Gallstone disease in children was historically regarded as an uncommon clinical entity; however, its Prevalance has risen over recent decades owing to improved diagnostic imaging, increased survival of children with chronic hematologic disorders, and heightened clinical vigilance. [1] Pediatric gallstones differ fundamentally from adult gallstones in both etiology and composition. [2] While cholesterol stones predominate in adults, children more commonly develop pigment stones, particularly in association with hemolytic conditions. [3] Hemolytic disorders are characterized by accelerated destruction of erythrocytes, resulting in persistent elevation of unconjugated bilirubin. [4] This excess bilirubin combines with calcium salts in bile to form calcium bilirubinate, the principal component of black pigment stones. [5] Conditions such as sickle cell disease, hereditary spherocytosis, thalassemia, and autoimmune hemolytic anemia are well-established risk factors for gallstone formation in children. [6] Children with hemolytic disorders are at risk not only for gallstone formation but also for earlier onset of biliary symptoms and complications, including acute cholecystitis, choledocholithiasis, biliary pancreatitis, and cholangitis. [7] Importantly, gallstones may remain asymptomatic for prolonged periods, delaying diagnosis until complications arise. [8] This underscores the importance of systematic evaluation and surveillance in high-risk pediatric populations. [9] Despite increasing recognition, regional data on the Prevalance of hemolytic disorders among children with gallstone disease remain limited, particularly from the Kashmir valley. [10] This study aims to bridge this gap by analyzing the Prevalance, clinical presentation, and outcomes of pediatric gallstone disease associated with hemolytic disorders in a tertiary care setting.

This retrospective observational study was conducted at a tertiary care teaching hospital over a one-year period from December 2024 to December 2025, following approval from the Institutional Ethics Committee. Study Population All pediatric patients aged ≤18 years diagnosed with gallstone disease during the study period were eligible for inclusion. Inclusion Criteria • Children with gallstones confirmed on abdominal ultrasonography • Complete medical records available for review Exclusion Criteria •Incidental gallbladder abnormalities without gallstones •Incomplete or missing clinical or laboratory data Data Collection Patient data were retrieved from hospital records and included: •Demographics (age, sex) •Clinical features (abdominal pain, jaundice, nausea/vomiting) •Laboratory investigations (hemoglobin, bilirubin fractions, LDH, reticulocyte count) •Hemolytic evaluation (hemoglobin electrophoresis, osmotic fragility test, Coombs test) •Imaging findings •Treatment details and hospital outcomes Statistical Analysis Continuous variables were expressed as mean ± standard deviation (SD) with 95% confidence intervals (CI), while categorical variables were expressed as frequencies and percentages. Comparisons between hemolytic and non-hemolytic groups were performed using the independent Student’s t-test for continuous variables and the Chi-square or Fisher’s exact test for categorical variables. Statistical significance was defined as a p-value <0.05. Analysis was performed using SPSS version 30.0.

Demographic Characteristics The mean age of the study population was 12.4 ± 3.6 years (95% CI: 11.3–13.5), with a male predominance (60%). Prevalance and Spectrum of Hemolytic Disorders Hemolytic disorders were identified in 37.5% (n = 15) of pediatric gallstone cases. Sickle cell disease was the most frequent diagnosis, followed by hereditary spherocytosis and thalassemia. Clinical Features Abdominal pain was the most common presenting symptom in both groups. Jaundice was significantly more prevalent among children with hemolytic disorders (60% vs. 12%; p = 0.003). Management and Outcomes Approximately 70% of symptomatic patients underwent cholecystectomy. There was no statistically significant difference in surgical rates or postoperative complications between hemolytic and non-hemolytic groups. However, children with hemolytic disorders had a significantly longer hospital stay. Table 1. Demographic Characteristics of Pediatric Patients with Gallstone Disease (n = 40) Variable Value Age (years), mean ± SD 12.4 ± 3.6 95% CI for mean age 11.3 – 13.5 Male sex, n (%) 24 (60.0) 95% CI for male sex 44.8 – 75.2 Continuous variables are expressed as mean ± standard deviation (SD). Categorical variables are expressed as number (%). Table 2. Prevalance of Hemolytic Disorders in Pediatric Gallstone Disease (n = 40) Etiology Number (%) 95% Confidence Interval Hemolytic disorders 15 (37.5) 22.7 – 52.3 Non-hemolytic causes 25 (62.5) 47.7 – 77.3 Table 3. Distribution of Hemolytic Disorders Among Affected Patients (n = 15) Hemolytic Disorder Number (%) 95% Confidence Interval Sickle cell disease 8 (53.3) 28.1 – 78.5 Hereditary spherocytosis 4 (26.7) 7.9 – 55.1 Thalassemia 2 (13.3) 1.7 – 40.5 Autoimmune hemolytic anemia 1 (6.7) 0.2 – 31.9 Table 4. Comparison of Clinical Features Between Hemolytic and Non-Hemolytic Groups Clinical Feature Hemolytic (n = 15) Non-Hemolytic (n = 25) p-value Risk Difference (95% CI) Abdominal pain 14 (93%) 19 (76%) 0.18 −5.2 to 39.4 Jaundice 9 (60%) 3 (12%) 0.003* 20.1 to 67.9 Nausea/vomiting 6 (40%) 10 (40%) 1.00 −30.5 to 30.5 Incidental detection 1 (7%) 6 (24%) 0.21 −35.9 to 2.3 *Statistically significant (p < 0.05). Table 5. Management and Outcomes of Pediatric Gallstone Disease Outcome Hemolytic (n = 15) Non-Hemolytic (n = 25) p-value 95% CI Symptomatic disease 14 (93%) 18 (72%) 0.12 −2.1 to 43.7 Cholecystectomy 11 (73%) 15 (60%) 0.39 −16.4 to 42.4 Postoperative complications 2 (13%) 1 (4%) 0.55 −9.5 to 27.9 Hospital stay (days), mean ± SD 5.1 ± 1.2 3.6 ± 1.0 0.001* 0.7 – 2.3 Table 6. Laboratory Profile of Patients with Hemolytic Disorders Laboratory Parameter Observation Hemoglobin Reduced Unconjugated bilirubin Elevated Serum LDH Elevated Reticulocyte count Increased Peripheral smear Evidence of chronic hemolysis

The present study highlights the significant contribution of hemolytic disorders to pediatric gallstone disease, with more than one-third (37.5%) of cases attributed to underlying hemolysis. This finding is consistent with existing literature, which identifies chronic hemolysis as one of the most important etiological factors for gallstone formation in children, particularly pigment stones.[11] Previous studies from both Western and South Asian populations have reported the prevalence of hemolytic disorders among pediatric gallstone patients to range from 20% to 60%, depending on regional disease burden and referral patterns, placing the present observations well within the expected spectrum. [12] Sickle cell disease emerged as the most common hemolytic disorder in this cohort, followed by hereditary spherocytosis and thalassemia. Similar dominance of sickle cell disease has been reported by Stringer et al. and Al-Salem et al., who demonstrated that repeated hemoglobin breakdown and chronic unconjugated hyperbilirubinemia significantly accelerate pigment stone formation. [13,14] Hereditary spherocytosis has also been consistently linked with early gallstone development, often presenting in late childhood or early adolescence, as observed in the current study. [15] Although thalassemia accounted for a smaller proportion, its presence reinforces the role of ineffective erythropoiesis and transfusion-related hemolysis in gallstone pathogenesis. [16] Clinically, abdominal pain was the most frequent presenting symptom across both hemolytic and non-hemolytic groups, aligning with prior reports that pain remains the dominant clinical manifestation in pediatric gallstone disease. However, jaundice was significantly more prevalent in children with hemolytic disorders (60% vs. 12%), a finding that strongly correlates with earlier studies showing higher bilirubin turnover and baseline hyperbilirubinemia in these patients. This observation underscores the importance of evaluating children with gallstones and jaundice for underlying hemolytic conditions, especially in regions with a high prevalence of inherited blood disorders. [17] Management patterns in this study revealed that the majority of symptomatic patients underwent cholecystectomy, with no significant difference in surgical rates or postoperative complications between hemolytic and non-hemolytic groups. [18] These findings are consistent with current evidence suggesting that laparoscopic cholecystectomy is safe and effective in children with hemolytic disorders, provided appropriate perioperative optimization is undertaken. [19] Studies by Davies et al. and Rescorla et al. similarly reported comparable surgical outcomes between hemolytic and non-hemolytic pediatric patients. [20,21] Notably, children with hemolytic disorders had a significantly longer hospital stay. This may be explained by the need for closer perioperative monitoring, management of anemia, transfusion requirements, and the presence of associated systemic complications. [22] Similar trends of prolonged hospitalization in hemolytic patients have been documented in prior studies, emphasizing the increased healthcare burden associated with this subgroup. [23] Laboratory findings in hemolytic patients—characterized by anemia, elevated unconjugated bilirubin, increased LDH, reticulocytosis, and peripheral smear evidence of hemolysis—further support the pathogenic link between chronic hemolysis and gallstone formation, as widely described in hematology and pediatric surgery literature. [24,25] Overall, the present study reinforces existing evidence that hemolytic disorders represent a major etiological factor in pediatric gallstone disease and significantly influence clinical presentation and hospital course. Early recognition and multidisciplinary management involving pediatricians, hematologists, and surgeons are crucial to optimize outcomes and reduce morbidity in this vulnerable population. Limitations • Retrospective design with potential for missing subclinical cases • Single-center study limiting generalizability • Lack of long-term follow-up data

Hemolytic disorders constitute a major etiological factor in pediatric gallstone disease. Early recognition, routine screening in high-risk children, and coordinated multidisciplinary management are essential to prevent biliary complications and ensure favorable outcomes. Author Contributions Conceptualized and designed the study by Dr. Syed Saad Ahmed Collected and compiled clinical data by Dr. Naushaba Mumtaz Performed data analysis and interpretation by Dr. Razaq Hussain Drafted the manuscript by Dr. Syed Saad Ahmed

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