We received hospital records from July, 2014 to June, 2019 of consecutive patients <18 years of age with cholelithiasis/sludge in the pediatric surgical unit of a tertiary center. Case records with incomplete data, and those with a diagnosis of choledochal cyst were excluded.

Records were reviewed for demographic information, symptoms (non-specific abdominal pain, right hypochon-driac pain or biliary colic, nausea,vomiting, jaundice), predisposing factors (body mass index, history of fast food eating habit, acute gastroenteritis, dehydration, hemolytic disorder, ceftriaxone injection, total parenteral nutrition) and complications (acute cholecystitis, chronic cholecystitis, choledocholithiasis, cholangitis, gall bladder perforation). Fast food eating habit was defined as frequent consumption of food containing a rich mix of refined sugars, salt, and fats, and low in fibers. The child was considered obese if BMI was >27 on IAP growth charts [4]. Ultrasonography (USG) findings included floating hyperechoic lesion in gall bladder with posterior acoustic shadow, echogenic sludge without posterior acoustic shadow, gall bladder wall thickening (>3 mm with 6 hours fasting), peri-cholecystic collection, common bile duct (CBD) stone, and CBD and intrahepatic biliary radical dilatation.

Cholelithiasis was classified according to etiology: pigment stones (due to hemolytic disorders; positive on hemoglobin electrophoresis), ceftriaxone pseudolithiasis (cholelithiasis noticed within 21 days of >3 days of intra-venous ceftriaxone therapy with a normal pre-ceftriaxone ultrasound report), stone or sludge secondary to TPN (developing after TPN); all others were labeled idiopathic. Hemoglobin electrophoresis was done for all patients with cholelithiasis diagnosed on ultrasound, and all patients with hemolytic disorders underwent an ultra-sound to document hemolytic stones.

Cholecystectomy (open or laparoscopic; depending on availability and patient condition) was performed for all pigment stones (on diagnosis or presentation with a complication). Medical therapy (Ursodeoxycholic acid (UDCA) 25 mg/kg/day for 6 months) was advised for all non-hemolytic stones. These patients were followed up with clinical examination and ultrasound every 3 months. The stone resolution was defined as an anechoic gall bladder on two consecutive three-monthly ultrasounds. Patients developing complications were dealt with in an emergent manner. Choledocholithiasis was managed with endoscopic stone extraction and interval cholecystec-tomy. Treatment is given (routine/emergent/medical/cholecystectomy) and outcomes were recorded.

Data analysis: Data analyses were performed using an online Graphpad analyzer. All variables were analyzed descriptively, and chi-square test or t-test were used for statistical analysis. A value of P<0.05 was considered significant.

A total of 426 children (53.7% females) with cholelithiasis fulfilled inclusion criteria, and were included in the analysis (Fig. 1). Commonest (56.2%) etiology was idiopathic; followed by ceftriaxone pseudolithiasis (26.83%). The median (IQR) age was 6 (3-14) years. Incidence of obesity, fast food habits, and biliary colic was highest in idiopathic stones. Thirteen patients (13.7%) had a history of ceftriaxone administration after abdominal surgery, associated with a history of starvation for more than 48 hours. Most (45.8%) patients were asymptomatic; non-specific abdominal pain was the commonest (40.4%) symptom. The distribution of predis-posing factors and symptoms among different etiologies is shown in Table I. On ultrasound, the largest stone size was 2.5 cm, and the mean size was not significantly different in all four etiological types of cholelithiasis. Solitary stone was the commonest (79.1%) presentation. Echogenic sludge without post acoustic shadow was found in all cases of TPN-associated cholelithiasis.

Fig. 1 Treatment provided for various types of pediatric cholelithiasis.

Pigment stones (n=46) were associated with the highest rate of complications (Table I) and underwent upfront elective cholecystectomy, planned cholecystec-tomy, and emergent cholecystectomy (for gangrenous cholecystitis) in 18, 22, and 6 patients, respectively. In idiopathic pediatric cholelethiasis (39.2%) had to undergo surgery because of biliary symptoms (37, 18.6%, elective cholecystectomy), complications (34, 17.1%, 5 emergent cholecystectomy), or failure of medical treat-ment in asymptomatic pediatric cholelethiasis (7, 3.5%). Complications viz. acute cholecystitis, chronic chole-cystitis and choledocholithiasis were significantly higher in pigment stones as compared to idiopathic stones (P=<0.001, P=0.02 and P=0.02, respectively). Medical management with UDCA for 6 months was effective in 121 (60.8%) patients with idiopathic cholelithiasis and all TPN-associated cases. TPN stones were associated with the highest incidence of obstructive jaundice. One patient underwent emergent cholecystec-tomy for gall bladder perforation and biliary peritonitis. Gall-stone pancreatitis was not seen in any patient.

Increasing prevalence of reversible ceftriaxone-associated biliary pseudolithiasis is due to the common use of ceftriaxone in children for abdominal infections and peri-operatively in gastrointestinal surgery [5]. Ceftria-xone is excreted in bile where it gets 20-150 times concentrated and readily forms a reversible insoluble salt with calcium which precipitates into pseudo-stone formation [6]. Moreover, biliary stasis is known to occur in gastrointestinal infection, starvation, after abdominal surgery, and gram-negative sepsis [7]. History of admission for acute gastroenteritis/dehydration or previous abdominal surgery with the administration of ceftriaxone was common in our CP patients. Compli-cations of cholelithiasis occur in 15-25% of pediatric patients; hence, guidelines for expectant/medical/surgical treatment are needed for its management [8,9]. Hemolytic stones are advised cholecystectomy as the first line of treatment because they do not respond well to medical dissolution therapy and have a higher rate of complications due to impaction [8,10]. Ceftriaxone associated cholelithiasis and TPN induced pediatric cholelithiasis, on the other hand, are known for their reversible character and respond well to medical treatment [11]. UDCA is known to resolve PC in 19-37% of patients with non-hemolytic stones [8,10,12]. Higher (60.8%) stone dissolution with UDCA in the present study is unexplained.

Indications of cholecystectomy in idiopathic pediatric cholelithiasis are less clear and the decision is often based on clinical judgment, concerns for complications, and the surgeon’s conviction (or lack of) in the efficacy of UDCA [13]. In our study, 40% of idiopathic cholelithiasis underwent surgery because of biliary symptoms or complications or failure of medical treatment in asymptomatic patients; supporting early surgery for symptomatic idiopathic stones. In the present study, the majority of idiopathic and asympto-matic idiopathic stones dissolved after medical treatment, suggesting a specific role of medical therapy in avoiding surgery. However, because of complications, medical treatment must be given under close observation. An unnecessary cholecystectomy entails needless risk and cost burden in a potentially dissolvable PC [14]. Also, pediatric cholecystectomy is more challenging for the surgeons because of its relative infrequency and the fact that surgical volume might not help lower complication rates [15]. The high incidence of ceftriaxone pseudo-cholelithiasis in our study raises concerns about the common use of ceftriaxone in pediatric practice. Awareness of this is important and consideration should be given to the use of equivalent antibiotic options.

Our algorithm (Web Fig. 1) allows a pre-emptive approach to avert complications, the best utilization of surgical options, and minimizes unnecessary surgery. Formulation of our protocol is based on the analysis of our data and lessons learned; it needs to be further tested in different settings and in a prospective design.

Our etiology-based treatment protocol developed with local data allows a judicious selection of pediatric cholelithiasis patients for surgery. Hemolytic and symptomatic stones warrant an early cholecystectomy. Asymptomatic idiopathic stones, ceftriaxone stones, and TPN-induced stones are candidates for medical therapy under close observation.

Ethics approval: Netaji Subhash Chandra Bose Medical College, Jabalpur, MP, India; No: IEC/NSCBMC/20/03, dated September 27, 2020.

Contributors: VA, AT: concept, design, definition of intellectual content, literature search, clinical studies, data acquisition, data analysis, manuscript preparation, editing and review; DS, RA: literature search, clinical studies, data acquisition, data analysis, manuscript preparation, editing, and review. All authors approved the final version of the manuscript, and are accountable for all aspects related to the study.

Funding: None; Competing interests: None stated.