Gilbert syndrome masked by recurrent choledocholithiasis: A case report

Abstract

BACKGROUND

Gilbert syndrome (GS) is a common hereditary condition characterized by unconjugated hyperbilirubinemia due to reduced uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) activity. Although GS is traditionally considered benign, its association with biliary tract disease is increasingly recognized.

CASE SUMMARY

We report a case illustrating the diagnostic challenge of GS masquerading as refractory cholestatic liver disease. A 40-year-old man with an 18-year history of intermittent jaundice developed recurrent obstructive jaundice caused by common bile duct stones. Despite three endoscopic retrograde cholangiopancreatography procedures, hyperbilirubinemia persisted. Liver biopsy demonstrated cholestatic hepatitis, and whole-genome sequencing identified a homozygous UGT1A1 missense variant, confirming GS complicated by secondary choledocholithiasis. Following complete ductal clearance and longitudinal follow-up, bilirubin levels returned to baseline.

CONCLUSION

This case highlights the importance of recognizing GS in recurrent biliary obstruction to avoid unnecessary invasive procedures.

Key Words: Gilbert syndrome; UGT1A1; Choledocholithiasis; Pigment stones; Recurrent; Case report

Core Tip: Gilbert syndrome (GS) is generally regarded as a benign hereditary disorder, but its role in pigment stone formation and recurrent biliary disease may be underestimated. This case demonstrates that GS can be masked by recurrent choledocholithiasis and prolonged obstructive jaundice, leading to diagnostic uncertainty and repeated interventions. Recognition of the interaction between impaired bilirubin metabolism and biliary obstruction is essential. Genetic confirmation of GS in selected patients with unexplained persistent hyperbilirubinemia may help guide individualized management and avoid unnecessary invasive procedures.

INTRODUCTION

Gilbert syndrome (GS) is the most common inherited disorder of bilirubin metabolism, characterized by intermittent unconjugated hyperbilirubinemia caused by reduced uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) activity[1]. Although traditionally considered a benign condition, accumulating evidence suggests that altered bilirubin metabolism in GS may increase susceptibility to pigment gallstone formation. However, GS presenting with recurrent choledocholithiasis and persistent severe jaundice remains uncommon and may create diagnostic challenges. This article reports a rare case of GS masked by recurrent choledocholithiasis, highlighting the importance of individualized and comprehensive etiological assessment to guide clinical decision-making and avoid unnecessary invasive procedures.

CASE PRESENTATION

Chief complaints

A 40-year-old man presented with an 18-year history of recurrent jaundice, with marked worsening over the preceding two months.

History of present illness

Two months before admission (September 2024), he developed transient fever and recurrent jaundice after ingestion of barbecued meat, resulting in four consecutive hospitalizations (Figure 1).

Figure 1 Dynamic changes of bilirubin during the course of the patient's illness. DBIL: Direct bilirubin; TBIL: Total bilirubin.

Given the discrepancy between the patient’s long-standing indirect hyperbilirubinemia and the current obstructive pattern, a third endoscopic retrograde cholangiopancreatography (ERCP) was performed in combination with liver biopsy and whole-genome sequencing.

History of past illness

Seven years earlier, he underwent laparoscopic cholecystectomy for cholelithiasis and cholecystitis. Persistent hyperbilirubinemia was noted postoperatively, but no further evaluation was performed because he remained asymptomatic.

Physical examination

His vital signs remained stable throughout the course of his illness. Upon admission, he had jaundice of the skin and sclera, but physical examination of the heart, lungs, and abdomen revealed no obvious abnormalities, and there was no edema in his lower extremities.

Laboratory examinations

At initial onset, total bilirubin (TB) was approximately 60 μmol/L, predominantly indirect.

Initial laboratory (during the first hospitalization) tests showed mild aminotransferase elevation (alanine aminotransferase: 188 U/L; reference range: 7-40 U/L; aspartate aminotransferase: 61 U/L; reference range: 13-35 U/L), marked cholestatic enzyme elevation (alkaline phosphatase: 205 U/L; reference range: 35-100 U/L; γ-glutamyl transferase: 1380 U/L; reference range: 7-45 U/L), and severe hyperbilirubinemia with direct predominance (TB: 240.2 μmol/L; reference range: 1.7-20 μmol/L; direct bilirubin: 152.3 μmol/L; reference range: 0-6 μmol/L). Inflammatory markers were elevated. Extensive evaluation, including viral hepatitis serologies, autoimmune markers, immunoglobulins, IgG4, ceruloplasmin, and tumor markers, was unremarkable.

However, bilirubin levels further increased, peaking at 523.7 μmol/L. Although bilirubin initially declined (384.3 μmol/L), it rebounded (416.1-464.7 μmol/L), and repeat imaging again demonstrated mid-common bile duct (CBD) stones. However, bilirubin levels fluctuated and remained markedly above the normal range (TB: 443.1 μmol/L to 459.2 μmol/L to 373.7 μmol/L to 324.8 μmol/L).

Liver biopsy showed marked cholestasis with bile thrombi, hepatocellular degeneration, and bile duct injury, consistent with cholestatic hepatitis (Figure 2). Whole-genome sequencing identified a homozygous uridine diphosphate-glucuronosyltransferase (UGT1A1) missense variant (NM_000463.3: C.211G>A, p.Gly71Arg), which was confirmed by Sanger sequencing and determined to be inherited from both parents (Figure 3).

Figure 2 Representative histopathological findings of the liver biopsy. A: Hematoxylin and eosin staining showed preserved hepatic plate architecture, prominent intrahepatocellular and canalicular cholestasis with bile thrombi, hepatocellular swelling and degeneration, and focal spotty necrosis; B: Cytokeratin 7 immunostaining highlighted biliary epithelial and ductular changes, supporting bile duct injury in a cholestatic pattern.

Figure 3 Genetic analysis of the UGT1A1 mutation. Pedigree showing biparental inheritance of the c.211G>A variant. Sanger sequencing chromatograms confirming homozygosity in the proband (c.211A/A) and heterozygosity in both parents (c.211G/A).

Imaging examinations

At the first hospital, an abdominal computed tomography (CT) revealed dilatation of the intra- and extrahepatic bile ducts, while magnetic resonance cholangiopancreatography (MRCP) reportedly demonstrated a CBD diameter of approximately 0.9 cm and a nodular hypointense lesion measuring approximately 1.6 cm × 1.0 cm in the distal CBD; however, the original electronic imaging data were unavailable for review. Repeat abdominal CT at our hospital demonstrated pneumobilia in the intrahepatic bile ducts and dilatation of the portal vein. MRCP continued to show multiple filling defects in the hepatic ducts and CBD, with the largest measuring 5.2 mm in diameter (Figure 4).

Figure 4 Abdominal computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography findings before third endoscopic retrograde cholangiopancreatography. A: Axial abdominal computed tomography shows pneumobilia in the intrahepatic bile ducts and dilatation of the portal vein; B: Axial abdominal magnetic resonance imaging shows multiple hypointense intraductal lesions within the hepatic ducts and common bile duct (CBD), with the largest measuring approximately 5.2 mm in diameter; C: Coronal maximum-intensity projection magnetic resonance cholangiopancreatography demonstrates multiple intraductal filling defects involving the hepatic ducts and CBD, extending over a longitudinal length of approximately 66.68 mm.

FINAL DIAGNOSIS

These findings established the diagnosis of GS complicated by secondary choledocholithiasis, with imaging and histopathology further supporting cholestatic hepatitis.

TREATMENT

Percutaneous transhepatic biliary drainage was performed because ERCP was not available at the first hospital. At a second hospital, ERCP was performed, during which multiple CBD stones were removed and a nasobiliary drain was placed. A second ERCP at our center extracted multiple pigment stones, and no evidence of a mass lesion was observed. A third ERCP revealed black mucinous material, and cholangiography confirmed complete ductal clearance. After being discharged from the hospital, he was treated with oral ursodeoxycholic acid.

OUTCOME AND FOLLOW-UP

At six-month follow-up, serum bilirubin levels had returned to baseline.

DISCUSSION

GS is caused by reduced UGT1A1 activity, resulting in impaired bilirubin conjugation and chronic unconjugated hyperbilirubinemia. Although generally considered benign, GS may predispose patients to pigment gallstone disease[1]. Bile in GS contains an increased proportion of bilirubin monoglucuronides, which are more susceptible to bacterial β-glucuronidase-mediated hydrolysis[2]. The released unconjugated bilirubin readily precipitates with calcium, promoting pigment stone formation, particularly in the presence of biliary stasis or infection[3,4].

Previous studies report gallstone prevalence rates of approximately 9% in patients with GS[5], with brown pigment stones most commonly observed[4]. Genetic studies further support this association, demonstrating increased gallstone risk in carriers of UGT1A1 polymorphisms, especially when combined with variants affecting biliary transport[6,7].

Recurrent or reappearing CBD stones after cholecystectomy are generally considered to be multifactorial. Reported risk factors include CBD dilatation, periampullary diverticulum, altered bile duct angulation, multiple or large stones, biliary stent placement, repeated ERCP, biliary infection, and bile stasis. In the present case, no single factor fully explained the rapid reappearance of bile duct stones. GS may have provided a metabolic background favorable for pigment stone formation by increasing the bilirubin load in bile. In addition, the presence of multiple bile duct stones, cholestatic hepatitis, repeated biliary interventions, and possible biliary bacterial colonization may have collectively promoted bile stasis, bilirubin deconjugation, calcium bilirubinate precipitation, and pigment-rich biliary sludge formation[4,8].

It is important to distinguish recurrent stones from retained stones. In many studies, bile duct stones detected within 6 months after ERCP are more commonly considered residual or retained stones rather than true recurrent stones. In this patient, however, complete duct clearance after the second ERCP was confirmed by repeated balloon sweeping and occlusion cholangiography, which demonstrated no residual filling defects and good contrast drainage into the duodenum. Therefore, although retained stones cannot be absolutely excluded, the subsequent rapid appearance of obstructive black mucus-like material was considered more consistent with newly formed pigment-rich biliary sludge or early pigment stone formation in a highly lithogenic biliary environment.

Importantly, GS complicates interpretation of postoperative or postprocedural hyperbilirubinemia. The median serum TB level in GS is approximately 3.3 mg/dL (56.43 μmol/L), with peak levels reaching up to 18 mg/dL (307.8 μmol/L)[9]. When additional contributing factors are present, TB levels in GS patients can escalate to as high as 660.3 μmol/L[10]. Transient bilirubin elevation related to fasting, hemolysis, febrile illness, menstruation, strenuous exercise, drugs that interact with the UGT1A1 pathway or contrast exposure[10-13]. These may mimic recurrent obstruction, increasing the risk of unnecessary invasive procedures. Early recognition of GS, ideally through genetic testing, is therefore critical.

GS is caused by impaired hepatic bilirubin-glucuronic acid conjugation, with UGT1A1 activity reduced to approximately 30%-50% of normal, resulting in limited bilirubin clearance and a reduced transport maximum[14]. Patients exhibit a lower hepatic bilirubin clearance rate and transport maximum, reflecting reduced sinusoidal uptake and diminished glucuronidation capacity[15]. Within 48 hours of reducing daily caloric intake to 400 kcal, serum bilirubin can double or triple[12,16]. Proposed mechanisms include enhanced enterohepatic bilirubin cycling, decreased availability of the cosubstrate uridine-5′-diphospho-glucuronic acid, and mobilization of bilirubin from adipose tissue[17-19]. These pathophysiological mechanisms likely account for the delayed and fluctuating decline in serum bilirubin observed in some patients with GS, including the current case.

Management should be individualized. ERCP remains the treatment of choice for acute obstruction or cholangitis, but repeated procedures should be avoided when possible. In stable patients without clear evidence of obstruction, noninvasive imaging and biochemical monitoring may help distinguish true stone recurrence from GS-related hyperbilirubinemia. However, in selected cases of intractable recurrence, surgical interventions, including biliary bypass procedures, may be considered to reduce the frequency of endoscopic treatment[20,21].

CONCLUSION

In conclusion, although GS provides a metabolic milieu conducive to pigment stone formation, the risk of recurrent choledocholithiasis is predominantly determined by biliary anatomy and infection. Optimal management requires balancing timely endoscopic intervention for acute events with prudent avoidance of unnecessary repeat procedures, complemented by lifestyle modification and preventive strategies tailored to patients with GS.

ACKNOWLEDGEMENTS

The authors sincerely thank Dr. Ke Wang from the Department of Radiology of Peking University First Hospital, for her assistance in reviewing and confirming the imaging findings, and Dr. Li Liang from the Department of Pathology of Peking University First Hospital, for her valuable support in verifying the pathological images presented in this case report.