Ultrasonographic Findings of Feline Cholangitis

Introduction

Ultrasound of the liver has become a standard diagnostic test to evaluate patients suspected of having hepatic disease based on clinical history and routine hematologic and biochemical analyses. Multiple studies have attempted to correlate ultrasonographic changes to specific disease types; however, no definitive criteria have been established.^1–3 A retrospective study utilizing a classification scheme to differentiate specific liver diseases based on sonographic findings in the liver and other abdominal organs found the best predictors of hepatic malignancies in cats to be abnormalities identified concurrently in the spleen and abdominal lymph nodes.¹ That same study was able to differentiate cholangitis/cholangiohepatitis (C/CH) complex from other hepatic diseases by the sonographic changes in the liver parenchyma and biliary system.¹ Specific changes to the biliary tract were not evaluated, and the diagnosis of cholangitis was not separated into subtypes.¹ In general, inflammatory liver conditions are characterized as having either normal or hypoechoic parenchyma with well-visualized portal markings.^1,3,4 However, cats with C/CH can have a liver parenchyma that is normal, hypoechoic, or hyperechoic in nature.³ Assessment of the biliary system for abnormalities with ultrasound is important in cats with suspected C/CH. The normal common bile duct diameter in cats has been determined to be ≤4 mm, with diameters >5 mm indicative of extrahepatic obstruction.⁵ Other diffuse liver disorders have sonographic changes that are similar in appearance. Hepatic lipidosis, the most common feline liver disorder, is sonographically characterized by an enlarged, diffusely hyperechoic liver.^3,6 Diffuse neoplastic disorders are more variable with hypoechoic nodules, diffuse hyperechogenicity, hypoechogenicity, or mixed parenchymal echogencity as possible sonographic changes.^3,7–9 Due to the inability to distinguish the multiple diffuse liver diseases, histologic sampling is recommended for definitive diagnosis.^1–3,10

In cats, the second most common hepatic disorder reported is C/CH.⁶ The histologic terminology of C/CH is confusing and has changed over the years. Because cholangitis often occurs in conjunction with cholangiohepatitis, the term C/CH is frequently used to describe this cholangitis. The C/CH complex is associated with neutrophilic, lymphocytic, and/or plasmacytic cellular infiltrates targeting the bile ducts with variable bile duct proliferation and fibrosis.¹¹ In the suppurative form, there is evidence of predominantly neutrophilic inflammation whereas lymphocytes predominate in the nonsuppurative forms.¹¹ Concurrent pancreatitis/inflammatory bowel disease is reported to occur more commonly with the suppurative form of this disease.¹² In 2003, the World Small Animal Veterinary Association Liver Disease and Pathology Standardization Research Group proposed a reclassification of C/CH complex in cats.¹³ Since the reclassification, cholangitis in cats has been subdivided into three categories: neutrophilic cholangitis, lymphocytic cholangitis, and chronic cholangitis associated with liver fluke infestation. These categories are based on the type of cellular infiltrate, degree of periportal fibrosis, presence of destructive lesions in the bile ductules, and evidence of fluke infestation. The neutrophilic form was subdivided into an acute form (predominantly neutrophilic infiltration) and a chronic form (having a mixed cellular infiltrate of neutrophils, lymphocytes, and plasma cells).¹³ The term “neutrophilic” is preferred over suppurative as true pus formation may not be present.¹³ Also, the term “cholangitis” is used in preference to cholangiohepatitis because the inflammatory disruption of the limiting plate to involve hepatic parenchyma is not a consistent feature, and if present, is usually an extension of primary cholangitis.¹³ Previous studies identifying ultrasonographic changes associated with feline the C/CH complex did not specifically evaluate the liver parenchyma, biliary system, pancreas, and duodenum. With the histologic changes noted, there may be differences in the ultrasonographic characteristics of neutrophilic cholangitis, lymphocytic cholangitis, and other infiltrative neoplastic and benign feline liver disorders.

The goal of this study was to evaluate the ultrasonographic changes within the liver, biliary system, pancreas, and small intestine of cats with known cholangitis and to answer two specific questions: (1) Is it possible to be more definitive in diagnosing cholangitis in cats based on particular sonographic changes? (2) For cats with a diagnosis of either lymphocytic or neutrophilic cholangitis, are there discriminatory sonographic findings associated with either subtype of the disease?

Materials and Methods

A medical record search from 1998 to 2007 was conducted searching for cats having liver disease. There were two inclusion criteria: histopathologic samples consistent with either the neutrophilic or lymphocytic form of cholangitis, and concurrent abdominal ultrasound. The remaining form of cholangitis with fluke infestation was not identified in the reports. Twenty-six cats met the inclusion criteria. Fourteen had the lymphocytic form and 12 had the neutrophilic form of cholangitis. For the purposes of this study, acute and chronic forms of neutrophilic cholangitis were combined into one group. The signalment, presenting complaint(s), and biochemistry values were evaluated. All ultrasound examinations were performed on one machine^a using a combination of linear 4–7 MHz or sector 3–10 MHz transducers. Static hard copy images and reports from 26 cats were evaluated by two board-certified radiologists. The radiologists were blinded to the specific histopathologic diagnoses, but did know all cats had histologic evidence of cholangitis. Ultrasound images were reviewed as the entire sonographic study for each cat, and consensus decision reached. The images were evaluated by the following criteria: liver echogenicity (normal, hypoechoic, hyperechoic); focal/multifocal nodules (present or absent); gallbladder wall (normal or thickened >1 mm); gallbladder wall (normal or hyperechoic); intraluminal gallbladder contents (normal, echogenic debris, or choleliths); biliary duct(s) size (normal, not identified, <4 mm, or dilated); pancreas (normal echogenicity, diffusely hypoechoic, or diffusely hyperechoic); pancreatic size (normal or enlarged >1cm thick); surrounding mesentery (normal or hyperechoic); duodenum (normal or thickened >2.5 mm); duodenal layering (normal or abnormal); and absence or presence of free fluid.

Results

The mean age of all affected cats in this study was 11.2 yr (range, 4–17 yr) with a median age of 11 yr. The mean age of cats with lymphocytic cholangitis was 11.4 yr (range, 4–16 yr) with a median age of 11.5 yr. For cats with neutrophilic cholangitis, the mean age was 10.7 yr (range, 4–17 yr) with a median age of 9.5 yr. Approximately 48% of the cats were spayed females, and 52% of the cats were neutered males. There was no sex predilection when dividing the cats into lymphocytic or neutrophilic cholangitis subsets. Eighty-five percent of the cats were either domestic shorthair or domestic longhair breeds. Other breeds included Himalayan, Siamese, Manx, and Maine coon (n=1 each).

The most common presenting complaints were anorexia and weight loss followed by vomiting and lethargy. Liver enzyme elevations were common in this population of cats, with 84.6% of cats having increased aspartate aminotransferase levels, 64.1% with increased alanine aminotransferase levels, 58.9% with elevated total bilirubin, 57.7% with elevated alkaline phosphatase levels, and 30.7% with elevated gamma-glutamyl transferase levels. Fifty-five percent of cats with neutrophilic cholangitis demonstrated leukocytosis. Thirty-three percent of cats with lymphocytic cholangitis had leukocytosis.

The frequency findings for the sonographic changes evaluated in all cats are listed in Table 1. The majority of cats had normal sonographic findings including liver size (69.2%), liver echogenicity (53.8%), gallbladder wall echogenicity (91.6%), and gallbladder contents (62.5%). In this population of cats, the proportion with abnormal findings was ≥20% for liver size, liver echogenicity, bile duct size, gallbladder contents, and pancreatic size. At the 0.05 level of significance, this increase was statistically significantly >20% for liver echogenicity (38.5%; P=0.023), gallbladder contents (37.5%; P=0.036), and pancreatic size (38.9%; P=0.051), but not for liver size (27.0%; P=0.252) or bile duct size (30.8%; P=0.131). No statistically significant changes were identified to differentiate neutrophilic cholangitis from lymphocytic plasmacytic cholangitis (Table 2); however, pancreatic size abnormalities were more frequently identified in cats with the neutrophilic form of cholangitis. Five of the eight (62.5%) cats with neutrophilic cholangitis that had representative images of the pancreas and/or comments in the imaging report had sonographic evidence of an enlarged pancreas. This tendency was not statistically significant (Fisher exact test P=0.1448). Two limitations of this study were that gallbladder content comments were unavailable for two cats and pancreatic size interpretations were absent for eight cats.

TABLE 1 Frequency and Proportion of all Cats with Normal and Abnormal Sonographic Variables

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TABLE 2 Results from Fisher Exact Test for an Association Between Abnormal Readings and Diagnosis for Selected Sonographic Measures

LPC, lymphocytic plasmacytic cholangitis; NC, neutrophilic cholangitis.

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Changes to the liver parenchyma and biliary tree were clearly identified on sonographic images. Liver parenchymal echogenicity changes, common bile duct dilation (Figure 1), and echogenic intraluminal gallbladder debris were noted (Figure 2). Two cats in the neutrophilic cholangitis group had choleliths and mineralization in the biliary tree. The pancreatic echogenicity was hypoechoic in 26.3% of the cats, and the pancreas was enlarged in 38.9% of them, with most of these from the neutrophilic cholangitis subgroup. Four of the cats had abdominal effusion. Three of those cats were diagnosed with lymphocytic plasmacytic cholangitis, and one was diagnosed with neutrophilic cholangitis. Duodenal and mesenteric changes, presence or absence of free fluid, and evidence of liver nodules were not statistically significant (Table 1).

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Discussion

The study population consisted of middle-aged and older cats. The lymphocytic cholangiohepatitis group was slightly older than the neutrophilic cholangitis group. This age schematic differs from other studies in which younger cats were more commonly diagnosed with lymphocytic plasmacytic cholangitis; however, older cats have been diagnosed with the lymphocytic form and younger cats with the neutrophilic form.^6,14 These numbers could reflect the small populations for each subtype and may not represent a real difference from previous findings. There was no evidence of breed or sex predilection in this population, which differs from other studies that denoted male predisposition to the neutrophilic form and purebred predisposition (Persians in particular) to the lymphocytic form.^14,15 The small sample size may account for this difference.

Nearly all of the cats in both subtypes of cholangitis presented with clinical signs including anorexia, weight loss, vomiting, and lethargy. In a previous report, cats with neutrophilic cholangitis were more likely to be symptomatic upon presentation, which was likely at the acute stage of the disease.^6,16 The severity of condition at time of presentation could account for this difference. As a tertiary referral center, many cases may have become chronic and long-standing at presentation for evaluation and diagnosis; hence, the study population may have been biased to those with more chronic forms.

Liver enzyme changes and hematology results were similar to previous reports with elevations in hepatocellular liver enzymes and total bilirubin. The predominance of elevated WBC count in cats with neutrophilic cholangitis compared with lymphocytic plasmacytic cholangitis follows previously reported changes.^6,15

Most cats in both subsets had normal sonographic findings, including liver size, liver echogenicity, and biliary systems. However, sonographic abnormalities in the combined population of cats indicated several commonalities, including enlarged liver, hyperechoic liver parenchyma, dilated common bile duct, and echogenic gallbladder contents. When taken together, these changes could indicate cholangitis and aid in differentiating this diffuse liver disease from lymphoma, hepatic lipidosis, vacuolar or toxic hepatopathy, or liver storage disorders. The biliary changes are consistent with a previous retrospective study distinguishing cholangitis from other diffuse liver diseases.¹ The cats with hyperechoic liver parenchyma differ from a previous report, and these changes suggest a more chronic stage of cholangitis in which fibrosis developed producing increased liver echogenicity.¹ Review of the histopathology reports indicates that multiple cats had fibrotic changes and several others had lipid deposits in the liver samples. Many of these patients were anorexic at the time of presentation, and fatty infiltrates in the liver causing liver hyperechogenicity are likely.

The biliary tract abnormalities, gallbladder wall thickness, and gallbladder contents are important changes to consider in the diagnosis of cholangitis, as an enlarged hyperechoic liver alone does not indicate diffuse liver inflammation. For cats with lesser, nonobstructive dilation of the common bile duct (<5 mm), cholangitis or chronic pancreatitis should be considered. The cats in this study had variable common bile duct dilation with most ducts measuring or appearing within normal limits. Many of the common and intrahepatic bile ducts were not measured with calipers to determine exact size. As C/CH can have variable bile duct proliferation and fibrosis, this could manifest as hyperechoic biliary walls on ultrasound. This sonographic finding was not graded, but might correlate with degree of histologic changes observed. Increased gallbladder wall thickness was not statistically significant in this study; however, bacterial cholecystitis can be associated with neutrophilic cholangitis and may have a sonographically thickened gallbladder wall. After reviewing the histology reports, three cats with neutrophilic cholangitis had evidence of concurrent cholecystitis. The echogenic contents in the gallbladder were likely secondary to biliary stasis or dysfunction. Currently, identifying gallbladder debris in cats is somewhat confounding and not necessarily considered an incidental finding as in dogs.¹⁷ Gallbladder debris has been identified as a complication of cholangitis in cats and has been linked to elevated liver enzymes indicative of hepatobiliary disorders.^6,18 As in humans, gallbladder debris/sludge in cats may correlate to the clinical history of fasting or indicate either intra- or extrahepatic cholestasis or intrinsic gallbladder disease.^6,19–23 In humans with primary sclerosing cholangitis, which is a diffuse fibrosing inflammation of the intrahepatic and/or extrahepatic bile ducts, secondary gallbladder disease is frequent.²¹ The gallbladder epithelium is part of the extrahepatic bile duct system and can be involved in chronic extrahepatic inflammation.²¹ Chronic inflammation from the small bowel/duodenum and/or pancreas in cats may lead to concurrent gallbladder disease.

Pancreatitis has been identified as a cause of gallbladder sludge in humans.²² This could be an aggravating factor for gallbladder debris in cats with neutrophilic cholangitis. Cats with neutrophilic cholangitis have been reported to have a higher incidence of concurrent inflammatory bowel disease and pancreatitis (a condition known as triaditis).^12,24 The anatomic relationship of the pancreatic duct and common bile duct opening onto the major duodenal papilla within the proximal duodenum predisposes cats to subsequent pancreatic and biliary tract inflammation.²⁵ Gastrointestinal infections that ascend into the pancreatic duct and common bile duct can lead to gallbladder disease and cholangitis.²⁶ Bacterial isolates from cats with acute neutrophilic cholangitis and cholecystitis have included enteric species likely secondary to ascending intestinal infections.¹⁶ In the current study, 2/17 cats with sonographic images of the duodenum had abnormalities in wall layering and thickness that may have indicated inflammatory bowel disease.

Although not statistically significant, cats with neutrophilic cholangitis had a tendency to have sonographic pancreatic changes, including diffuse enlargement and a hypoechoic parenchyma, which were suggestive of pancreatitis. This lack of significance may be related to the small sample size. With a larger group of affected cats, pancreatic changes could have provided a more definitive sonographic finding in patients with neutrophilic cholangitis; however, the sonographic diagnosis of pancreatitis in cats is challenging. Typical sonographic findings of pancreatitis include: an enlarged, hypoechoic pancreas; and hyperechoic surrounding mesentery, with or without the presence of free fluid. These changes may or may not be present in cats with pancreatitis and have been shown to have little correlation with histopathologically diagnosed pancreatitis.^27,28 It has been suggested that evaluating the feline pancreas for more subtle changes, such as pancreatic duct size, may be a more sensitive indicator for pancreatitis than the previously stated criteria.²⁸ Normal and age-related values for pancreatic duct size have been reported previously; however, abnormal values related to pancreatic disease have not been reported.^29,30 Recently, the pancreas in healthy and diseased cats was evaluated with power and color Doppler (with and without contrast enhancement). Cats with pancreatic disease had increased blood flow compared with healthy cats in all Doppler techniques.³¹

Four of the cats in the combined group had evidence of free abdominal fluid. Three of the cats were diagnosed with lymphocytic cholangitis, and the fourth cat with neutrophilic cholangitis. This is similar to findings in other studies in which cats with lymphocytic cholangitis were more likely to develop free abdominal fluid.¹⁴

There are several limitations to this study. The small sample size hampered statistical significance and contributed to individual variation. Due to the retrospective nature of the study, a standardized protocol was not formulated for image collection or reported findings. Additionally, different sonographers performed the studies introducing individual variability. Finally, some of the studies were partial abdominal examinations that did not include all of the organs analyzed in this study. In the future, a prospective, large-scale clinical trial with standardized sonographic examination and histologic samples of the liver, pancreas, and small intestine are needed to elucidate if any distinguishing features are present between lymphocytic and neutrophilic cholangitis.

Conclusion

The cholangitis complex continues to be a challenging disease to diagnose with ultrasound, and definitive changes for either neutrophilic or lymphocytic forms were not identified as statistically significant. However, in cats with neutrophilic cholangitis, there was a tendency to identify pancreatic changes consistent with pancreatitis. Additionally, gallbladder debris, common bile duct dilation, liver enlargement, and hyperechoic liver parenchyma are sonographic changes associated with either form of cholangitis. Further prospective studies with large clinical caseloads are needed to determine the significance of the sonographic changes identified in the pancreas and to make additional attempts to diagnose the subtypes of cholangitis with ultrasound.