2. Thirteen infants (five female, eight male) had been treated with third-generation cephalosporins, 11 with ceftriaxone and two with cefotaxime (Table 2).
3. Six others were diagnosed antenatally. Only three of them were available for follow-up. In two the echogenic material disappeared within 2 months and in one it persisted for 4.5 years.
Before the diagnosis of cholelithiasis the medical history of the infants include the following:
3: Born by Cesarean section.
2: ABO incompatibility.
2: Born premature and treated for respiratory distress syndrome; one of them was also treated with TPN (patient 15).
One mother (of patient 8) had been treated with carbamazepine and hydantoin during pregnancy.
One with immunoglobulin A deficiency (patient 9)
One with chronic cholestatic liver disease.
The biochemical evaluation of the asymptomatic infants was normal.
Presenting complaints included fever, recurrent vomiting and excessive crying in one, minimal cholestatic jaundice in two and one with failure to thrive and acholic stool. The causes of dehydration were: prolonged poor feeding and weight loss, gastroesophageal reflux disease, gastroenteritis and urinary tract infection (UTI). Fevers were caused by viral infection, UTI and clinical dysentery.
Possible etiology or known risk factors for the development of cholelithiasis were found in 28 infants (83%) of groups 1 and 2 (Tables 1 and 2). Eight had more than one risk factor. In six of the 34 children (17%) no etiology was found.
A familial history of cholelithiasis was present in three children. In case 21 the mother underwent cholecystectomy during pregnancy.
Cholelithiasis in children generally is reported in association with hemolytic disorders and congenital anomalies of the biliary tree. More recently, use of TPN, furosemide therapy and gastrointestinal surgery have become the most commonly reported risk factors for the development of gallstones (1). These stones consist mostly of calcium bilirubinate and result from bile stasis within the gallbladder (7). In early infancy the stones are mainly black pigmented (1) or brown pigmented (8). Infection, especially as the result of Gram-negative bacilli, may have a lithogenic effect on bile by decreasing the independent bile salt flow. Moreover, the lithogenic effect of bacterial glycoproteins per se, together with the dehydration that commonly develops during infection, could also contribute to this lithogenesis. Indeed, the association of UTI and cholelithiasis has been previously reported in 10 infants and was related to the aforementioned causes (9). In our study UTI was diagnosed in seven infants, five of whom had been treated with ceftriaxone, a well-known lithogenic medication. The results of our study suggest that cholelithiasis in infancy and young childhood is less commonly related to prematurity, TPN or hemolysis than previously presumed.
Dehydration was found in 10 of 34 (29.4%) of our infants. In a few cases, dehydration developed gradually over days to weeks as a result of poor intake (1) or syndromes of recurrent vomiting associated with dehydration and electrolyte imbalance such as pseudohypoaldosteronism and Addison's disease. This association has been previously reported (Table 1) (2,10). The pathophysiologic mechanism of gallbladder stone formation during low intake or fasting is related to low cholecystokinin levels, which may lead to gallbladder stasis and subsequent biliary stones. An inverse relationship between cholecystokinin level and gallbladder sludge has been reported. Oral feeding or treatment with cholecystokinin may prevent this outcome (11,12).
A MEDLINE literature survey of cholelithiasis in infancy revealed the following reports. Friesen and Roberts reported that stones were associated with TPN in 29%, abdominal surgery in 29%, sepsis in 15% and bronchopulmonary dysplasia in 13% of infants (1). Schirmer et al. described 12 infants diagnosed in the early eighties with cholelithiasis; eight had been treated with TPN. Spontaneous resolution was documented in three (13). Thirteen infants with cholelithiasis were reported by St-Vil et al. Five had spontaneous resolution within 6 months of diagnosis. All were asymptomatic and none had known risk factors (2). Ljung et al. reported five infants <7 months old with cholelithiasis. One had acute hemolysis and some had vomiting and diarrhea (14). Holcomb et al. attributed most of the gallstones diagnosed from birth to 2 years of age to the use of TPN in premature infants or to small bowel resection (15). Stringer et al. published a study of stone composition in 20 infants and children. Ten had black pigmented stones (16). Halpren et al. analyzed the bile of infants younger than 1 year and found a shorter nucleation time and increased lithogenicity (17).
Reversible ceftriaxone-associated biliary pseudolithiasis was first reported by Schaad et al. in 1988. Parameters associated with pseudolithiasis were prolonged treatment (4-22 days), high doses and older patient age (18). Our group of 11 infants who developed pseudolithiasis during ceftriaxone therapy were characterized by their younger age and the short duration of treatment (48 to 96 hours). Previously, similar cases of short treatment leading to cholelithiasis have been reported only rarely (19). Two other infants diagnosed with pseudolithiasis had been treated with cefotaxime. This association has not been reported previously. The prognosis for pseudolithiasis was good; spontaneous resolution occurred in all patients and none developed cholecystitis.
Choledocholithiasis is one of the rarer manifestations of gallbladder disease in infants. It was observed in three of our patients. One needed endoscopic retrograde cholangiopancreatography and stone extraction (black pigmented). The other two had spontaneous resolution. Debray et al. have reported 40 infants younger than 1 year of age with cholelithiasis. Thirty-four presented with lithiasis of the common duct or cystic duct. Their initial symptom was mainly cholestatic jaundice (3).
Jonas et al. reported seven infants with choledocholithiasis. Six were born prematurely and had necrotizing enterocolitis, hemolysis and asphyxia and were treated with TPN (4).
Fetal cholelithiasis was observed by routine antenatal ultrasound in six fetuses. No significant associated risk factors were found and none are reported in the literature. Brown et al. reported 26 fetuses with echogenic material in the gallbladder. In only three did the echogenic material persist for many months after birth (20).
The overall prognosis for infants with cholelithiasis is favorable. Seventeen of 19 infants remained asymptomatic after presentation (two died but their death was not attributable to gallbladder disease). Cholecystitis was uncommon in our series and was observed in only two infants (20 and 21), 4 months and 1 year after diagnosis, respectively. Spontaneous resolution occurred in nine infants (42%) of group I possibly as a result of stone migration through the common bile duct or stone dissolution.
Treatment for one symptomatic infant (patient 1) with choledocholithiasis required invasive treatment. Endoscopic retrograde cholangiopancreatography and papillotomy were performed and the calculi extracted. Eight years later a small stone was found in the gallbladder. On further follow-up 4 years later no gallstone was found. Of the two infants with cholecystitis, one underwent cholecystectomy and one asymptomatic patient (patient 9) had an elective cholecystectomy at the age of 3.5 years.
Ursodeoxycholic acid therapy was tried in three infants but was discontinued by the parents after a few weeks; hence, its long-term effect cannot be evaluated. Gamba et al. found that ursodeoxycholic acid was ineffective in the treatment of gallstones in five children younger than 2 years of age. One infant underwent cholecystectomy; the stone was found to be a bilirubin stone (21).
Our results reflect the occurrence of cholelithiasis in infancy in a general pediatric ward population being evaluated and treated for common pediatric problems such as excessive crying, evaluation of jaundice, recurrent vomiting or UTI, in contrast to what has been published in the past (1,3,22). Based on our experience we recommend that pediatricians be aware of the more common risk factors for the development of gallbladder stones and screen for them. In infants with known gallbladder stones one should consider the uncommon complication of cholecystitis. From our follow-up we conclude that stones found during infancy usually disappear within 1 year. Only in one case (patient 1) did a stone reappear and subsequently disappear again spontaneously. In the absence of other clinical or imaging evidence of biliary tract disease, conservative management and serial sonograms are advised.
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Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
Cholelithiasis; Infancy treatment; Cephalosporin