First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.

BACKGROUND: Recent data in mice suggest that acid suppression during pregnancy yields offspring with type 2 T helper-dominant immunity, suggesting a predisposition for allergy. OBJECTIVE: To determine the association of in utero exposure to acid-suppressive medications and the subsequent development of allergic diseases in children. METHODS: We studied a population-based observational cohort formed by linking data from three Swedish national healthcare registers: the Medical Birth Register, the Hospital Discharge Register, and the Swedish Prescribed Drug Register. Main outcome measures included a hospital discharge diagnosis of an allergic disease or prescription for asthma medications, epinephrine auto-injectors, antihistamines or steroid ointments in children. Data were analysed using the Mantel-Haenszel procedure. RESULTS: Twenty-nine thousand four hundred and ninety (5.03%) children had a discharge diagnosis of allergy or prescriptions for allergy medications. Five thousand six hundred and forty-five (0.96%) children had been exposed to acid suppression therapy during pregnancy; of these, 405 (0.07%) were treated for allergic diseases. Exposure to acid-suppressive medications in utero was associated with an increased odds ratio (OR) for developing allergy (OR 1.43, 95% confidence interval (95% CI) 1.29-1.59). We observed this association irrespective of the type of drug, time of exposure during pregnancy, and maternal history of allergy. The use of maternal acid-suppressive medication was associated with an increased OR for the development of childhood asthma (3.7% in the population at large vs. 5.6% in exposed children, OR 1.51, 95% CI 1.35-1.69), but not for other allergic diseases. CONCLUSION: These data provide first evidence of a significant association between in utero exposure to acid-suppressive drugs and the risk of developing childhood asthma.

Allergic esophagitis in children: a clinicopathological entity.

Infiltration of esophageal epithelium by eosinophils is seen in reflux esophagitis and allergic gastroenteritis. This study was performed to identify differences between patients with acid reflux esophagitis and those with non-acid reflux, possibly allergic, esophagitis. Intraepithelial eosinophils were demonstrated in posttherapy esophageal biopsy specimens in 28 children treated for gastroesophageal reflux disease (GERD). These patients were divided into three groups based on their response to treatment and the results of esophageal pH probe monitoring. Eleven patients (Group A) had incomplete clinical response and normal pH probe monitoring results. Ten patients (Group B) had incomplete response but did not have pH probe monitoring. These two groups formed the index population. Seven patients (Group C) had clinical improvement with GERD therapy and abnormal pH probe monitoring characteristic of GERD; they constituted the control population. Clinical, laboratory, and pathologic features were evaluated to detect differences between index and control populations. Dysphagia, food impaction, failure to thrive, peripheral eosinophilia, and abnormal allergen skin test results were detected only in Group A and B patients. Biopsy specimens of the distal 9 cm of the esophagus, after GERD therapy, contained larger numbers of eosinophils in Groups A and B than in Group C as shown on high-power fields (HPF) (A: 31/HPF +/- 19.5; B: 28/HPF +/-23.7; versus C: 5/HPF +/-6.7; p = 0.009). Eosinophil aggregates were identified only in Groups A and B (p = 0.07). Eosinophils located preferentially in the superficial layers of the squamous epithelium were noted only in Groups A and B (p = 0.02). Group A and B patients demonstrated clinical improvement when given antiallergic therapy. The authors identified a group of pediatric patients characterized by an allergic history, lack of adequate response to GERD therapy, normal esophageal pH probe monitoring results, and large numbers of eosinophils in esophageal biopsy specimens obtained after GERD treatment. On the basis of these features, the authors propose that these patients represent examples of allergic esophagitis.

Carbohydrate malabsorption following fruit juice ingestion in young children.

We performed breath hydrogen analyses in 13 healthy children (9 to 36 months of age) and seven children (14 to 27 months of age) with chronic nonspecific diarrhea after they had ingested pear, grape, and apple juices and a 2% sorbitol solution. Excess breath H2 excretion was found in virtually all study subjects following the ingestion of either pear juice (with approximately 2% sorbitol content) or the 2% sorbitol solution, in approximately 50% of those ingesting apple juice (0.5% sorbitol), and in 25% of those ingesting grape juice (no sorbitol) (P less than .001, analysis of variance). No differences were noted between the healthy children and those with chronic nonspecific diarrhea. Forty percent of all study subjects in whom excess breath hydrogen excretion occurred also had diarrhea and abdominal cramping. Carbohydrate malabsorption appears to be frequent following the ingestion of common fruit juices and in some children may be associated with nonspecific gastrointestinal symptoms.

Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study.

Allergic proctocolitis is a major cause of rectal bleeding in infants, but its clinical features and laboratory results are often nonspecific. Our previous retrospective study demonstrated that large numbers of eosinophils in colonic mucosal biopsy specimens were highly associated with cases of allergic proctocolitis. Therefore, we prospectively examined 60 colonic mucosal biopsy specimens from the same sites (4, 8, and 12 cm from the anal verge) in 20 infants with clinically confirmed allergic proctocolitis to validate this morphologic feature, to characterize its distribution, and to correlate these data with the clinical information. The patients (age range, 4 to 304 days) were fed breast milk or a variety of formulas and all presented with rectal bleeding. Sigmoidoscopic examination was abnormal in 19 cases, typically characterized by focal areas of mucosal erythema. The major histologic finding was a strikingly focal increase in the number of eosinophils in all mucosal compartments, with a predilection to aggregate in close association with lymphoid nodules. Eosinophilic infiltration varied not only between biopsies at different sites, but also within individual biopsy specimens. Only 12 of 20 patients (60%) had all three of their biopsy specimens categorized as abnormal; in the remainder, only one (four patients) or two (four patients) of the three biopsy specimens were abnormal. The average number of eosinophils per high-power field of lamina propria for all cases was 15.6. No significant correlation was identified between the number of eosinophils in the mucosa and the patient's age, length of illness, endoscopic appearance, or type of inciting formula. In summary, eosinophils appear to be an excellent marker for infantile allergic proctocolitis. Given the focal distribution of the eosinophils, multiple mucosal biopsy specimens should be obtained and several levels of each examined to confirm the diagnosis.

Long-term nutritional and metabolic consequences of pancreaticoduodenectomy in children.

BACKGROUND: The long-term nutritional and metabolic consequences of pancreaticoduodenectomy in children are unknown. METHODS: Five children were evaluated in a clinical research center 2.5 to 10 years after pancreaticoduodenectomy to assess their nutritional status based on patterns of growth and to assess their gastrointestinal function. Investigation included vitamin levels, a bentiromide study, and serum immunoreactive trypsinogen levels to evaluate pancreatic function and a d-xylose absorption and a radionuclide gastric emptying scan for intestinal absorption and motility. RESULTS: Children were able to grow after pancreaticoduodenectomy. Three remained in low percentile groups for height/weight ratio, and two were near or above normal. Low normal levels of the fat-soluble vitamins were present. Very low levels of pancreatic function were found based on the bentiromide and trypsinogen studies, whereas intestinal absorption of d-xylose was normal except for one patient with extremely rapid gastric emptying. CONCLUSIONS: After pancreaticoduodenectomy children can grow and develop normally if given adequate levels of oral pancreatic supplements to replace the severely decreased level of endogenous pancreatic enzymes after operation. Routine supplementation of the fat-soluble vitamins should be considered.

Long-term hepatic regeneration and function in infants and children following liver resection.

BACKGROUND: Hepatic regeneration and function after resection has been evaluated in adults, but long-term quantitative assessment has not been performed in children. Semiquantitative short-term evaluations, including radioisotope scans, have suggested that hepatic regeneration occurs quickly in children, but the effect of chemotherapy on hepatic regeneration has not been evaluated. Treating hepatoblastoma in children increasingly includes chemotherapy before resection, hence evaluating regeneration is critical. STUDY DESIGN: A retrospective evaluation was done of ten children older than one year following anatomic hepatic resection for benign or malignant tumors. Three components were evaluated. First, hepatic function was evaluated by a series of tests of synthetic function. Second, the metabolic function of the liver was evaluated by measuring the hepatic conversion of lidocaine to its breakdown product, monoethylglycinexylidide (MEGX). Third, hepatic volume was assessed by magnetic resonance imaging scan. RESULTS: All children were clinically well at the time of evaluation. Results of tests of synthetic function were essentially normal in all patients. Serum ammonia levels were mildly elevated in six patients. Hepatocellular enzymes were mildly elevated in several children, and the alkaline phosphatase level was mildly elevated in three. A lidocaine infusion study demonstrated normal levels of MEGX in all of the children except one with positive hepatitis C serology. Studies demonstrated that hepatic volumes were below but near the expected levels in most children. Sequential studies in six children demonstrated progressive growth of the livers. No adverse effect on hepatic size was noted in the children who received chemotherapy. CONCLUSIONS: The cohort of children had adequate regeneration and function of the liver following hepatic resection. No adverse effect of perioperative chemotherapy could be identified.

Quality-of-life assessment after ileoanal pull-through for ulcerative colitis and familial adenomatous polyposis.

BACKGROUND/PURPOSE: The ileoanal pull-through procedure (IAP) is gaining increasing favor and use in the surgical treatment of children with ulcerative colitis (UC) and familial adenomatous polyposis (FP). Although physiological studies have been performed to assess the outcome of these children, no long-term quality-of-life assessment after the procedure has been performed. METHODS: Forty-three patients were identified who had an IAP at our institution in the last 10 years and were at least 6 months postsurgery. Thirty-four were contacted, and 32 agreed to participate in the survey, which was approved by the Human Studies Committee. Participants completed the standardized Medical Outcome Study Short Form-36 (SF-36), which has well-established normative values. Several supplemental questions were prepared in a similar format dealing with issues specific to the ileoanal pull-through procedure. RESULTS: Of the 32 participants, 19 (59%) were girls and 26 (81%) had ulcerative colitis. Mean age at the time of survey was 18.1 years with 12 less than 18 years and 20 > or =18 years. Data from the latter group could be compared with national normative values for this age. The study group was not statistically different from age-appropriate US population normal values on all assessable scales of physical and mental health in the SF-36 survey including physical functioning, role limitations-physical, bodily pain, general health, vitality, social functioning, role limitations-emotional, and mental health (all P>.05 or mean difference SD units <0.8). The supplemental questionaire demonstrated little adverse effect of the surgery. There was limited consumption of medications to control bowel frequency and little restriction of activity because of the frequency of bowel movements or fear of incontinence. The surgical scar was the sole negative factor of significance. CONCLUSIONS: The ileoanal pull-through procedure is an excellent surgical option for children with ulcerative colitis or familial adenomatous polyposis, and it produced minimal, if any, adverse effects on their long-term quality of life.

Hypertension associated with unilateral hydronephrosis as a complication of Crohn's disease.

Obstructive uropathy with hydronephrosis is a well-known complication of Crohn's disease. The treatment for this condition is still controversial. This is the case study of a 14-year-old girl with documented right-sided obstructive uropathy secondary to Crohn's disease associated with renin-mediated hypertension secondary to her obstructive uropathy. The patient had complete resolution of her hypertension following surgery, which involved only resection of the involved bowel without ureterolysis.

Surgery for Crohn's disease in infants and children.

The course of Crohn's disease is quite variable in children. To assess the frequency and indications for surgery with current medical therapy, the authors reviewed the cases of 204 children (ages, 0.2 to 18.8 years at diagnosis, median, 12.8 years) who had Crohn's disease treated at a single institution from December 1968 to January 1994, with a median of 3.8 years of follow-up (range, 0.0 to 22.2 years). Ninety-four children (46%) required surgical resection for the following indications: (1) failure of medical therapy with persistent symptoms or growth retardation (n = 44, 47%), (2) intraabdominal abscess or perforation (n = 15, 16%), (3) fistula formation (n = 13, 14%), (4) obstruction (n = 15, 16%), (5) hemorrhage (n = 4, 4%), and (6) appendectomy at exploration for diagnosis (n = 3, 3%). The probability for surgery 3 years after diagnosis is 28.8% and by 5 years is 47.2%. Resections included ileocolectomy (71 children), colectomy (n = 16), small bowel resection (n = 4), and appendectomy (n = 3). Fourteen fistulas in 13 children required surgical intervention (7 enteroenteral, 3 enterovesical, 2 enterovaginal, and 2 enterocutaneous). The median duration from diagnosis to surgery for the fistulas was 2.6 years (range 0.1 to 9.8 years). Forty patients experienced recurring disease after resection during follow-up with a median of 1.8 years (range 0.4 to 18.1 years). The authors found that the course of the disease was unpredictable, with some children requiring early surgical intervention and others continuing with medical therapy for years.

Gastrointestinal manifestations of vascular anomalies in childhood: varied etiologies require multiple therapeutic modalities.

BACKGROUND/PURPOSE: Vascular anomalies, including hemangiomas and vascular malformations afford complex diagnostic and therapeutic challenges when gastrointestinal (GI) manifestations are present. METHODS: Twenty-one patients evaluated or treated in our Vascular Anomalies Program from 1993 through 1997 were reviewed retrospectively with regard to presentation, treatment modalities, and outcome. RESULTS: Four patients had hemangiomas, and 17 had various vascular malformations. GI symptoms began in infancy or early childhood in all patients. Manifestations included GI bleeding (n = 15), obstruction (n = 2), diarrhea (n = 2), ascites (n = 2), pain (n = 1), emesis (n = 1), ileo-ileal intussusception (n = 1), protein-losing enteropathy (n = 1), and hypersplenism (n = 1). Four patients had proven portal hypertension. Fourteen had associated musculoskeletal or cutaneous lesions. Congestive heart failure, partial anomalous pulmonary venous return, pulmonary edema, and pleural or pericardial effusion occurred in one patient each. Bleeding was the most common symptom of both hemangiomas and malformations. Of four patients with hemangiomas, three were treated with corticosteroids or interferon. Endoscopic banding and embolization of an associated arterioportal hepatic shunt were each used in one patient. One patient died. The malformations were treated with resection (n = 8), endoscopic banding or sclerosis (n = 7), percutaneous or intraoperative sclerosis (n = 5), embolization or device interruption (n = 3), and portosystemic shunt (n = 2). GI symptoms were ameliorated in 12 patients with malformation, improved in two, unchanged in two, and one died after prolonged palliation. CONCLUSIONS: Vascular anomalies with gastrointestinal manifestations are heterogeneous in their presentation and type. Although bleeding is the most common symptom of both hemangiomas and vascular malformations, treatment differs. Pharmacological angiogenesis inhibition is the mainstay of hemangioma therapy. Resection, endoscopic or radiologic vascular obliteration, and portal decompression are important in treating vascular malformations. An individualized and interdisciplinary approach is often required to successfully diagnose and treat these complex lesions.

Apple juice. An unappreciated cause of chronic diarrhea.

Chronic nonspecific diarrhea (CNSD) remains a common pediatric problem. Previous reports have suggested disordered small intestinal motility, food intolerances, dietary fat restriction, and excessive fluid consumption as possible contributory factors. We have recently encountered a subset of children with CNSD in whom nonexcessive apple juice intake seemed to cause their diarrhea. In five subjects, ingestion of 240 mL of apple juice disclosed evidence of significant carbohydrate malabsorption by breath-hydrogen testing and resulted in diarrhea. Withdrawal of apple juice from the diets of these subjects was curative in all cases. Before embarking on an expensive and time-consuming evaluation for CNSD in otherwise healthy children, a brief restriction of apple juice intake may be warranted.

Addition of a mannose-6-phosphate-containing oligosaccharide alters cellular processing of low density lipoprotein by parental and LDL-receptor-defective Chinese hamster ovary cells.

Low density lipoprotein (LDL) was chemically modified by the addition of omega-(6-phospho)-tetra(alpha 1-3)mannosyl-(alpha 1-2)mannose (M56P), a phosphorylated oligosaccharide containing a terminal mannose 6-phosphate residue. Uptake and degradation of this modified LDL (M56P-LDL) by Chinese hamster ovary (CHO) cells occurred via the lysosomal enzyme (mannose 6-phosphate) receptor pathway. Cellular processing of M56P-LDL was saturable, specific for the mannose 6-phosphate marker, and occurred with approximately threefold higher affinity than that of native LDL by the LDL receptor pathway. Mannose 6-phosphate receptor activity, as measured by degradation of M56P-LDL, was ninefold lower than the LDL receptor activity. Degradation of M56P-LDL was more sensitive to inhibition by the lysosomotropic agent chloroquine than was degradation of LDL, suggesting differences in the intracellular processing of mannose 6-phosphate-bearing ligands and LDL. Previously isolated CHO cell lines defective in LDL receptor activity resembled parental CHO cells in their ability to process M56P-LDL. The potential use of M56P-LDL in the isolation of cells with pleiotropic mutations affecting receptor-mediated endocytosis is discussed.

The antegrade colonogram: extending the small bowel follow through for children suspected of having colonic disease.

Fifty pediatric patients suspected of having colonic disease were evaluated by antegrade barium study ("antegrade colonogram") and by colonoscopy with multiple biopsy specimens. Radiographic patterns of mucosal irregularity, nodularity, or ulceration, haustral asymmetry or edema, and narrowing of the colonic lumen were easily recognized. Correlation between colonographic patterns, biopsy findings, and gross appearance at colonoscopy showed the colonogram to have an overall accuracy of 77-88%. The antegrade colonogram is easily performed and often provides information regarding areas of the colon not seen by the endoscopist. In some cases it may also be useful in the evaluation of response to therapy for inflammatory bowel disease.

Recent advances in diagnosis and treatment of gastrointestinal hemorrhage in infants and children.

Gastrointestinal bleeding is a common and occasionally life-threatening problem in infants and children. A careful history and physical examination as well as the application of new endoscopic and radiographic techniques will reveal the source of hemorrhage in most patients. The utility of recently introduced pharmacologic agents and endoscopic techniques in the treatment of peptic disease and variceal hemorrhage in children remains to be determined. A cooperative effort among pediatricians, radiologists, and surgeons should minimize the morbidity and mortality from gastrointestinal tract bleeding in this population.

Cyclosporine treatment of autoimmune chronic active hepatitis.

A 14-yr-old boy with a 5-yr history of autoimmune chronic active hepatitis refractory to corticosteroid therapy was given cyclosporin A (5 mg/kg X day). Before cyclosporine therapy, serum aminotransferase levels were 20 times normal and immunoglobulin G was 4 g/dl. Within 2 wk of starting cyclosporine therapy, aminotransferase levels decreased; by 2 mo they were almost normal, and at 1 yr into therapy they were normal. A decrease in cyclosporine dosage was associated with an increase in aminotransferase levels, which then again decreased as the dose was increased. Severe growth failure observed during previous corticosteroid therapy reversed during cyclosporine treatment and the patient displayed "catch-up" growth. No significant side effects were noted after 1 yr of cyclosporine therapy. Further evaluation of cyclosporine in the treatment of corticosteroid-unresponsive autoimmune chronic active hepatitis appears warranted.

Clinical and laboratory correlates of esophagitis in young children.

To develop clinical and laboratory criteria to identify young children with gastroesophageal reflux (GER) who are at particular risk for esophagitis and then to monitor their clinical course we have prospectively studied 40 subjects (ages 2-22 months, mean 8 months) with persistent symptoms of GER with 18 h intraesophageal pH monitoring, endoscopy, and grasp and suction esophageal biopsies. Esophagitis was found in 16 of 20 patients under 7 months, 12 of 14 between 7 and 12 months, and five of six between 12 and 24 months. Esophagitis was equally frequent in those patients with or without poor weight gain, wheezing, or irritability. Only 15% of patients with esophagitis had occult blood in their stool. No parameter of intraesophageal pH monitoring was both sensitive and specific in identifying patients who were ultimately found to have either mild or severe esophagitis. Follow-up data (37 patients) revealed that fundoplication was eventually required in four of eight patients with severe esophagitis, three of 22 with mild esophagitis, and none of seven without esophagitis. Currently used clinical and laboratory assessments of GER have limited value in identifying those children with either normal esophageal mucosa or at risk for varying degrees of esophagitis. Preliminary observations suggest that the presence of severe histologic esophagitis at the time of initial evaluation may have prognostic value in identifying those patients most likely to fail medical therapy and require fundoplication.

Regulation of low density lipoprotein receptor function in a human hepatoma cell line.

Low density lipoprotein (LDL) processing was investigated in a human hepatoma-derived cell line, Hep G2. Hep G2 cells bound, internalized and degraded LDL via a saturable, high affinity (Kd approximately 2 X 10(-8)M) pathway similar to that present in other mammalian cells. Although 80% of the uptake and degradation of 125I-LDL was inhibited by 40-fold excess native LDL, the same concentration of methylated LDL, which cannot bind to LDL receptors, had virtually no effect on processing. When added at low concentrations, the lysosomotropic agent, chloroquine, inhibited degradation (I50 approximately 15 microM) without affecting the rate of lipoprotein internalization. Receptor activity was decreased 60% by preincubation of the cells in medium containing a source of cholesterol (LDL or unesterified cholesterol) and increased 1.7-fold by preincubation with compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. The Hep G2 cell line may prove a useful system both for the further study of hepatic lipoprotein metabolism and for the evaluation of new antihypercholesterolemic agents.

Intraoperative enteroscopy in the diagnosis of partial intestinal obstruction in infancy.

We present the case of a 4-month-old infant with a prolonged illness due to an occult intestinal stricture. Diagnosis of the lesion escaped conventional radiologic and surgical methods and required intraoperative enteroscopy. Resection of the stricture lead to prompt clinical improvement. Our patient illustrates a primary diagnostic use of intraoperative enteroscopy in the detection of a partial intraluminal small bowel obstruction. As further experience accumulates with small bowel endoscopy, roles for therapeutic enteroscopy (such as polypectomy, photocoagulation, and perhaps balloon dilatation) will certainly arise. Such endeavors will depend on the continued productive collaboration between members of the surgical and gastroenterological teams.

Endoscopic ligation of esophageal varices in children.

Seven consecutive patients presenting acutely with suspected variceal hemorrhage underwent endoscopic variceal ligation (EVL) of esophageal varices. Active bleeding had ceased by the time of the initial EVL session in all patients, although active variceal hemorrhage was controlled by EVL in one patient during a subsequent episode of bleeding. Treatment sessions were repeated at approximately monthly intervals until varices were reduced in size to grade 1 (< 4 mm diameter) or eradicated. All patients had portal hypertension secondary to intrahepatic disease. Patient age ranged from 2.4 to 14.5 years (mean, 8.5 years). One patient underwent successful liver transplantation 1 week after the initial treatment session. The remaining six patients required a mean (+/- SD) of 4.0 +/- 1.3 treatment sessions for elimination of varices. One episode of recurrent variceal hemorrhage and one episode of treatment-related hemorrhage occurred in two separate patients. Transient, mild dysphagia or odynophagia occurred in all patients. No other complications were reported during a mean (+/- SD) follow-up period of 13.8 +/- 4.6 months (range, 8-20 months). Recurrent varices were seen in three of four (75%) patients returning for follow-up endoscopy between 5 and 8 months from initial eradication. All underwent repeat EVL without complication. Endoscopic variceal ligation may be a suitable substitute for sclerotherapy in children with bleeding esophageal varices.

Type 1 procollagen as a biochemical marker of growth in children with inflammatory bowel disease.

Using radioimmunoassay, we measured the levels of the C-terminal propeptide of type I procollagen (pColl-I-C) in sera from 69 children with functional bowel disease (control population), 18 children with ulcerative colitis, and 35 children with Crohn disease. Sexually mature fully grown adolescents from all three patient groups had mean pColl-I-C concentrations (12.0 +/- 0.8 micrograms/dl) similar to those previously reported for adults (5 to 17 micrograms/dl). Children with functional bowel disease and normal growth had significantly higher concentrations (32.8 +/- 1.7 micrograms/dl) (P less than 0.001) than did the fully grown adolescents. In patients with inflammatory bowel disease a significant relationship between growth velocity and pColl-I-C concentrations was noted (P less than .001). Lower pColl-I-C concentrations were found in patients receiving daily prednisone therapy compared with those receiving alternate-day therapy (P less than 0.01) or those not taking the drug (P less than 0.01). These data suggest that pColl-I-C concentrations reflect growth activity in children. Repeated determinations may allow rapid assessment of the effects of various therapeutic modalities on growth in children with inflammatory bowel disease.