Introduction

Gallbladder agenesis (GA) is an extremely rare condition in dogs, with only three cases previously reported in the English veterinary literature. The condition has been reported in two young Maltese and in one Chihuahua.^1–3 GA is also a rare condition in humans with a prevalence range of 0.007–0.13%.⁴ In humans, GA arises as a result of abnormal development of the cystic bud during early fetal development. This occurs as an isolated abnormality in 70–82% of cases or in association with other biliary or distant developmental anomalies in 12.8–30% of cases.⁴ The gold standard for diagnosis in humans is an area of debate; however, one study has shown computed tomography (CT) to be the most accurate diagnostic test.⁵ To the authors’ knowledge, this is the first case report in the English literature that describes the condition in a young, asymptomatic dog for whom clinicopathological, liver histopathology, and CT findings are available.

Case Report

A 15 mo old male intact French bulldog weighing 9 kg was presented to the referring veterinarian (M.M) for castration and surgical correction of brachycephalic upper-airway syndrome. The dog was otherwise clinically normal with no signs of disease potentially attributable to the hepatobiliary system. The physical examination was unremarkable, and the dog was in good body condition. Preanaesthetic biochemistry showed a marked elevation in alanine aminotransferase (ALT) concentrations (853 U/L, reference range 10–125 U/L) and a mild elevation in alkaline phosphatase concentrations (229 U/L, reference range 23–212 U/L). The remainder of the biochemistry and complete blood count was unremarkable. Pre- and postprandial bile acids were 9 umol/L and <5 umol/L (reference range <12 umol/L), respectively. S-adenosylmethionine^a was prescribed, and repeat biochemistry performed 7 days later showed persistently elevated ALT concentrations (587 U/L). Biochemistry was repeated after 4 wk and a further increase in ALT concentration was detected (636 U/L). As the dog remained asymptomatic, no further investigations were performed, but repeat biochemistry was performed after another 4 wk. ALT concentrations had increased further (>1000 U/L), and alkaline phosphatase concentrations remained slightly elevated (227 U/L); as such, further investigation was deemed warranted.

The dog was anesthetized, and laparoscopic liver biopsies taken and submitted for histopathology. The biopsy samples were evaluated by a board-certified veterinary pathologist and showed marked, multifocal portal fibrosis with bile duct hyperplasia and vascular proliferation (Figure 1). The hepatocytes were considered unremarkable, and a sparse inflammatory cell infiltrate of lymphocytes, plasma cells, and neutrophils was present.

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Based on the histopathology findings, the dog was referred for further investigation and diagnostic imaging. Both CT and ultrasonography were offered to the owner. Upon considering the advantages and disadvantages of both imaging modalities, it was decided to pursue CT given its superior sensitive for detecting congenital malformations, particularly vascular anomalies. Abdominal CT was performed 3 wk following the laparoscopy procedure under general anesthesia using a 64-slice CT^b scanner with the patient positioned in sternal recumbency. Data were obtained using the following parameters: slice thickness of 1.5 mm, 1.2 mm reconstruction interval, 512 × 512 matrix, a pitch factor of 0.6, gantry rotation speed of 0.6, 150–180 mA, 110 kVp, and 179 mm display field of view. The postcontrast series were taken after intravenous administration of 2 mL/kg of iodinated nonionic contrast agent^c using a power injector^d at 3 mL/s. The scan delay was determined by bolus tracking, placing the region of interest at the descending aorta just cranial to the diaphragm. Tracking of the Hounsfield Units was started immediately after the start of contrast injection. After 150 Hounsfield Units were reached within the aorta, the scan started after a 10 s delay, running in a craniocaudal direction, including the abdomen from the level of the 10th thoracic vertebra to level of the fifth lumbar vertebra. The venous phase started ∼60 s from the start of the intravenous contrast injection. The venous phase extended from the level of the 9th thoracic vertebra to the caudal aspect of the ischium in a craniocaudal direction. The images were reconstructed using bone and soft tissue algorithms and were evaluated using DICOM viewer software^e. The image width and level were adjusted as needed. Multiplanar reconstructions of the abdomen were performed in order to evaluate the portal vasculature. All images were reviewed by a board-certified veterinary radiologist. The CT study revealed the absence of an identifiable gallbladder at its normal location between the right medial and quadrate liver lobes (Figure 2A). The biliary ducts appeared mildly distended and could be followed to their termination in the cystic duct and common bile duct (Figure 2A). The common bile duct was mildly dilated (∼5 mm at its widest diameter) with no evidence of abnormal contents and could be followed to its termination in the duodenal papilla (Figure 2B). The liver was normal in size and shape with normal attenuation. The intrahepatic vasculature appeared unremarkable. In the postcontrast series, a very small vessel arising from the cranial aspect of the gastric fundus could be followed into the phrenic vein. The remaining viscera were within normal limits. The findings were suggestive of GA, mild dilation of the common bile duct and biliary ducts (of unknown origin), and a gastro-phrenic shunt. Given the size of the vessel (presumably shunting a small volume of blood) and the site of drainage (gastric fundus rather than small intestine), this communication was considered to be clinically irrelevant.

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The dog remained clinically asymptomatic over the course of the investigations and recovered uneventfully from anesthesia. It was advised that the previously prescribed s-adenosylmethionine be continued and that ursodeoxycholic^f acid be started along with avoiding high-fat foods. Follow-up data attained from the referring veterinary practice confirmed that the dog remains clinically asymptomatic, 8 mo following investigations.

Discussion

GA appears to be a rare condition in humans and extremely rare in dogs. In dogs, the liver and gallbladder develop from a ventral diverticulum of the foregut. This diverticulum gives rise to cranial (hepatic) and caudal (cystic) parts, with the caudal part of the hepatic diverticulum forming the gallbladder, and cystic duct and the cranial part forming the liver and intrahepatic bile ducts.⁶ Two theories have been proposed in the human literature as to how this anomaly occurs. The first suggests that the hepatic diverticular bud fails to develop into the cystic duct and gallbladder, whereas the second proposes that there is failure of recanalization of the cystic duct and gallbladder during solid-phase development.⁷ GA occurs as an isolated anomaly in 70–2% of human cases. Of those cases in which another developmental anomaly occurs, 9% have atresia of the bile ducts or other abnormalities of the biliary tree, whereas infants with multiple distant anomalies account for another 12.8–21%.⁴ Cases of GA diagnosed in infants have been associated with concurrent malformations affecting the cardiovascular, gastrointestinal, genitourinary, and skeletal systems, and these cases are often incompatible with life.⁸

When diagnosed, human patients are divided into one of three groups: asymptomatic (35%), symptomatic (50%), and in children with multiple developmental anomalies (15%).⁹ The most commonly reported symptoms are right upper-quadrant pain (90%), nausea and vomiting (66%), intolerance of high-fat foods (37%), jaundice (35%), and dyspepsia (30%).¹⁰ The cause of symptoms is assumed to be because of concurrent biliary pathology such as choledocholithiasis or biliary dyskinesia.⁸

GA is reported to be commonly misdiagnosed as cholelithiasis, cholecystitis, or sclero-atrophic gallbladder in humans based on ultrasonographic findings. It has been thought that the aforementioned biliary pathologies can cause an inability to visualize the gallbladder as a result of excessive contraction in some patients, with these patients subsequently diagnosed with GA during unnecessary surgery.⁴ Multiple imaging modalities have been used in humans with clinical signs attributable to biliary disease including ultrasonography, CT, magnetic resonance cholangiography (MRC), and endoscopic retrograde cholangiopancreatography. Ultrasonography is the modality of choice in humans to detect biliary stones, the main differential for GA, with a reported sensitivity between 95 and 98% and an accuracy of 61–100% depending on changes seen.¹¹ Endoscopic retrograde cholangiopancreatography is associated with significant morbidity and mortality in humans and an inability to visualize the gallbladder is often misinterpreted as occlusion of the cystic duct.⁴ One study has suggested MRC to be the most useful imaging modality, whereas another has shown CT to be the most successful modality at making the correct preoperative diagnosis.^5,12

In the previous three cases reported, the diagnosis was confirmed in each dog during exploratory laparotomy.^1–3 To the authors’ knowledge, this is the first report that includes CT findings in a dog with GA. It has recently been recommended in humans that should the gallbladder not be visualized on ultrasonography, either CT or MRC should be pursued as the next diagnostic step.¹³

The dog reported here has remained asymptomatic. Two of the previously reported dogs were symptomatic, with one presenting for vomiting and retching and the other for vomiting and anorexia.^1,2 The dog in this case was investigated for persistent elevations in ALT concentrations. This finding along, with variable elevations of other hepatobiliary enzymes, was also reported in the previous three cases. The cause of the reported clinical signs and elevated enzyme concentrations in dogs remains unknown, but secondary cholangiohepatitis or cholestasis have been suggested.² In this case, CT showed mild distension of the intrahepatic and common bile ducts, and retrograde cholangiography performed in one of the previously reported cases showed distension of the common bile duct.³ This could be suggestive of cholestasis or a compensatory storage mechanism for bile. Liver histopathology in this case showed a mild, mixed inflammatory cell population, a finding not reported in the two previous cases for which histopathology was available. This could be considered supporting evidence for a secondary cholangiohepatitis. Dilation of the bile ducts and biliary dyskinesia with associated elevated sphincter of Oddi pressure have also been reported in humans with GA and sphincterotomy has successfully relieved clinical symptoms in a small number of patients.^14,15 Reflux of pancreatic and/or duodenal contents as a result of elevated sphincter of Oddi pressure and associated increased retrograde phasic muscular contractions may predispose to cholangiohepatitis.⁸

Concurrent abnormalities affecting the liver have been reported in two dogs with GA. The quadrate lobe was malformed in one dog, and the right medial and lateral lobes were reduced in size in the other.^2,3 In both cases. the authors hypothesized that these changes were congenital and may reflect abnormal development of both the pars hepatica and pars cystica during early embryonic development. The liver parenchyma appeared normal on CT and during laparoscopy in this case, but histopathology showed changes remarkably similar to those described in the two previous cases. Histopathology of the liver in all three dogs showed bridging fibrosis and bile duct hyperplasia. These changes are consistent with congenital hepatobiliary malformation.¹⁶

As mentioned earlier, a number of humans with GA show an improvement in clinical symptoms following sphincterotomy. However, the majority are treated symptomatically, with smooth muscle relaxants and analgesics being effective.¹⁷ In asymptomatic cases, no treatment is recommended and the condition carries an excellent prognosis.⁸ Treatment recommendations in dogs have thus far been empirical. Drugs thought to support normal liver function and guard against damage caused by a secondary hepatopathy have been prescribed along with the recommendation that a low-fat diet be fed.^1–3 In this case, it was recommended that s-adenosylmethionine be continued as it has recently been shown to have protective effects against oxidative and inflammatory induced cell damage in canine hepatocytes.¹⁸ Treatment with ursodeoxycholic acid was started for its proposed choleretic effects and ability to prevent apoptosis in hepatocytes.¹⁹ No specific dietary modifications were made, although it was suggested that the owner avoid feeding high-fat treats. This recommendation was made as 37% of symptomatic human patients appear intolerant of fatty foods.¹⁰ The benefit of feeding a low-fat diet is questionable as it has been shown in humans following cholecystectomy that adaptive changes occur to compensate for the lack of a gallbladder including increased daily circulation of bile salts.²⁰

Conclusion

GA appears to be an extremely rare condition in dogs, and until more cases with long-term follow-up are described, the prognosis remains unknown. The histopathology findings are consistent with a congenital abnormality, and there is evidence to suggest that secondary cholestasis or cholangiohepatitis may contribute to the clinical and clinicopathological findings. The condition should be considered as a differential in symptomatic and asymptomatic dogs presenting with elevations in hepatobiliary enzymes and in whom ultrasonography fails to visualize the normal gallbladder. Advanced imaging such as CT should be considered to confirm or refute the diagnosis. Although no treatment is recommended in asymptomatic humans, it seems reasonable to recommend that dogs be treated with hepatoprotective agents in an attempt to ameliorate any potential secondary sequelae.