Gallbladder Agenesis in a Patient With Klinefelter Syndrome Presenting With Hematemesis and Right Upper-Quadrant Pain

Introduction

Gallbladder Agenesis (GA) is a rare congenital anomaly (10–65 per 100 000) resulting from failed cystic bud development or canalization during weeks 4–7 of embryogenesis [1]. It is more common in females (3: 1) and may be mistaken for a contracted gallbladder or prior cholecystectomy when surgical history is unclear [1]. While many remain asymptomatic, up to 50% develop postprandial right upper-quadrant pain [1]. GA can mimic biliary colic or cholecystitis, often leading to unnecessary surgical exploration [1–3]. This may result from increased sphincter of Oddi pressure due to compensatory bile storage in intrahepatic ducts. Although fibrosis and inflammation can obscure the diagnosis, recognition has improved with modern imaging. Ultrasound may be used to initially assess biliary colic but is unreliable and operator-dependent. Diagnosis of GA can be made after hepatobiliary iminodiacetic acid scan (HIDA), magnetic resonance cholangiopancreatography (MRCP), or computed tomography, and management consists of conservative treatment and antispasmodics.

Klinefelter syndrome is a genetic syndrome with a prevalence of 1 in 500 to 1 in 1000 males and is characterized by the presence of 2 or more X chromosomes in a phenotypic male on chromosome karyotype analysis [4]. Symptoms of Klinefelter syndrome include tall stature, gynecomastia, azoospermia, and small testes [4].

Though typically sporadic, GA has been reported in familial clusters, suggesting a possible genetic component [5,6]. It has been reported with syndromes such as cerebrotendinous xanthomatosis, G syndrome, trisomy 18, Klippel-Feil syndrome, and thalidomide exposure [7]. An association of GA with Klinefelter syndrome is undocumented but merits exploration. This report describes the case of a 38-year-old man presenting with hematemesis and right upper-quadrant pain with a diagnosis of GA.

Case Report

A 38-year-old man with known Klinefelter syndrome (47, XXY) and no history of abdominal surgery presented with 5 days of dark-red-to-brown hematemesis, lightheadedness, and right upper-quadrant pain. He denied NSAID, tobacco, or alcohol use. No other developmental or genetic abnormalities were identified, and his family history was negative for hepatobiliary disease. A physical exam showed mild epigastric tenderness in the right upper quadrant, without bruising or jaundice.

Laboratory evaluation showed mild transaminitis with AST 86 U/L (10–40 U/L), ALT 117 U/L (7–56 U/L), normal total bilirubin 0.84 mg/dL (0.1–1.2 mg/dL), direct 0.3 mg/dL, and indirect 0.52 mg/dL. Alkaline phosphatase was 152 U/L (44–147 U/L), GGT 385 U/L (9–48 U/L), and ferritin 503 ng/mL (24–336 ng/mL). Hemoglobin was stable at 12.9 g/dL (13.5–17.5 g/dL).

Imaging studies included a computed tomography angiography (CTA), which demonstrated hepatic steatosis, mild splenomegaly, and absence of the gallbladder fossa, without evidence of varices, portal hypertension, or active bleeding. Esophagogastroduodenoscopy (EGD) showed mild antral gastritis and a small hiatal hernia, but no active bleeding. A hepatobiliary iminodiacetic acid (HIDA) scan revealed normal biliary flow without gallbladder visualization. The absence of the gallbladder was corroborated on ultrasound, CTA (Figure 1), and MRCP (Figure 2). CTA was prioritized over ultrasound to evaluate hematemesis and possible vascular causes; subsequent multimodal imaging confirmed congenital agenesis and avoided unnecessary surgical exploration. The patient was discharged in stable condition with hepatology follow-up after resolution of his abdominal pain and hematemesis.

Discussion

Gallbladder agenesis (GA) is frequently diagnosed intraoperatively as opposed to preoperatively; therefore, meticulous history-taking and awareness of this anomaly are essential to prevent misdiagnosis [1–3,7,8]. GA can manifest with biliary-type pain despite the absence of a gallbladder, often mimicking cholecystitis or biliary colic. Misinterpretation of such presentations can lead to unnecessary surgical exploration resulting in surgical risk to the biliary tree, hepatic vasculature, and small bowel during exploration. In this case, hematemesis prompted diagnostic imaging that incidentally revealed GA, underscoring the importance of maintaining a broad differential diagnosis when typical and atypical gastrointestinal symptoms coexist.

Accurate diagnosis of GA relies on a multimodal imaging approach, with MRCP regarded as the gold standard [9]. If only a HIDA scan and endoscopic retrograde cholangiopancreatography had been performed, a cystic duct obstruction would have been assumed [9]. CTA and ultrasound served complementary roles in confirming the anatomic absence of the gallbladder and assessing associated biliary structures. In this patient, no visualization of the gallbladder on MRCP established the diagnosis of congenital agenesis and prevented misclassification as other biliary etiology.

Earlier recognition might have been achieved if the absence of the gallbladder had been identified on initial CTA interpretation or if ultrasound had been employed as the first-line modality. The patient underwent a multiday hospitalization for comprehensive evaluation but ultimately avoided unnecessary laparoscopic exploration and was managed conservatively. The etiology of hematemesis remains unclear.

While no causal relationship between GA and hematemesis has been described underrecognized biliary or gastric hemorrhage may be involved. The patient’s hematemesis resolved spontaneously and could not be explained by findings on EGD or CTA. There are few documented associations between biliary tract anomalies and upper-gastrointestinal bleeding. The literature on hemobilia suggests that most cases stem from rupture of atherosclerotic aneurysms of the right hepatic artery into the biliary ductal system – a condition that would have been readily identified on CTA [10].

There are no previously reported cases of Klinefelter syndrome presenting with GA, raising the question of whether a subtle developmental correlation exists between this patient’s relatively common chromosomal disorder and his atypical presentation with hematemesis. Alternatively, the coexistence of these findings may be coincidental, as the embryologic origins of Klinefelter syndrome and GA are distinct – one arising from chromosomal nondisjunction and the other from structural failure of the caudal hepatic diverticulum. Nevertheless, hepatobiliary anomalies often exist in individuals with Klinefelter syndrome. The presence of GA in this context may therefore broaden the phenotypic spectrum of hepatobiliary manifestations associated with sex-chromosome aneuploidy, reflecting a potential influence of aberrant chromosomal balance on endodermal organogenesis.

The presence of hepatic steatosis in this patient may reflect metabolic features of Klinefelter syndrome rather than direct consequence of GA, as approximately 45% patients with Klinefelter syndrome experience metabolic dysfunction-associated steatotic liver [11].

Conclusions

Gallbladder agenesis should be considered in patients with biliary-type symptoms and absent gallbladder visualization, especially without prior cholecystectomy. Diagnosis relies on clinical evaluation and multimodal imaging – most definitively MRCP – to prevent unnecessary surgical exploration. This case is notable for its atypical presentation with hematemesis, which led to the incidental discovery of gallbladder agenesis, and raises the possibility of a previously unrecognized association with Klinefelter syndrome.