respond may indicate that the underlying cause of the secondary hepatic lipidosis has not been adequately addressed. Negative prognostic factors include anemia, hypokalemia, old age, and cases of secondary hepatic lipidosis.
Cholangitis
Clinical signs of cholangitis can be similar to hepatic lipidosis, such as anorexia, weight loss, vomiting, and lethargy. Unlike idiopathic hepatic lipidosis, fever (in neutrophilic cholangitis) or abdominal effusion (in lymphocytic cholangitis) may be seen. Laboratory abnormalities that may help distinguish cholangitis from hepatic lipidosis may include neutrophilia with a left shift, an elevated ALT>ALP, and hyperglobulinemia.
Cholangitis may occur by itself or concurrently with inflammatory bowel disease and/or pancreatitis (triaditis). In a study by Fragkuo et al 2012, 47 cats (27 sick cats and 20 healthy cats) had liver, GI, and pancreatic biopsies via laparotomy.
• 13 cats had IBD only (eight of which were symptomatic, five from the healthy group),
• Six cats had cholangitis only (two symptomatic, four from a healthy group),
• 16 cats had IBD + cholangitis (six symptomatic and 10 from a healthy group),
• Three cats had IBD + pancreatitis (two symptomatic and one healthy), and
• Eight had IBD + pancreatitis + cholangitis (all eight were in the symptomatic group)
So although it is common to have inflammatory changes in more than one system, subclinical cases were fairly common.
In a study by Center et al. 2022 of 168 cats with suppurative cholangitis, many cats had other concurrent diseases. 60/68 (88%) intestinal biopsies had inflammatory bowel disease and 41/44 (93%) pancreatic biopsies had concurrent pancreatitis.
Treatment of cholangitis is based on whether it is neutrophilic (acute and chronic) or lymphocytic in nature. In the author's practice, the lymphocytic form is more common than neutrophilic cholangitis.
SAMe and ursodeoxycholic acid may be used in either form. For neutrophilic cholangitis, antibiotics (based on culture and sensitivity) are generally indicated for six to eight weeks. In one study, 69% of cats were positive for bacteria on FISH analysis. In the Center et al. 2022 study of 168 cats with suppurative cholangitis, 94% were positive by immunohistochemistry (vs. 69% positive via routine culture). E. coli and Enterococcus were the most common bacteria involved. Pending culture and sensitivity results, good empirical choices include amoxicillin, amoxicillin-clavulanate, or fluoroquinolones combined with metronidazole. Prednisolone may be added in cases of chronic neutrophilic cholangitis that do not adequately respond after a few weeks of appropriate antibiotic therapy.
Unlike cases of neutrophilic cholangitis, finding bacteria in lymphocytic cholangitis (either by FISH or culture) is rare. Prednisolone is the cornerstone of the treatment of lymphocytic cholangitis. The initial dose is usually 1-2mg/kg PO BID, then slowly tapered over several months. In a study by Otte et al., 2014 using serial liver biopsies, prednisolone was more effective than ursodiol in reducing inflammation in cats with lymphocytic cholangitis. In another retrospective review of 28 cats with lymphocytic cholangitis, cats treated with prednisolone had a longer survival time than cats treated with ursodiol (>900 days vs. 365 days).
Response to therapy is generally monitored by rechecking the liver enzymes. If there is no response, other immunosuppressive drugs such as chlorambucil, cyclosporine, or methotrexate can be tried. Failure to respond may also be due to poor owner compliance, incorrect diagnosis, concurrent illness not being treated, or occult infectious disease (such as toxoplasmosis). Some recent evidence suggests that Helicobacter may play a role in cholangitis, but Helicobacter was also found in normal livers.
The prognosis for cats with cholangitis is fair. With neutrophilic cholangitis, a median survival of 29 months has been reported. With lymphocytic cholangitis, a median survival of 795 days with a 74% one-year survival, 56% two-year survival, and 35% three-year survival was reported by Otte et al. 2013. In another study, the median survival of cats with lymphocytic hepatitis was 37 months.
Lymphoma
Lymphoma is best treated with chemotherapy. A combination protocol including vincristine, cyclophosphamide, prednisolone, and doxorubicin +/- L-asparaginase is recommended for lymphoblastic lymphoma. The complete response rates for feline lymphoma are approximately 50-75% with a median survival of six to eight months. Some (30-40%) cats that obtain a complete remission survive up to two years.
For lymphocytic lymphoma, therapy with oral prednisolone and chlorambucil is used. Cats with low-grade (i.e., small cell lymphocytic) GI lymphoma have prolonged survival (median survival of 17 months in one study).
Pancreatitis
The spec fPL (feline pancreas-specific lipase), run by Idexx and Texas A&M GI laboratory, is the diagnostic test of choice for pancreatitis. A spec fPL > 5.4 μg/L is 48-100% sensitive and 54-80% specific for the diagnosis of pancreatitis. Some studies have shown a fair correlation between the spec fPL and PSL assay by Antech. In comparison, abdominal ultrasound is 1184% sensitive and 73-100% specific. Serum amylase and lipase are not useful for the diagnosis of pancreatitis in cats.
According to a study by Krasztel et al. 2021, the CBC may be a useful screening test for pancreatitis. If the total WBC is <18,000, bands <270, and eos >300, pancreatitis is unlikely (91.8% sensitivity). Unfortunately, an abnormal CBC is not specific for pancreatitis.
Treatment of pancreatitis in cats may involve IV fluids and analgesic medications similar to the treatment of canine pancreatitis. A major difference is that most cats with pancreatitis are not vomiting and require enteral nutritional support to prevent the development of hepatic lipidosis. Nasoesophageal, esophagostomy, or gastrostomy tubes can be used successfully in many cases of feline pancreatitis. Some cats, however, may require jejunostomy feeding tubes or parenteral nutrition.
In one study, 11/31 (35%) of cats with pancreatitis had bacteria in the pancreas found on FISH analysis. This was most often found in cats with moderate-severe acute pancreatitis. Thus, antibiotic therapy should be considered in cats with moderatesevere acute pancreatitis.
Cats with chronic pancreatitis may benefit from immunosuppressive therapy with either prednisolone or cyclosporine. A study by Wu et al. presented at ACVIM 2022 revealed that either prednisolone or cyclosporine were equally effective in reducing fPL in cats with chronic pancreatitis.
ADAM HONECKMAN
DVM, DAVCM (Small Animal Internal Medicine)
Dr. Adam Honeckman graduated from Purdue University School of Veterinary Medicine in 1992 and completed an internship at Purdue in 1993. After four years of general practice in the Chicago area, he was accepted for a small animal internal medicine residency at the prestigious Animal Medical Center in New York City. During his residency, Dr. Honeckman developed a special interest in ultrasonography and endoscopy. After completion of his residency, he started his own mobile internal medicine practice in the Orlando area. After 20 years of mobile practice, he moved to his permanent location and founded Veterinary Specialty Solutions. In his spare time, Dr. Honeckman is also an internal medicine consultant for the Veterinary Information Network.
