Gallstones in a Seven-Year-Old Revealed Hidden Blood Disorder, Prompting New Diagnostic Algorithm

When a seven-year-old girl arrived at the emergency department of Fondazione IRCCS San Gerardo dei Tintori in Monza, Italy, with abdominal pain, vomiting, and jaundice, the clinical team expected a routine case of gallstone disease. What they uncovered instead was a hidden chronic blood disorder that had silently shaped her health since birth. The case, published in Frontiers in Hematology, describes how a seemingly straightforward bout of biliary disease unmasked hereditary spherocytosis, a congenital condition in which red blood cells are structurally fragile and prone to premature destruction. More importantly, the pediatric researchers behind the report used the experience to build a practical diagnostic flowchart designed to help clinicians everywhere recognize when gallstones in a child are not merely a dietary or metabolic problem, but the first visible clue to an underlying hemolytic anemia.

Pediatric gallstone disease, known medically as cholelithiasis, has become increasingly common over the past two decades. The authors attribute this rise largely to the growing prevalence of childhood obesity, alongside the widespread use of abdominal ultrasound, which can detect even asymptomatic stones incidentally. Against that backdrop, gallstones caused by hematologic disorders have remained comparatively stable, accounting for roughly five to twenty percent of pediatric cases. That stability, however, masks a genuine diagnostic hazard. In children, gallstones may represent the very first clinical manifestation of a chronic hematologic condition, and if the underlying anemia is mild or well compensated, the standard laboratory picture can look deceptively normal. Early recognition of anamnestic, clinical, and biochemical warning signs is therefore essential to ensure timely referral to a pediatric hematologist.

The girl in this report had a normal body mass index, which already distinguished her from the typical profile of a child with metabolic gallstone disease. Her medical history held one crucial clue: she had experienced hemolytic jaundice as a newborn. There was no family history of hematologic disorders, no recent travel to regions endemic for parasitic infections, no chronic medication use, and no exposure to antibiotics such as ceftriaxone, a drug well known for its association with biliary sludge in children. On examination, physicians noted jaundice, tenderness in the right upper quadrant of the abdomen, and mild enlargement of the spleen. The combination of gallstone disease and splenomegaly would ultimately prove to be the pivotal observation that redirected the entire diagnostic workup.

Laboratory findings at presentation were strikingly ambiguous. Her blood counts were nearly normal, with hemoglobin of 12.3 grams per deciliter sitting just above the lower limit of the reference range, and red cell indices such as mean corpuscular volume and mean corpuscular hemoglobin falling entirely within normal limits. Yet the biochemistry told a more troubling story: elevated indirect bilirubin and transaminases, a mild rise in pancreatic enzymes, and cola-colored urine suggesting hemoglobinuria from intravascular red cell destruction. Abdominal ultrasound revealed a distended gallbladder containing biliary sludge and a five by five millimeter gallstone, with normal-caliber bile ducts and an enlarged spleen. The team established a diagnosis of obstructive choledocholithiasis with biliary pancreatitis and splenomegaly, a combination that is itself a medical emergency in children.

Within forty-eight hours, the situation deteriorated. Repeat laboratory testing showed further increases in transaminases, pancreatic enzymes, and total bilirubin, with the direct bilirubin fraction rising sharply, a pattern consistent with obstruction rather than simple hemolysis. Repeat ultrasonography demonstrated obstruction of the distal common bile duct at the level of the pancreatic duct confluence, with a moderately distended gallbladder containing hyperechoic sludge. The team performed endoscopic retrograde cholangiopancreatography, or ERCP, with sphincterotomy and stone extraction to relieve the obstruction. Three days later, after magnetic resonance cholangiopancreatography allowed adequate delineation of the biliary tree, the girl underwent elective laparoscopic cholecystectomy. The acute crisis was resolved, but the question of why a healthy, normal-weight seven-year-old had formed a pigment stone in the first place remained unanswered.

The answer lay in the convergence of three findings: cholelithiasis, splenomegaly, and laboratory evidence of hemolysis. Hematologic evaluation confirmed the hallmark markers of chronic red cell destruction, including elevated indirect bilirubin and lactate dehydrogenase, together with a depressed haptoglobin level, the protein that mops up free hemoglobin in the plasma. A peripheral blood smear revealed anisopoikilocytosis with spherocytes and occasional elliptocytes, accompanied by an increased red cell distribution width and reticulocytosis, the bone marrow’s compensatory surge of young red cells. Immune-mediated hemolysis, hemoglobinopathies, and red cell enzymatic defects were systematically excluded. Functional testing of red cell membrane integrity, including the eosin-5-maleimide binding test and osmotic fragility testing, confirmed hereditary spherocytosis, and subsequent membrane protein analysis demonstrated a deficiency of spectrin, the structural protein that gives red cells their flexible biconcave shape. Because neither parent showed clinical or laboratory evidence of the disease, the girl’s condition was considered most likely a de novo mutation, which neatly explained the absent family history.

The pathophysiology connecting her two diagnoses is elegant and well established. Chronic hemolysis increases bilirubin turnover, promoting the precipitation of calcium bilirubinate and the formation of pigment gallstones rather than the cholesterol stones typical of obesity-related disease. Classic hemolytic anemias usually announce themselves in early childhood with recurrent hemolytic episodes, anemia of variable severity, jaundice, and splenomegaly. Hemoglobinopathies such as thalassemia and sickle cell disease, while not clinically apparent at birth, generally become evident within the first year of life or early childhood. The danger lies in the milder phenotypes: certain forms of non-transfusion-dependent thalassemia, compound heterozygosity involving alpha-globin gene triplications or quadruplications paired with beta-globin mutations, sickle cell disease combined with other hemoglobin variants, or homozygosity for hemoglobin C or E may remain undiagnosed until adulthood and can first declare themselves through biliary colic. Missing such conditions risks complications, undertreatment, inadequate monitoring, and reproductive counseling failures.

To close this diagnostic gap, the Monza team proposed a two-section flowchart that they identify as one of the main strengths of the report. The first section provides an algorithm for general practitioners and pediatricians, aimed at identifying mild congenital hemolytic anemias that may present with acute gallbladder pathology. The second outlines the hematologist’s own stepwise pathway, organized into first-, second-, and third-level investigations. Notably, the direct antiglobulin test is included among the first-line investigations to promptly distinguish immune-mediated from congenital hemolysis; although autoimmune hemolytic anemia only rarely presents with gallstone disease as the initial manifestation, the test is a standard component of the hemolysis workup and should be performed early. Bone marrow assessment is deliberately reserved for rare conditions such as congenital dyserythropoietic anemias and for cases of diagnostic uncertainty or involvement of multiple hematopoietic lineages. Accurate diagnosis, the authors stress, relies on integrating clinical findings, hematochemical parameters, red cell indices, smear morphology, functional membrane assays, and, when indicated, molecular genetic testing.

The report also weighs in on surgical decision-making, an area of genuine controversy. Intervention is clearly indicated in symptomatic cholelithiasis and in obstructive or infectious complications, but the management of asymptomatic stones remains debated in both pediatric and adult populations, with decisions about prophylactic cholecystectomy individualized according to the underlying disease, patient risk factors, and the likelihood of future biliary complications. Current guidelines do support concomitant cholecystectomy in patients with chronic hemolytic anemia undergoing elective splenectomy when gallstones are present, even asymptomatic ones, and in sickle cell disease, perioperative care including transfusion support, antibiotic and antithrombotic prophylaxis when indicated, early mobilization, and respiratory physiotherapy may reduce complications. The authors’ closing message is a call for systematic screening: at the initial assessment of gallstone disease in children, particularly complicated cases, clinicians should obtain a complete blood count with red cell indices, reticulocyte count, peripheral blood smear, lactate dehydrogenase, haptoglobin, bilirubin, and a direct antiglobulin test. In a normal-appearing seven-year-old whose counts were nearly normal, those subtle markers made all the difference, transforming an emergency gallbladder crisis into a lifelong diagnosis caught before it could strike again.

Subject of Research: Pediatric cholelithiasis as a presenting sign of underlying hereditary hemolytic anemia

Article Title: Case Report: A diagnostic algorithm for pediatric cholelithiasis: recognizing underlying hemolytic anemia through a case of hereditary spherocytosis

Article References: Fantasia, M., Faraguna, M. C., Pagani, R., Catalano, A., Colombo, D., Paredi, M., Guerra, F., Ferrari, G. M., & Corti, P. (2026). Case Report: A diagnostic algorithm for pediatric cholelithiasis: recognizing underlying hemolytic anemia through a case of hereditary spherocytosis. Frontiers in Hematology, 5, Article 1858024. https://doi.org/10.3389/frhem.2026.1858024

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1858024

Keywords: cholelithiasis, hereditary spherocytosis, hemolytic anemia, pediatrics, gallstones, splenomegaly, biliary pancreatitis, ERCP, diagnostic algorithm, bilirubin, spectrin deficiency, hematology