How I approach… The cat with cholangitis

Introduction – a historical perspective

As early as 1996, veterinarian Dr. Sharon Center adeptly summarized the peculiarities of the feline hepatobiliary system and highlighted distinct disease differences between cats and dogs, stating that “cholangitis and cholangiohepatitis are more common in the cat than the dog. The anatomic difference in the biliary duct/pancreatic duct anatomy has long been considered an important predisposing factor in this species difference.” 1. Dr. Center collected, analyzed, and cited studies in cats going back to the 1980’s that described suppurative cholangitis and chronic lymphocytic cholangitis 2 3 and dug deep enough to uncover the description of 47 icteric cats from 1977 4. She actually anticipated feline triaditis, noting that “although evaluation for inflammatory bowel disease and pancreatitis has not been thorough in every cat reported to date, they appear to be commonly associated [with cholangitis] conditions.”

1996 was also the year that the first study was published quantifying the association in cats between inflammatory hepatic disease, inflammatory bowel disease (IBD), pancreatitis, and nephritis (the condition that fell out of the equation, to leave “triaditis”) 5. This marked the beginning of a serious and fruitful effort to better understand liver disease in cats, or (as it was then referred to) the feline cholangiohepatitis complex, or feline cholangitis/cholangiohepatitis 6. Clinical research attempted to characterize feline inflammatory and lymphocytic liver disease using ultrasound, immunohistochemistry, and clinical presentation 7 8 9. Potential infectious etiologies, such as Bartonella, Enterococcus, and Helicobacter, were described, and the first report of an infectious organism ascending from the gastrointestinal tract to cause cholangitis in a kitten appeared in the literature 10 11 12 13.

A decade later the World Small Animal Veterinary Association Liver Standardization Group attempted to categorize the defining features of feline biliary disease and organize the vocabulary for the veterinary profession 14, and the remainder of this discussion will focus on what we have learned since then. But it is important to realize that although our understanding of this condition has been helped by new technologies and diagnostics, the foundation had been laid and the pathway had been paved by those featured in the cited chapter 1, including Dr. Center herself.

The approach

We start with a sick cat. Sick cats present to veterinarians because they are vomiting, or having diarrhea, or eating less (or maybe not eating at all), losing weight, hiding or becoming “clingy”, less active, vocalizing and seemingly painful, salivating excessively, or just looking miserable. Reasons for the depth and variety of clinical presentations consistent with feline cholangitis are that I) it’s a cat, and II) cats frequently bring more than one problem with them to the veterinarian. Although feline triaditis is a named example of this phenomenon, there are a dozen conditions that might easily be associated with cholangitis: these include IBD, pancreatitis, chronic bacterial infection(s) including pyelonephritis, trematode infestation, toxoplasmosis, septicemia, cholelithiasis, extrahepatic biliary obstruction (EHBO) and neoplasia 1. Although there is long way to go before establishing a diagnosis, potentially helpful information to obtain at the outset, with history and physical examination, include:

• Gender and age
• Does the cat live in North America, Europe or elsewhere?
• Does the cat live in an area that is known for liver flukes? (a cause of feline cholangitis which is not covered here)
• How long has the cat been sick (a few days, a few weeks)?
• Has the cat lost weight?
• Is the cat vomiting, does it have diarrhea, is it nauseous, lethargic or anorexic?
• Are the clinical signs consistent, persistent, progressive, or intermittent?
• Is the cat yellow (icteric, jaundice)?
• Is the cat febrile or dehydrated?
• Does abdominal palpation reveal discomfort (and if so where?), organomegaly (and if so what?), or free fluid?
  
  

Some notes of caution

1. If, as you gaze into the eyes (or more specifically, the sclera) of the cat on the examination table you notice that the cat is yellow (icteric, jaundiced), do not jump for joy assuming you have arrived at a diagnosis simply by walking into the exam room and looking at your patient, because you should not jump to the conclusion that this cat has liver disease. If the cat is icteric then its total bilirubin will likely be ≥ 2.5-3.0 mg/dL, and if you had to place a bet, you would in fact bet on primary liver disease. However, it would be much more prudent to first exclude causes of pre-hepatic hemolysis of erythrocytes (Table 1).
2. If, as you gaze into the eyes of the cat on the examination table you notice that the cat is not yellow (icteric, jaundice), do not announce to the owner that their cat’s total bilirubin will be normal and liver disease is “off the table”, because cats may have a total bilirubin that is above normal without being high enough to turn the cat yellow. Cats with a total bilirubin ≤ 2.5-3.0 mg/dL but above the normal reference range are hyperbilirubinemic. If you had to place a bet, you would in fact bet on something other than pre-hepatic hemolysis or primary liver disease (e.g., reactive liver disease), but it would again be much more prudent to work through the differentials for other diseases that might impact the liver as collateral damage, which includes almost anything.
3. Although post-hepatic causes of hyperbilirubinemia (extrahepatic biliary obstruction [EHBO]) are rare in cats, they do occur and need to be considered (Table 2).

The liver as the culprit in the cat

Having considered, and appropriately ruled out both pre- and post-hepatic causes of hyperbilirubinemia in the yellow cat, or having settled on the liver as the most likely etiology for the sick cat, we now target that organ with our diagnostic effort.

The terminology

Although hepatic lipidosis is one of the most prevalent conditions diagnosed in yellow cats (Figure 1), it is beyond the scope of this article, as are reactive hepatopathies, neoplastic diseases, and vascular disorders. Chronic cholangitis associated with liver flukes (Platynosomum concinnum – also known as P. fastosum) 15 is an inflammatory liver disease that will also not be covered. This paper will focus on the two most common WSAVA inflammatory liver diseases 16, namely neutrophilic cholangitis (acute or chronic), and lymphocytic cholangitis, using case reports to identify key features of these conditions and to emphasize the need for a methodical approach to the diagnosis.

Case presentation 1

The patient is an 11-year-old male castrated Norwegian Forest Cat with a 3-month history of progressive vomiting and diarrhea. The cat has a mildly decreased appetite and has lost some weight. The owner perceives a yellowish tinge to the cat’s pinna (Figure 2) but otherwise the cat appears bright and interactive. Physical examination confirms jaundice and hepatomegaly, but is otherwise unremarkable.

Key features

First, the patient is an icteric Norwegian Forest Cat being seen at a clinic in Europe; this has got to be a clue! A recent survey found that the most frequent liver diseases in cats from the UK, based on histopathology, included neutrophilic cholangitis (20.5% of cases) and lymphocytic cholangitis (6.8%) 17. In another recent study from the Netherlands, 2 of 14 cases of lymphocytic cholangitis used to investigate immunohistochemical markers were Norwegian Forest Cats 18, and the majority of clinical studies on lymphocytic cholangitis come from Europe 8 19. That being said, 3 of 44 cats undergoing necropsy at the University of Pennsylvania Veterinary Hospital were identified as having lymphocytic cholangitis 20.

This particular patient is an older cat, and although there are generalizations about the age of presentation, it is clear that all forms of feline inflammatory liver disease can afflict a very broad range of age groups. It is noteworthy that this case is chronic and progressive, although the cat is not yet lethargic, anorexic, or febrile. Such a presentation should raise the index of suspicion for lymphocytic cholangitis. The chronicity and course of disease are certainly not pathognomonic, and cats with lymphocytic cholangitis can present as quite ill, with ascites and in poor body condition, but it would be unusual for a cat with acute neutrophilic cholangitis to be handling such an illness as well as this cat is at presentation.

Diagnosis

Going forward with the diagnostic work-up, the complete blood count (CBC) is not likely to be markedly abnormal, although some cats will have a significant lymphocytosis and a mild anemia with chronic disease. The elevation in liver enzymes and total bilirubin will be mild to moderate. Once the bilirubin is elevated enough to turn the cat yellow the bile acids test is redundant – it will be abnormal. FeLV/FIV testing will be negative, clotting times may be somewhat prolonged, but the most striking biochemical abnormality will most likely be a hyperglobulinemia (with gammaglobulins being the predominant peak should you run protein electrophoresis). If present, free abdominal fluid would have a high-protein content (again, increased globulin levels) and contain a variety of inflammatory cells.

Abdominal ultrasound would be a reasonable diagnostic recommendation in this case, not necessarily for what it will show (non-specific hepatic changes and lymphadenopathy), but for what it will not show. The gallbladder and biliary tree in this cat will most likely look unremarkable.

As we will discuss in the next case, fine-needle aspirate (FNA) of the liver is a low-risk procedure, but owners should be warned that it is also often a low-yield diagnostic that frequently produces frustrating rather than fruitful results. If the gallbladder contents, and particularly, the gallbladder wall look normal, studies suggest that aspiration of the gallbladder contents would also be low yield (see next case).

The most compelling argument for obtaining a liver biopsy is, of course, the fact that it is the best way to obtain a definitive diagnosis. In this case, the rule-out that looms largest on the list of differentials would be lymphoma, with FIP perhaps entering the argument in a cat of the appropriate age (high-protein ascites and hyperglobulinemia). In either case, hepatic histopathology would distinguish between these possibilities. The other compelling argument for obtaining a liver biopsy is that you could also obtain biopsy samples of the pancreas and the intestinal tract. The identification and treatment of concurrent diseases is absolutely critical to the successful treatment of a cat with any form of cholangitis.

Treatment

Having arrived at either a definitive (histopathology – (Figure 3)) or speculative (case presentation) diagnosis of lymphocytic cholangitis the treatment targets include non-specific support and an immune-mediated etiology. Non-specific therapy will include vitamin K₁ (5 mg/cat SC q24H) with several doses given in support of the cat’s coagulation pathways prior to hepatic FNA or placement of an esophageal feeding tube, and ursodeoxycholic acid (10-15 mg/kg PO q24H for 2-3 months). This drug is traditionally used to help move bile out of the biliary system, and may have a number of additional beneficial properties for a liver in need 21.

Antibiotics should not be necessary if the disease is an immune-driven infiltration of lymphocytes. Even if the original inciting cause was a bacterial infection, at the time of this case presentation, infection is a historical event. That said, some clinicians recommend a 2-4 week course of antibiotics covering enteric and/or anaerobic bacteria at the beginning of treatment (see Case 2), and bacteria may be present, not as the cause, but as a consequence of the immune-mediated disease 19.

Placement of an esophageal feeding tube is recommended as an early and effective intervention in any cat that has stopped eating (Figure 4). It is also an excellent way to empower the owner to better medicate and care for their cat in the comfort of their own home. At CSU we use the 14Fr MILA International, Inc. esophagostomy feeding tube and tunneler.¹

¹ www.milainternational.com; www.youtube.com/watch?v=qF14Jfajkhw&t=89s

The specific treatment for lymphocytic cholangitis is glucocorticoid therapy, prednisolone being the drug of choice. Some clinicians will start as high as 4 mg/kg/day, many will start closer to 2 mg/kg/day, but all will taper slowly over a 3-month duration.

Clinical signs, mucosal color, and abnormalities in liver enzymes and total bilirubin are all reasonable markers to follow in documenting a response to therapy.

Case presentation 2

This patient is a 6-year-old male castrated domestic longhair seen in the United States. The cat is presenting for a history of vomiting, anorexia, and lethargy for four days. Physical examination reveals an icteric, febrile, dehydrated cat (Figure 5) that is uncomfortable on abdominal palpation and may be nauseous and salivating. A biochemical profile shows hyperbilirubinemia, hyperglobulinemia, moderate to significantly elevated ALT activity with a variable elevation in ALP, and non-specific changes associated with dehydration (azotemia), stress or acute pancreatitis (hyperglycemia), and electrolyte abnormalities. In addition to a mild anemia the CBC also shows some significant changes not found in Case 1: namely, a lymphopenia, leukocytosis, and a neutrophilia with a left shift.

Key features

Unlike the previous case in a Norwegian Forest Cat, in the United States we have no geographically-specific exotic breeds, and as for age, this is simply an adult cat, although younger than the cat in Case 1. (Outside of the US, we might be featuring such breeds as the Burmese, Persian, Siamese, or the British Shorthair). The clinical signs are quite similar to Case 1, with the biggest differences being the brief and relatively more severe presentation of the patient. The difference in severity is highlighted by the presence of a fever and an inflammatory leukogram, and a greater number of abnormalities on the biochemical profile. Such a presentation should raise the index of suspicion for neutrophilic cholangitis. The discomfort on abdominal palpation may be the result of an acutely inflamed, infected, and enlarged liver, or the presence of pancreatitis – again, highlighting the commonality and importance of concurrent conditions (including pancreatitis, IBD, EHBO, cholecystitis or cholelithiasis, etc.). It is likely this cat will have some degree of a coagulopathy requiring vitamin K₁, and again, by the time the hyperbilirubinemia is turning the cat yellow the bile acids test will be abnormal and redundant. It is prudent to test a fasted serum sample for fPLI and cobalamin levels.

Diagnosis

Abdominal ultrasound will now be critical for what we do find, and what we take (Figure 6). Imaging the pancreas and intestinal wall thickness/architecture will help in the pursuit of feline triaditis; changes in the hepatic parenchyma will still be non-specific, but the gallbladder will likely serve as the site and source of a diagnosis. It is possible for a cat with neutrophilic cholangitis to present with a biliary system that images normally, but in many cases the gallbladder wall will be thick and irregular, even palisading (Figure 7) 22. Sludge (Figure 8) or choleliths may be present, and it is important to follow the biliary tract to the duodenum to rule out EHBO. The common bile duct is obstructed in many of these cats. Ascites may be present, in which case aspiration and fluid analysis is warranted.

It is gallbladder aspiration (ultrasound-guided percutaneous cholecystocentesis) for cytology and culture that is most likely to produce a diagnosis, and direct treatment (Figure 9) 23. This procedure is most likely to yield abnormal cytology and positive bacterial culture results if the gallbladder appears abnormal on imaging, e.g., if wall thickness is > 1 mm, there is irregular or palisading wall thickness, or significant hyperechoic content (“sludge”) (Figure 10) 22 24. Note that gallbladder wall rupture and/or leakage of contents and bile peritonitis is a potential risk with aspiration, but there are very few problems when performed by an experienced ultrasonographer in a cooperative and/or sedated patient. However, if the gallbladder wall appears emphysematous, the risks are considerable, and either surgical removal or trial treatment should be considered instead.

Aspirated bile may appear grossly normal or as a purulent exudate. Cytology is likely to be dominated by neutrophils in various states (i.e., normal to degenerate) with or without evidence of intracellular bacteria 25. Unsurprisingly the most frequently cultured organism is E. coli, followed by an extensive list of enteric and anaerobic organisms, such as Enterococcus, Streptococcus, Klebsiella, Actinomyces, Clostridium, Bacteroides, Pseudomonas, Staphylococcus, and Pasteurella species, and Salmonella enterica serovar Typhimurium.

Again liver FNA is minimally invasive but often of low yield in these patients. At CSU it is rare that we would seek a biopsy sample for hepatic histopathology, although we will perform abdominal laparoscopy on a number of these cats, collect biopsy samples of the liver and the pancreas, and aspirate the gallbladder with direct visualization during this procedure. Although histopathology helps obtain a definitive diagnosis and identify concurrent diseases, cholecystocentesis is most likely to be diagnostically fruitful and therapeutically relevant.

Treatment

These cats are frequently sick enough to benefit from hospitalization, supportive care (fluids, pain management, nutrition, etc.), and IV medications (antibiotics, anti-emetics, etc.).

Bacterial culture and sensitivity results from cholecystocentesis will ideally guide the choice of antibiotic, and cytology with gram stain may help in the initial choice while awaiting culture results. If a selection must be made without the benefit of either of these diagnostics, the choice of antibiotic(s) should be directed at E. coli with a spectrum broad enough to cover common enterics, including anaerobes [e.g., clavimox, metronidazole, pradofloxacin, etc.]. Recommendations for the length of treatment vary from 4-6 weeks to 3-6 months, following clinical signs and liver enzyme elevations for feedback as to effectiveness.

In addition to chronic neutrophilic cholangitis, one potential consequence of acute neutrophilic cholangitis might well be lymphocytic cholangitis, with infection as the original etiology but also acting as an inciting stimulus for a persistent immune-mediated response. Therefore these cases may go on to require treatment with prednisolone at some point following their course of antibiotics.

Vitamin K₁ and ursodeoxycholic acid, as described in Case 1, liver protectants, such as S-adenosylmethionine, and cobalamin supplementation should also be considered. As with Case 1, it is critical to recognize the potential importance of concurrent diseases in these cats.

Neutrophilic cholangitis (both acute and chronic forms) appears to be the most common feline inflammatory liver disease in both the United States and the rest of the world, whilst lymphocytic cholangitis seems to show a preference for cats outside of the US, such as the Norwegian Forest Cat and Persian. In both cases, it appears that concurrent diseases are common, and commonly the cause of the demise of the cat. Once again, cats remind us that whether it is diabetic ketoacidosis, hepatic lipidosis or cholangitis, they may ignore the “Diagnostic Parsimony of Occam’s Razor” (i.e., the idea that if a patient has multiple clinical signs, a single diagnosis should be sought that accounts for all the clinical features, rather than attributing a different diagnosis to each), and will instead subscribe to Hickam’s Dictum, which states “Patients can have as many diseases as they damn well please.”