Leo A. Heitlinger

Shwachman syndrome: Phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar

OBJECTIVES With the use of clinical data from a large international cohort, we evaluated and compared affected siblings and isolated cases. STUDY DESIGN Data from 116 families were collected, and patients conforming to our predetermined diagnostic criteria were analyzed. Phenotypic manifestations of affected siblings and singletons were compared with the use of t tests, Wilcoxon scores, and chi2 analysis. RESULTS Eighty-eight patients (33 female, 55 male; median age 5.20 years) fulfilled our predetermined diagnostic criteria for Shwachman syndrome; 63 patients were isolated cases, and 25 affected siblings were from 12 multiplex families. Steatorrhea was present in 86% (57 of 66), and 91% (78 of 86) displayed a low serum trypsinogen concentration. Patients older than 4 years more often had pancreatic sufficiency. Neutropenia occurred in 98%, anemia in 42%, and thrombocytopenia in 34%. Myelodysplasia or cytogenetic abnormalities were reported in 7 patients. Short stature with normal nutritional status was a prominent feature. CONCLUSIONS Clinical features among patients with Shwachman syndrome varied between patients and with age. Similarities in phenotype between isolated cases and affected sibling sets support the hypothesis that Shwachman syndrome is a single disease entity.

Is cyclic vomiting syndrome related to migraine

OBJECTIVE To examine the overlap between cyclic vomiting syndrome (CVS) and migraine by comparing 2 subsets of children with migraine-associated and non-migraine-associated CVS. METHODS We studied all children <18 years of age who met the consensus criteria for CVS after presentation to our pediatric gastroenterology service from 1986 to 1998. The clinical patterns and responses to treatment were obtained from a combination of chart reviews and structured interviews. RESULTS Among 214 children identified as having CVS, 82% were classified as having migraine-associated CVS based on 1 of 2 criteria either a family history of migraines or subsequent development of migraine headaches. Compared with the non-migraine CVS subgroup, the migraine subset had milder episodes (20.7 27.3 SD vs 39.5 66.5 emeses/episode, P =.006); more symptoms of abdominal pain (83% vs 66%), headache (41% vs 24%), social withdrawal (40% vs 22%), photophobia (36% vs 16%, all P <.05); more frequent triggering events (70% vs 49%, P =.013) including psychologic stress (39% vs 22%), physical exhaustion (23% vs 3%), and motion sickness (10% vs 0%); and a higher positive response rate to anti-migraine therapy (79% vs 36%, P =.002). CONCLUSIONS The majority of children with CVS were subclassified as having migraine-associated CVS. The migraine-associated subgroup had less severe vomiting, manifested symptoms typical of migraine headaches, and had higher response rates to anti-migraine therapy. These findings strengthen the relationship between migraine and CVS.

Relationship of endomysial antibodies to jejunal mucosal pathology: specificity towards both symptomatic and asymptomatic celiacs.

Serum immunoglobulin A class antibodies reactive to the endomysial lining of the smooth muscle bundles of the gastrointestinal tract have recently been reported to be specific and sensitive indicators of celiac disease (CD). A total of 203 subjects were examined for serum endomysial antibodies (EmA) and in 103 small bowel biopsies were obtained. EmA were detected in 43 cases including 26 CD patients evaluated during the gluten challenge phase of diagnosis by European Society for Pediatric Gastroenterology and Nutrition criteria, 11 of 53 symptomatic patients, and 6 asymptomatic family members. All patients with detectable antibody at the time of biopsy exhibited grade III-IV villous atrophy. Disaccharidase activities performed in 19 cases revealed severe deficiencies. EmA were not detected in 160 subjects including 42 infants and children with chronic nonspecific diarrhea. Eighteen of these possessed grade II-III villous atrophy with moderate disaccharidase deficiency and 24 were found to have normal histology and enzymes. The EmA were also not detected in 3 CD patients who were well maintained on a gluten-free diet for greater than 1 year and 25 asymptomatic family members exhibiting normal histology and enzymes. An additional 90 infants and children with other gastrointestinal and liver diseases were also negative for the serum EmA. Fourteen of these patients underwent biopsies and were demonstrated to have normal histology.

Human intestinal disaccharidase activities: correlations with age, biopsy technique, and degree of villus atrophy.

The relationship between intestinal morphology, disaccharidase activity, and disaccharide absorption is controversial. A retrospective study of 798 consecutive biopsies was performed to determine whether disaccharidase activities varied by subject age, biopsy technique, and degree of villus atrophy. Lactase activity was inversely correlated with age in the absence or presence of villus atrophy; sucrase, maltase, and palatinase activities did not correlate with age. Biopsies obtained by capsule or endoscopy had similar disaccharidase activities. In subjects 24 months of age or younger, the degree of mucosal injury was inversely correlated with lactase activity. In subjects older than 24 months, the degree of mucosal injury was inversely correlated with maltase and, to a lesser extent, lactase activities. The data suggest that disaccharidase activities in mucosal biopsies, whether obtained by endoscopy or capsule, are diminished in the presence of mucosal injury and correlate inversely with the degree of injury.

Cisapride for Intractable Constipation in Children: Observations from an Open Trial

Twelve patients with chronic constipation refractory to the vigorous use of emollients, enemas, and/or laxatives were chosen for study of the investigational prokinetic agent, Cisapride. The patients included 8 boys and 4 girls with diagnoses of functional constipation. Ages ranged from 2 to 13 years; duration of symptoms before Cisapride use ranged from 1.5 to 9.75 years; duration of previous treatment ranged from 0.75 to 6 years. The mean number of doses of anticonstipation agents employed per week was 14. Of the 12 patients, 10 had persistent encopresis, while 11 required hospitalization for disimpaction an average of 1.6 times in the year prior to Cisapride use. Three had chronic urinary tract complaints. Anal manometry suggested a sensory deficit in 8 of 10 patients tested. Ganglion cells were identified by rectal biopsy in all 12 patients. Cisapride treatment (0.14–0.3 mg/kg/dose) spanned 26–72 weeks (61 ± 12). Stool frequency per week was not significantly changed, but five of seven patients who had reported hard stools had softer stools on the drug (p < 0.05). Encopresis ceased in 8 of 10 cases, while the number of episodes decreased substantially in the other 2 cases (p < 0.05). All alternate forms of anticonstipation therapy were withdrawn in 8 of 12 cases (p < 0.0001). Urinary problems improved in two of the three patients reporting symptoms. One patient showed no improvement in any parameter while on the agent, despite 26 weeks of administration. Side effects were infrequent, generally occurred early, and were limited to cramping, nausea, mild vomiting, anorexia, and headaches. One patient ceased use of the drug for persistent headaches. This open trial suggests the need for a controlled study of the drug Cisapride for the indication of unremitting constipation and encopresis in childhood.

Gastrointestinal gas formation and infantile colic

Gastrointestinal gas causes distress in many patients and their parents. Most often, patients do not have an actual increase in gastrointestinal gas volume, but rather their complaints derive from a misunderstanding of normal physiology, a misinterpretation of symptoms (colic), or an increase in intestinal sensitivity (irritable bowel syndrome). Symptoms from actual increases in intestinal gas volume are seen most frequently in children who swallow excessive amounts of air, have a dysmotility syndrome, or consume foods containing poorly absorbed carbohydrates. Although many therapies are used in the treatment of gas-related symptoms, under close scrutiny, the commonly recommended agents (e.g. simethicone) do not have proven efficacy. An understanding of the physiology of gas production and disposal is of practical use to pediatricians in determining the appropriate method of intervention for patients with these complaints.

Transport of Glucose Polymer-Derived Glucose by Rabbit Jejunum

Mechanisms for the assimilation of glucose polymers have been inferred from perfusion studies. To further define these mechanisms, the results of measurements of unidirectional glucose fluxes across short-circuited rabbit jejunal segments in vitro are reported. Glucose polymer-stimulated short-circuit current was similar to that of glucose [19 +/- 6.0 microA/cm2 (n = 7) and 26 +/- 5.7 microA/cm2 (n = 13), respectively] and was inhibited by both acarbose and phlorizin. Acarbose, an alpha-glucosidase inhibitor with no effects of glucose transport, was used to uncouple digestion from absorption. Mucosal-to-serosal flux of glucose polymer-derived glucose was lower than that of an equal weight/volume of glucose [124 +/- 62 nmol.h-1.cm-2 (n = 4) vs. 452 +/- 121 nmol.h-1.cm-2 (n = 6); P less than 0.05] and was inhibited by both phlorizin and acarbose. No glucose polymers were detected in the serosal bath solutions by thin-layer chromatography. It is concluded that glucose polymer-derived glucose is transported by a phlorizin-inhibitable process at a rate slower than that of free glucose, a finding that suggests that hydrolysis limits glucose polymer assimilation.

Enterohepatic Distribution of Carnitine in Developing Piglets: Relation to Glucagon and Insulin

ABSTRACT: L-Carnitine plays a crucial role in the perinatal transition from carbohydrate to lipid-derived energy. To examine the potential contribution of assimilated dietary carnitine to the elevated hepatic concentrations in newborns, we measured carnitine concentrations in sow milk, jejunum, and liver, and in vitro jejunal carnitine transport in piglets aged 1–36 d. Hepatic and sow milk total carnitine concentrations peaked soon after birth and declined with age (p = 0.035 and 0.026, respectively). Although jejunal total carnitine concentrations remained stable, jejunal carnitine flux was higher at 2 d of age than in older piglets. To examine the possible signals that regulate hepatic carnitine, portal enteroinsular hormones were measured by RIA. Portal glucagon (p = 0.0006), insulin (p = 0.0001), and glucagon:insulin ratio (p = 0.037) were related to age. Portal glucagon was highest in newborns and during weaning, whereas insulin increased progressively with age; the portal glucagon:insulin ratio, like hepatic carnitine, peaked soon after birth and fell with age. A multiple regression analysis indicated a positive association between glucagon and hepatic carnitine and a negative one between insulin and hepatic carnitine (R = 0.802, p = 0.001). An overall pattern of elevated dietary carnitine levels and increased small intestinal absorption and hepatic accumulation of carnitine is noted in early development. The finding of a similar pattern in glucagon-to-insulin ratio suggests that both hormones may participate in the regulation of enterohepatic carnitine distribution in newborns.

Rectal Myopathy in Chronically Constipated Children

We examined full-thickness rectal biopsies from 30 children who had chronic constipation, including 5 children with constipation associated with clinical symptoms of intestinal pseudo-obstruction. Biopsies from 9 patients who required colonic interposition and from 7 with Hirschsprungs disease were used as controls. Tissues were evaluated for muscularis mucosae thickness (in mm), for absolute circular and longitudinal muscle layer thicknesses and their ratio, and for the intensity of neural vasoactive intestinal peptide (VIP) immunohistochemical staining. Atrophy of the rectal musculature with focal muscle fiber vacuolation or muscle fiber disappearance was found in all children with chronic constipation. Muscularis mucosae thickness was increased (P < .01) and the circular-to-longitudinal muscle ratio was decreased in the constipation group, with the greatest degree of atrophy being demonstrated in the circular layer. Two of the patients had additional biopsies up to 9 years after the first that illustrate progressive myopathic changes over time. This study demonstrates muscular atrophy in the rectum of children with chronic constipation. Besides primary idiopathic disease, potential etiologies include chronic distention, denervation, functional obstruction from obstipation, alteration in gut hormones, and toxic, ischemic, or neural injury.

Enzymes in mother's milk and their possible role in digestion.

Human breast milk contains many enzymes, some of which may assist in digestion; other enzymes may have other diverse functions. The loci and regulation of milk enzyme synthesis remain to be elucidated, but multiple loci and complex hormonal regulation seem to be likely. In a similar fashion, multiple mechanisms of protein release have been described, but stimulus secretion coupling has not been directly demonstrated. The possible physiologic importance of milk as compensatory mechanisms for the relatively limited digestive capabilities of young infants is but one of many reasons why breast milk should not be heated, if possible, prior to feeding.