Introduction

In humans, congenital pancreatobiliary maljunction is rare, and it increases the risk of cholangitis, biliary carcinoma, and pancreatitis.¹ The main possible cause of congenital biliary dilatation is pancreaticobiliary maljunction (PBM), wherein the main pancreatic duct and common bile duct are joined outside the duodenum without the sphincter of Oddi.¹ In PBM, the pancreatic juice readily flows back through the high-pressure pancreatic duct into the biliary tract, resulting in general cystic dilatation of the biliary system.^1,2 PBM is usually definitively diagnosed by endoscopic cholangiopancreatography based on the abnormal joining of the main pancreatic duct and common bile duct outside the duodenal wall. In addition, high pancreatic enzyme activity in the bile, caused by the reflux of pancreatic juice into the biliary tract, serves as a powerful auxiliary diagnosis.^1,3,4

In veterinary medicine, several cases of congenital biliary dilatation with cholangitis have been reported in cats; in these reports, as in those on humans, PBM involvement was suspected. However, the details were not provided and therefore remain unknown.^5–7 In cats, the main pancreatic duct often joins with the common bile duct within the wall of the duodenum, forming a single common duct that opens into the major duodenal papilla,⁸ and owing to their particular anatomical characteristics, cholangitis and pancreatitis are more frequent in cats than in dogs.⁹ Furthermore, studies have reported many feline cases of a tortuous path from the cystic duct to the common bile duct.¹⁰

In this study, we report the case of a young cat suspected of developing severe cholangitis associated with duodenal papillary stenosis, with PBM as the underlying disease.

Case Report

The authors declare that consent from the Institutional Animal Care and Use Committee was not needed. Consent for the procedure and publication of this case report was obtained from the cat’s owner.

A 1 yr old spayed female Scottish fold cat was presented for further investigation of acute hyporexia, vomiting, and diarrhea, which had started 3 days before the visit. Serum biochemistry test results showed severely elevated alanine aminotransferase (ALT) (987 U/L; reference interval 24–70 U/L) and aspartate aminotransferase (AST) (660 U/L: reference interval 10–24 U/L) activities and mildly elevated alkaline phosphatase (ALP) (126 U/L; reference interval 30–110 U/L) and γ-glutamyltransferase (GGT) (8 U/L; reference interval 0–8 U/L) activities and total bilirubin (TBil) (1.0 mg/dL; reference interval 0.1–0.3 mg/dL) levels. Abdominal ultrasonography revealed severe dilatation and tortuosity of the gallbladder, cystic duct, common bile duct, and hepatic ducts but no obvious bile duct obstruction (Figure 1A). Investigations raised suspicion for cholangitis; however, because of the cat’s critical condition and the perceived risks associated with bile sampling, empiric treatment was initiated as follows: Ringer’s acetate solution was administered IV at 3 mL/kg/hr, with subcutaneous enrofloxacin at 2.5 mg/kg once daily, maropitant citrate at 1 mg/kg once daily subcutaneously, and ursodeoxycholic acid at 10 mg/kg q 12 hr orally. Although the cat’s general condition showed slight improvement, no biochemical improvement was observed (ALT 989 U/L, AST 606 U/L, ALP 116 U/L, GGT 7 U/L, and TBil 0.9 mg/dL). Because of a lack of improvement, computed tomography (CT) was performed to assess for confounding factors. The results were similar to those of the ultrasound examination; intrahepatic and extrahepatic biliary ducts were severely dilatated and tortuous, but no definite common bile duct obstruction was observed (Figure 1B). Simultaneously, cholecystocentesis was performed under ultrasound guidance (Figure 1C), which was considered to be a large amount compared with the amount of bile secreted in healthy cats (0.3–4.5 mL).¹⁰ Bile cytology documented degenerated neutrophils, and bile culture was positive for Enterococcus faecium, which were susceptible to faropenem and resistant to enrofloxacin. Therefore, the treatment was switched to dosing of faropenem (5 mg/kg per os q 12 hr for 14 days). As a result, the liver enzyme activities and TBil levels (ALT 110 U/L, AST 45 U/L, ALP 80 U/L, GGT 4 U/L, and TBil 0.3 mg/dL) improved on the 14th day of faropenem administration (30th day of illness). However, these levels increased again on the 51st day of illness (ALT 756 U/L, AST 345 U/L, ALP 121 U/L, GGT 6 U/L, and TBil 1.0 mg/dL), and repeat ultrasonography documented ongoing biliary dilatation; therefore, further investigations were elected. Thus, treatment with faropenem was discontinued, and laparotomy was conducted on the 60th day of illness for a detailed examination and liver biopsy.

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At laparotomy, severely dilated and tortuous cystic duct, common bile duct, and hepatic duct were noted with severe cholestasis; however, definite common bile duct obstruction could not be determined macroscopically at this stage (Figure 1D). When the duodenum was incised to investigate bile duct obstruction at the duodenal papilla, severe enlargement and hyperemia of the major duodenal papilla were evident (Figure 1E). A 3-Fr feeding tube catheter^a was inserted through the major duodenal papilla, and a strong resistance to the catheter was noticed, possibly because of stenosis caused by inflammation in the area of the major duodenal papilla (Figure 2A). Thereafter, retrograde cholangiopancreatography was performed via the inserted catheter, and contrast imaging showed no obvious obstruction in the common bile duct but indicated that the main pancreatic duct and common bile duct seemed to be joined outside the duodenal wall (Figure 2B). Generally, the main pancreatic duct joins the common bile duct inside the duodenal wall and then opens into the major duodenal papilla in healthy cats (Figure 2C). However, the main pancreatic duct and common bile duct appeared to be abnormally joined outside the duodenal wall in this cat (Figure 2D). The morphological characteristics were suggestive of PBM. Furthermore, stenosis due to duodenal papillitis could have caused severe cholestasis. Therefore, a duodenal papilla incision was made to improve the excretion of the bile and pancreatic juice. First, an incision was made in the major duodenal papillary sphincter muscle with a sharp-edge scalpel (No. 11) along the catheter inserted during imaging tests. Thereafter, a curved mosquito forceps with a fine tip was inserted into the major duodenal papilla and expanded laterally, while the papillary outlet was widened enough to complete the procedure (Figure 1F). Subsequently, the duodenal incision was closed with simple interrupted sutures using 4-0 PDS^b. Finally, routine closure of the abdomen was performed without immediate complications. Results of the bacterial culture of the bile sample collected from the region near the common bile duct during surgery were negative. The pancreatic enzyme activity in the bile was measured, revealing bile amylase activity of 554 U/L (range <100–591 U/L) and bile lipase activity of 4670 U/L (range 18–754 U/L).¹¹ Liver histology collected at the time of surgery documented chronic, moderate, diffuse, lymphoplasmacytic neutrophilic cholangiohepatitis, proliferation of interlobular bile ducts, and bridging fibrosis in the portal vein region (Figure 2E). However, pancreatic biopsy revealed no obvious pancreatic abnormalities.

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Postoperative treatment included IV administration of Ringer’s acetate solution at 3 mL/kg/hr and cefmetazole (25 mg/kg IV q 8 hr) to prevent secondary bacterial infection due to potential intraperitoneal contamination from the duodenal incision site, along with mosapride citrate 0.5 mg/kg q 12 hr orally, and ursodeoxycholic acid 10 mg/kg q 12 hr orally. On the fourth postoperative day, the cat’s general condition improved, and cephalexin 25 mg/kg q 12 hr orally and ursodeoxycholic acid were prescribed before hospital discharge. On the 14th postoperative day (74th day of illness), a drastic improvement was noted in the dilatation of the biliary tract on ultrasonography, and serum biochemistry test results improved (ALT 167 U/L, AST 40 U/L, ALP 86 U/L, GGT 3 U/L, and TBil 0.5 mg/dL). Abdominal ultrasonography on the 143rd and 323rd days of illness showed mild biliary dilatation (Figure 2F), liver enzyme activity levels were normal, and the cat was in good condition. Therefore, only ursodeoxycholic acid was continued, and the cat’s condition was monitored.

Discussion

Feline cholangiohepatitis is a common disease, although cholangiohepatitis with severe biliary dilatation caused by congenital disease, as seen in the present case, has been reported in only a few cases in the past.^5–7 Furthermore, only one study has reported four cases of cats suspected of having congenital biliary dilatation while also being diagnosed with congenital biliary dilatation based on imaging and/or macroscopic findings.⁵ In that case report, PBM involvement was suspected, but cholangiopancreatography and biliary pancreatic enzyme activity analysis were not conducted.⁵ To the best of our knowledge, this is the first case report to document an association with pancreaticobiliary maljunction in a cat presenting with cholangiohepatitis. Cholangiopancreatography and levels of pancreatic enzyme activity in the bile were consistent with a diagnosis of PBM in humans.^1,3,4

In human medicine, endoscopic cholangiopancreatography is the main method for the definitive diagnosis of PBM, and it is necessary to use the confluence and show that the common duct is outside the duodenal wall.^1,4 Furthermore, the common duct within the duodenal wall is not enhanced because of the action of the sphincter of Oddi, and the boundary line (notch) between the common duct outside the duodenal wall and the duodenal wall itself is also needed for a more reliable diagnosis.¹² During cholangiopancreatography under laparotomy in our case, anastomosis between the main pancreatic duct and common bile duct was noted outside the duodenal wall, and the presence of PBM was strongly suspected (Figures 2B, D). In previous reports, the running patterns of the bile duct and pancreatic duct in humans and cats have been reported to be similar,^8,13 and cats have also been used as experimental models for PBM in humans.¹⁴ Further, in a report on cholangiopancreatography performed during autopsies to investigate the biliary morphology in healthy cats, the common bile duct was observed to penetrate the duodenal wall to join the main pancreatic duct and open at the main duodenal papilla, surrounded by the hepatopancreatic ampulla.¹⁰ Therefore, although there are few imaging findings, compared with the findings of that report, the confluence of the main pancreatic duct and common bile duct in our report was located outside the duodenal wall, which is very similar to the findings of PBM in humans. However, in the present case, it was difficult to identify the disease using CT and echography, and performing cholangiopancreatography during open surgery is not common because of its invasive nature.

Meanwhile, measurement of pancreatic enzymatic activity in the bile is relatively simpler than contrast imaging tests, and it is also used as a useful auxiliary diagnostic method for PBM in humans.^1,3 In human medicine, pancreatic enzymatic activity in the bile is usually evaluated by measuring amylase activity. The normal baseline bile amylase activity in humans is ≤1000 U/L,¹⁵ whereas in PBM, it is reported to be ≥10,000 U/L.¹⁶ A previous report has investigated the baseline pancreatic enzyme activity in the bile of healthy cats, but the method of measuring bile amylase activity is controversial.¹¹ In addition, although this report states that the range for bile amylase activity is <100–591 U/L and that for bile lipase activity is 18–754 U/L, only 1 animal out of 52 exhibited a bile amylase activity of 594 U/L and bile lipase activity of 754 U/L; thus, this case could be an outlier. Therefore, if the reference intervals for bile amylase activity and bile lipase activity were constructed according to the usual reference interval, with values including 95% of cases, the reference intervals for bile amylase and bile lipase activities would be <100–238 U/L and 18–58 U/L, respectively. Based on this information, the bile amylase and bile lipase activities in this case were higher than the reference intervals, with bile lipase activity (4670 U/L) being significantly higher. The values were comparable to the elevated levels of biliary pancreatic enzyme activity observed in human PBM, leading to a high suspicion of spontaneous PBM.

In PBM of humans, the “protein plug theory” explains the mechanism of biliary dilatation.¹² According to this theory, dissolved lithostathine in the pancreatic juice flows back into the bile duct, and simultaneously, insoluble lithostathine is formed by reacting with trypsin that has flowed back. The aggregation of this insoluble lithostathine forms a fibrous protein plug, which is then impacted in a narrowed duodenal papilla or common bile duct, increasing the pressure in the biliary duct. In addition, bacterial infection or the action of enterokinase damages the epithelium of the biliary and pancreatic ducts, and the entire biliary system becomes dilated, causing duodenal papillitis, cholangitis, cholelithiasis, pancreatitis, and, in severe cases, jaundice. In this case, Enterococcus faecium were detected in the bacterial culture of a bile sample obtained during a CT scan. When faropenem was administered, liver enzyme activities levels temporarily improved. However, liver enzyme activities levels subsequently increased again despite continuing faropenem. Therefore, considering the possibility that an underlying disease caused recurrent biliary dilatation and cholangitis, we performed a laparotomy and discovered a stricture due to duodenal papillitis. At the same time, cholangiopancreatography was performed during surgery, and the morphology of the confluence of the main pancreatic duct and common bile duct was suggestive of PBM. Furthermore, because the biliary pancreatic enzyme activity was found to be abnormally high, we assumed that in this case, reflux of pancreatic juice into the biliary tract because of PBM may have caused stenosis due to duodenal papillitis, resulting in severe cholestasis and consequently in the development of severe biliary dilatation and cholangitis.

In human medicine, extended extrahepatic bile duct resection and hepatic duct-jejunostomy are the current standard treatments for PBM.³ However, because of the small size of cats, this procedure is considered technically difficult. A previous report in which six cats with bile duct obstruction due to cholangiohepatitis underwent Oddi sphincterotomy demonstrated a favorable postoperative course with an improvement in bile excretion.¹⁷ Therefore, in this case, a duodenal papillotomy was performed, the dilatation of the biliary tract improved, and the patient progressed well; additionally, liver enzyme activities did not increase after surgery. In addition, this procedure may have unclogged the protein plug, facilitated drainage of pancreatic juice into the duodenum, and reduced the backflow of pancreatic juice into the biliary tract. However, more cases consistent with PBM are necessary to determine whether this method of therapy is effective in both the short and long term.

Conclusion

When cholangitis with severe biliary dilatation is observed in a young cat, anatomic abnormalities such as PBM should also be considered as a contributing factor, and cholangiopancreatography may be necessary for definitive diagnosis. Measurement of biliary pancreatic enzymatic activity might also be a useful screening test for this disease. In the future, we plan to measure biliary pancreatic enzymatic activity in cats with cholangitis accompanied by biliary dilatation and, if possible, conduct cholangiopancreatography to investigate its relationship with PBM.

The authors thank Editage (www.editage.com) for English language editing. The authors received no financial support for the research, authorship, and/or publication of this article.