Gallstone disease is one of the most prevalent disorders of the hepatobiliary system worldwide, with cholelithiasis affecting a substantial proportion of adults and contributing meaningfully to surgical admissions and healthcare costs [1,2]. Although many patients remain asymptomatic, cholelithiasis can progress to complications, including acute cholecystitis, pancreatitis, and choledocholithiasis [3,4]. Common bile duct (CBD) stones are clinically crucial because missed stones can precipitate biliary obstruction, cholangitis, and pancreatitis, and may increase postoperative morbidity after cholecystectomy [5]. Choledocholithiasis may be symptomatic or clinically silent. Asymptomatic CBD stones are frequently overlooked during routine preoperative work-up, particularly when jaundice, cholangitis, or pancreatitis are absent. Undetected stones at the time of cholecystectomy are associated with adverse outcomes, including retained stones, bile leak, recurrent biliary events, and re-intervention [6]. This underscores the importance of preoperative risk stratification, particularly in settings where universal advanced imaging is not feasible. Diagnostic pathways for suspected CBD stones include transabdominal ultrasonography, MRCP, EUS, and ERCP. Ultrasound is widely available but has limited sensitivity for CBD stones, especially small or distal stones [7]. MRCP provides high diagnostic accuracy but may be limited by cost and access [8]. EUS has excellent sensitivity for small CBD stones and is often used to confirm stones prior to therapeutic ERCP, which is now primarily reserved for intervention due to its complication profile [9,10]. Current society guidance supports selective use of EUS/MRCP and ERCP based on clinical and biochemical risk stratification [11,12]. Cholestatic liver enzymes—particularly gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP)—rise with biliary obstruction and have been evaluated as accessible predictors of choledocholithiasis [13,14]. Mei et al. reported improved diagnostic performance when GGT and ALP were used in combination to predict asymptomatic choledocholithiasis in patients with cholelithiasis [14]. However, prospective data from Indian clinical settings remain limited. This study, therefore, aimed to evaluate serum GGT and ALP as predictors of asymptomatic choledocholithiasis in patients with cholelithiasis and to assess perioperative trends in these markers following intervention.

This prospective observational study was conducted in the Department of General Surgery at Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, over 18 months. Adult patients admitted with a diagnosis of cholelithiasis were screened for eligibility. Ethical approval was obtained from the Institutional Ethics Committee, and written informed consent was secured from all participants prior to enrolment. Patients aged 18-75 years with ultrasonography-confirmed cholelithiasis were included in the study if they had elevated cholestatic liver enzymes, specifically serum gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP). Only patients who were clinically asymptomatic with respect to choledocholithiasis—that is, without features of jaundice, cholangitis, or biliary pancreatitis—were enrolled. Patients with altered hepatocellular enzyme patterns (predominant AST/ALT elevation), symptomatic choledocholithiasis, known chronic liver disease, chronic pancreatitis, other hepatobiliary malignancies, or hemodynamic instability were excluded to avoid confounding biochemical interpretation. All enrolled patients underwent detailed clinical evaluation, including history, physical examination, and baseline laboratory investigations. Liver function tests, including ALP, GGT, bilirubin, AST, and ALT, were recorded preoperatively. Transabdominal ultrasonography was performed to confirm cholelithiasis and assess the CBD diameter. Patients with biochemical suspicion of CBD stones subsequently underwent endoscopic ultrasonography (EUS) for definitive evaluation. When CBD stones were identified, therapeutic ERCP with stone extraction and/or biliary stenting was performed, followed by cholecystectomy. Patients without evidence of CBD stones proceeded directly to cholecystectomy. Postoperative assessment included serial measurements of serum ALP and GGT on postoperative days 1 and 7 to evaluate the biochemical response following biliary intervention and gallbladder removal. Clinical outcomes, including symptom resolution and postoperative complications, were documented. Statistical Analysis Data were entered into Microsoft Excel and analyzed using IBM SPSS Statistics version 22. Continuous variables were expressed as mean ± standard deviation, while categorical variables were presented as frequencies and percentages. Pre - and postoperative enzyme levels were compared using paired t-tests or repeated-measures ANOVA, depending on the distribution of the data. Associations between categorical variables were assessed using the chi-square test or Fisher’s exact test, where appropriate. A p-value of less than 0.05 was considered statistically significant. Graphical representations were used to illustrate trends in ALP and GGT levels over time.

A total of 40 patients were included in the study, with a mean age of 47.8 ± 17.0 years. Females constituted 57.5% of the cohort. Common bile duct stones were detected in 70% of patients on EUS, and all such patients underwent ERCP with biliary stenting followed by cholecystectomy. Figure 1. Trend in Mean ALP Levels Over Time Mean ALP levels showed a marked decline from the preoperative period to postoperative day 1 and day 7, indicating progressive resolution of cholestasis following intervention. Figure 2. Trend in Mean GGT Levels Over Time Mean GGT levels showed a significant and sustained postoperative reduction, reflecting effective biliary decompression and recovery of hepatobiliary function. Table 1. Demographic Characteristics of the Study Population (n = 40) Variable Value Mean age (years) 47.8 ± 17.0 Age range (years) 18–75 Gender Female sex, (%) 23 (57.5%) Male sex (%) 17 (42.5%) Co-morbidities Diabetes mellitus, n (%) 14 (35.0%) Hypertension, n (%) 16 (40.0%) Both diabetes and hypertension, n (%) 9 (22.5%) The study population had a mean age of 47.8 years, with a slight female predominance. Metabolic comorbidities such as diabetes mellitus and hypertension were commonly observed, either alone or in combination, reflecting the typical clinical profile of patients presenting with gallstone disease. Table 2. Detection and Management of Common Bile Duct Stones Parameter Number (%) CBD stones detected on EUS 28 (70.0%) No CBD stones on EUS 12 (30.0%) ERCP performed 28 (70.0%) ERCP with biliary stenting 28 (70.0%) Cholecystectomy performed 40 (100%) Common bile duct stones were detected in 70% of patients on endoscopic ultrasonography. All patients with confirmed choledocholithiasis underwent ERCP with biliary stenting, followed by definitive cholecystectomy, while patients without CBD stones proceeded directly to cholecystectomy. Table 3. Changes in Serum ALP and GGT Levels Over Time Time point ALP (U/L), Mean ± SD GGT (U/L), Mean ± SD Pre-operative 538 ± 37 273 ± 66 Post-operative Day 1 234 ± 37 183 ± 46 Post-operative Day 7 140 ± 54 113 ± 30 Both serum ALP and GGT levels were significantly elevated preoperatively and declined progressively after biliary intervention and cholecystectomy, indicating resolution of cholestasis and restoration of normal biliary flow. Table 4. Clinical Outcomes Following Intervention Outcome Number (%) Improvement in liver function tests 37 (92.5%) Complete symptom resolution 38 (95.0%) Post-operative complications 2 (5.0%) Residual or recurrent biliary symptoms 2 (5.0%) Most patients showed marked biochemical improvement and complete symptom resolution following treatment. Postoperative complications and persistent biliary symptoms were infrequent, indicating favorable short-term clinical outcomes.

This prospective study evaluated serum gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) as predictors of asymptomatic choledocholithiasis among patients with cholelithiasis. It assessed their perioperative trajectories after endoscopic and surgical management. The findings support the clinical value of cholestatic enzymes as practical screening markers to identify patients who warrant definitive CBD evaluation with EUS and, when indicated, therapeutic ERCP. Female predominance in the cohort is consistent with the established epidemiology of gallstone disease. Stinton and Shaffer previously described a higher prevalence of gallbladder disease among women, attributed in part to hormonal influences and bile composition changes [4]. Lammert et al. further emphasised sex-related and metabolic contributors to gallstone disease across populations [3]. The demographic pattern observed in the present cohort aligns well with these population-level observations. Metabolic comorbidities such as diabetes mellitus and hypertension were common in this cohort. Sung et al. described gallstone disease as a multifactorial condition influenced by metabolic and lifestyle factors [15]. These findings suggest that patients with metabolic comorbidities may represent a higher risk subgroup in whom biochemical screening for biliary obstruction assumes greater clinical importance. Endoscopic ultrasonography detected CBD stones in 70% of patients, underscoring its diagnostic utility when biochemical suspicion exists despite minimal symptoms. Rösch et al. demonstrated the high diagnostic accuracy of EUS for detecting choledocholithiasis, particularly small or distal stones [8]. Freeman highlighted the procedural risks associated with diagnostic ERCP, reinforcing the importance of EUS as a less invasive confirmatory modality prior to therapeutic intervention [9]. Serum ALP declined significantly postoperatively, consistent with the resolution of cholestasis following biliary drainage and cholecystectomy. Costa et al. demonstrated that ALP is a useful biochemical marker associated with choledocholithiasis and may reduce reliance on advanced imaging when interpreted appropriately [13]. Mei et al. similarly reported improved diagnostic performance of ALP when combined with GGT for the prediction of asymptomatic CBD stones in patients with cholelithiasis [12]. In contrast, Tozatti et al. observed that although ALP is useful, its diagnostic performance varies and should be interpreted alongside other biochemical and imaging findings rather than in isolation [16]. GGT also decreased substantially postoperatively, supporting its sensitivity to biliary obstruction and recovery following decompression. Lippi and Plebani reviewed the diagnostic relevance of GGT in hepatobiliary disease and its responsiveness to cholestatic injury patterns [11]. Lin et al. further reported the value of GGT-based biochemical indicators in predicting choledocholithiasis even when MRCP findings are negative [14]. In a scoping review of liver function tests, Yuen et al. identified GGT and ALP as the most significant biochemical predictors of choledocholithiasis. However, cutoff values varied across studies [17]. Björnsson and Björnsson additionally noted that marked elevations of liver enzymes may occur in choledocholithiasis and should be interpreted in the context of overall biochemical patterns rather than isolated values [18]. All patients in the present study underwent cholecystectomy, and those with CBD stones were managed with ERCP followed by definitive gallbladder removal. Maple et al., in the ASGE guidelines, emphasised selective ERCP use based on pretest probability and timely, definitive management to prevent recurrent biliary events [10]. Manes et al. in the ESGE guidelines similarly advocate coordinated endoscopic and surgical management following duct clearance [19]. The high rates of biochemical improvement and symptom resolution observed in this cohort support adherence to these guideline-directed strategies.

This study demonstrates that serum gamma glutamyl transferase and alkaline phosphatase are valuable, inexpensive, and readily available biochemical predictors of asymptomatic choledocholithiasis in patients with cholelithiasis. Their combined assessment improves preoperative risk stratification and helps identify patients who may benefit from further evaluation with EUS or ERCP. Significant postoperative reductions in both enzymes reflect effective biliary decompression and successful intervention. Incorporating these markers into routine preoperative assessment may reduce missed CBD stones and postoperative complications. Larger multicentric studies with longer follow up are required to validate these findings and establish standardized diagnostic cut off values.

1. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet. 2006;368(9531):230-9. 2. Di Ciaula A, Wang DQ, Portincasa P. An update on the pathogenesis of cholesterol gallstone disease. Curr Opin Gastroenterol. 2018;34(2):71-80. 3. Lammert F, Gurusamy K, Ko CW, Miquel JF, Méndez-Sánchez N, Portincasa P, Van Erpecum KJ, Van Laarhoven CJ, Wang DQ. Gallstones. Nature reviews Disease primers. 2016 Apr 28;2(1):1-7. 4. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: Cholelithiasis and cancer. Gut Liver. 2012;6(2):172-87. 5. Williams EJ, Green J, Beckingham I, et al. Guidelines on the management of common bile duct stones. Gut. 2021;60(12):1564-74. 6. Lindor KD, McKinley C, Luthringer DJ. Abdominal ultrasound in biliary tract disease. Mayo Clin Proc. 2002;77(1):100-108. 7. Vitellas KM, Keogan MT, Spritzer CE. MR cholangiography: The imaging of choice for bile duct stones. Radiology. 2000;217(1):207-216. 8. Rösch T, Hofrichter K, Frimberger E. Endoscopic ultrasonography in the diagnosis of choledocholithiasis. N Engl J Med. 1998;339(20):1473-1478. 9. Freeman ML. Adverse outcomes of ERCP. Gastrointest Endosc. 2002;56(6):S273-282. 10. Maple JT, Ben-Menachem T, Anderson MA, Appalaneni V, Banerjee S, Cash BD, Fisher L, Harrison ME, Fanelli RD, Fukami N, Ikenberry SO. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointestinal endoscopy. 2010 Jan 1;71(1):1-9. 11. Lippi G, Plebani M. Gamma-glutamyltransferase: New perspectives for an old enzyme. Clin Chem Lab Med. 2012;50(5):761-8. 12. Mei Y, Chen L, Zeng PF, et al. Combination of GGT and ALP for diagnosing choledocholithiasis. World J Clin Cases. 2019;7(2):137-44. 13. Costa PH, Sousa JH, Lima IT, Noronha MA, Aranha GL, Arienzo VP, Lucas PF, Steinman M, Tustumi F. The use of serum alkaline phosphatase as a choledocholithiasis marker to mitigate the cost of magnetic resonance cholangiography. einstein (São Paulo). 2023 Aug 11;21:eAO0204. 14. Lin H, Zhou X, Zhang Z. The Diagnostic Value of GGT‐Based Biochemical Indicators for Choledocholithiasis with Negative Imaging Results of Magnetic Resonance Cholangiopancreatography. Contrast Media & Molecular Imaging. 2022;2022(1):7737610. 15. Sung JY, Shaffer EA, Costerton JW. Gallstones: A worldwide multifactorial disease. Dig Dis Sci. 2017;62(10):2499-2508. 16. Tozatti J, Mello AL, Frazon O. Predictor factors for choledocholithiasis. ABCD. Arquivos Brasileiros de Cirurgia Digestiva (São Paulo). 2015 Apr;28:109-112. 17. Yuen WY, Piteša R, McHugh T, Poole G, Singh PP. Liver function tests as predictors of choledocholithiasis: a scoping review. AME Surgical Journal. 2023 Aug 10;3. 18. Björnsson HK, Björnsson ES. A significant proportion of patients with choledocholithiasis have markedly elevated alanine aminotransferase. Scandinavian Journal of Gastroenterology. 2019 Sep 2;54(9):1155-1159. 19. Manes G, Paspatis G, Aabakken L, Anderloni A, Arvanitakis M, Ah-Soune P, Barthet M, Domagk D, Dumonceau JM, Gigot JF, Hritz I. Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2019 May;51(05):472-491.