Paediatric Castleman disease: report of seven cases and review of the literature.

UNLABELLED: Castleman disease is a distinct lymphoproliferative disorder of unknown origin. Seven new cases in children are reported here and 76 cases from the paediatric literature are reviewed. The disease has been reported in 46 females and 37 males, their age ranging from 2 months to 17 years. The disease was localized in 72 cases and multicentric in 11 cases. The hyalinovascular type was more frequently encountered (54%) than the plasma cell type (24%). Laboratory abnormalities were more often associated with the plasma cell type and were mainly represented by anaemia and hypergammaglobulinaemia. Treatment of the localized tumour consisted of surgical excision, whereas treatment of the multicentric form was medical, comprising prednisone and other immunosuppressor drugs. The disease in the paediatric population seems to have a more favourable course than in adults. CONCLUSION: The paediatric features of the disease suggest that Castleman disease in this population could represent an earlier form of the pathology or even suggest a benign lymphoproliferative disorder.

Liver disease in children with cystic fibrosis: US-biochemical comparison in 195 patients.

PURPOSE: To determine if abnormal liver architecture at ultrasonography (US) is related to abnormal function in children with cystic fibrosis (CF). MATERIALS AND METHODS: For 1 year, all 195 children (112 boys, 83 girls; mean age, 8.5 years) attending a CF clinic underwent abdominal US and a standard set of liver function tests. Aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase levels were analyzed. US signs were interpreted as follows: hypoechogenicity with prominent portal tracks as edema, hyperechogenicity as steatosis, and increased attenuation and nodules within or at the edge of the liver as cirrhosis. Signs of portal hypertension also were sought. US signs were compared with liver function test results. RESULTS: Liver sonograms were abnormal in 38 children (19%); of these, 24 (63%) had abnormal test results. The 157 children with normal liver architecture had a much lower prevalence of biochemical abnormality (33 patients [21%]; P < or = .001). All eight children with signs of portal hypertension had abnormal test results. Fourteen (82%) of 17 children with signs of cirrhosis had abnormal liver function. Eight (57%) of 14 patients with signs of steatosis had abnormal function. Diffuse hypoechogenicity of the liver with prominent portal tracks in 16 patients was associated with abnormal function in only five patients. CONCLUSION: The relation between abnormal liver architecture at US and results of three liver function tests in children with CF was significant. The most specific US abnormalities related to abnormal function are signs suggestive of portal hypertension and cirrhosis.

Autoimmune enteropathy.

Autoimmune enteropathy (AIE) is an entity reported primarily in infancy, resulting in intractable diarrhea and associated with small bowel villous atrophy and the presence of circulating anti-enterocyte (AEA) antibodies. It is a multisystem disorder with a response, in many cases, to immunosuppressive therapy.

Cisapride in pediatric gastroesophageal reflux.

BACKGROUND: Gastroesophageal reflux is a common condition that in infants may lead to serious complication. This study assessed the efficacy and safety of oral cisapride suspension in the treatment of children 6 weeks to 2 years old with daily regurgitant reflux. METHODS: A randomized, prospective, double-blind, placebo-controlled clinical trial was conducted at three study sites. After a 1 week baseline assessment, 45 infants 6 weeks to 2 years old were randomized to a double-blind trial in which they received a 6 week course of cisapride (0.2 mg/kg q6h) or a placebo suspension. Efficacy was assessed with 24 hour esophageal pH monitoring, esophageal manometry, and esophageal biopsy before and after the treatment period. A diary of regurgitation frequency and severity was kept by the parents. Safety was assessed by adverse event monitoring and standard laboratory measurements. RESULTS: Compared with placebo, cisapride significantly (p < 0.05) reduced the mean duration of upright and supine reflux episodes. Compared to baseline, cisapride significantly reduced the mean duration of the longest reflux episode, and placebo increased the mean number of reflux episodes longer than 5 minutes. Cisapride was not significantly different from placebo for the following mean measurements: percent of total time pH < 4, number of reflux episodes, lower esophageal sphincter pressure, swallow pressure, regurgitation frequency or global evaluation scores. CONCLUSIONS: Cisapride is a safe, well tolerated prokinetic agent that improves the esophageal clearance of refluxed gastric acid in children under the age of 2 years.

Ursodeoxycholic acid improves the hepatic metabolism of essential fatty acids and retinol in children with cystic fibrosis.

OBJECTIVE: Several clinical trials of ursodeoxycholic acid (UDCA) have shown improvement of liver-function test results in cystic fibrosis (CF) with liver disease; however, there is no evidence that the long-term course will be affected. In view of the observations that UDCA can change the lipid profile and that patients with CF and liver disease are more likely to have essential fatty acid (EFA) deficiency, we elected to examine changes in the lipid profile and in the status of fat-soluble vitamins in response to UDCA. METHODS: Nineteen children with CF and liver dysfunction were recruited for a double-blind, crossover study of 1 year's duration, followed by treatment of the entire group. UDCA was administered at a dosage of 15 mg/kg per day, which, in the absence of a 50% decrease of alanine transaminase or aspartate transaminase or both within 2 months, was increased to 30 mg/kg per day. RESULTS: At entry, all patients had biochemical evidence of EFA deficiency. The lipid profiles during an average period of 25 months of follow-up showed a significant decrease in triglycerides (p <0.002), cholesterol (p <0.02), and total fatty acids (p <0.006). In addition, UDCA therapy led to an improvement in EFA status, as indicated by an increase (p <0.05) in the n-6 fatty acid concentration and a reduction (p <0.04) in the 20:3n-9/20:4n-6 fatty acid ratio. Although no change in vitamin E levels was observed, retinol metabolism was altered. There was an increase (p <0.02) in the unesterified retinol/retinol binding protein molar ratio in the absence of a difference in retinol binding protein concentration. Furthermore, retinyl esters, which normally account for less than 3% of circulating retinol, decreased (p <0.05) from 13.7% +/- 3.6% to 8.1% +/- 1.7%. CONCLUSIONS: This study confirms that UDCA alters lipoprotein metabolism and shows that it improves the EFA and retinol status of patients with CF and liver disease.

Supplementation with carotenoids corrects increased lipid peroxidation in children with cystic fibrosis.

Evidence of lipid peroxidation previously documented in cystic fibrosis (CF) implies an imbalance between free radical generation and antioxidant defense mechanisms. The aim of the present study was to examine the relation between plasma concentrations of malondialdehyde, a marker of lipid peroxidation, and the exogenous antioxidant line of defense. Malondialdehyde concentrations (90.2 +/- 4.7 nmol/L) in 25 children with CF aged 9.6 +/- 0.8 y were higher (P < 0.001) than concentrations (69.1 +/- 2.6 nmol/L) in 17 children used as control subjects and were not correlated with any marker of disease severity. In contrast with their all-rac-alpha-tocopherol status, which was normal as a result of routine supplementation with a 200-mg dose of all-rac-alpha-tocopheryl acetate/d, beta-carotene was very low. A 2-mo open trial in which 12 children with CF aged 11.5 +/- 0.8 y were given 4.42 mg (8.23 mumol) beta-carotene three times per day led to normalization of the malondialdehyde concentration in all but 1 patient, in conjunction with an increase of plasma beta-carotene from 0.08 +/- 0.03 to 3.99 +/- 0.92 mumol/L. Their plasma concentrations were inversely correlated (r = -0.54, P = 0.006) [corrected] with malondialdehyde when the values measured pre- and posttreatment were pooled. We conclude that beta-carotene deficiency contributes to lipid peroxidation in CF and that supplementation may eventually prove to be a useful adjunct for the management of the disease.

Bile formation and hepatic plasma membrane composition in guinea-pigs and rats.

We compared bile formation, and biliary and liver plasma membrane composition in guinea-pigs and rats in an attempt to explain the observation that the bile flow rate and the bile acid independent fraction of bile flow (BAIF) in guinea-pigs is about five to seven times higher than in rats. Analysis of electrolytes in bile showed that bicarbonate was significantly [acid] higher in guinea-pigs while Cl-, phosphate and Ca2+ were markedly lower than in rats. High bile independent secretion in guinea-pigs was associated with a significantly lower concentration of total bile acid, phospholipid and cholesterol than in rats. Bile acid distribution studies showed that glycine conjugated chenodeoxycholate and ketolithocholate were the main bile acids in guinea-pigs, while taurine conjugated cholate and muricholate were the predominant bile acids in rats. Total fatty acid analysis of bile indicated that in rats the major fatty acids were palmitic acid (C16:0) and linoleic acid (C18:2, n-6). In guinea-pigs, the contribution of these fatty acids was lower than in rats and compensated with a significantly higher percentage of oleic acid (C18:1, n-9). Concentrations of anionic polypeptide fraction (APF), an acidic calcium binding apoprotein closely associated with biliary phospholipid and cholesterol secretion was also significantly lower in guinea-pigs. Canalicular plasma membrane analysis showed that as compared with rats, specific activities of Na+,K+ ATPase, and cholesterol and phospholipid content were markedly lower in guinea-pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Variable expression of familial heterozygous hypobetalipoproteinemia: transient malabsorption during infancy.

Rare instances of symptomatic fat malabsorption have been reported in patients with heterozygous hypobetalipoproteinemia, but with an unclear pathogenesis. An 8-month-old boy with chronic diarrhea and failure to thrive was found to have abnormally low plasma total cholesterol (85 mg/dl), LDL-cholesterol (48 mg/dl), apoB (52 mg/dl), apoA-I (53 mg/dl), and vitamin E (0.22 mg/dl). Decreased plasma LDL-C and apoB were noted in the father (34 and 40 mg/dl, respectively), as well as several other family members. Fasting triglycerides were normal but did not increase normally in response to a fat meal test. Lipoprotein composition showed an abnormal profile of very low density (VLDL, d 1.006 g/ml), low density (LDL, d 1.063 g/ml), and high density (HDL, d 1.21 g/ml) lipoproteins. A fasting jejunal biopsy revealed lipid-laden enterocytes. Electron microscopy of the jejunal biopsy revealed the absence of lipid particles in the intercellular spaces after a fat meal. Jejunal explants cultured with [14C]palmitate and [3H]leucine showed limited synthesis of triglycerides and apolipoproteins (36 and 42% of controls, respectively), whereas the father's results were close to normal. At 1 year of age, improvement in intestinal fat absorption was accompanied by the presence of chylomicrons in the intercellular space, concomitant with the enhanced synthesis of lipids and apoB by jejunal explants. These data provide evidence that heterozygous hypobetalipoproteinemia may present early in life as transient, symptomatic lipid malabsorption. The mechanisms responsible for improved lipid transport despite persistent hypobetalipoproteinemia remain to be established.

The potential of the hydrocarbon breath test as a measure of lipid peroxidation.

The straight chain aliphatic hydrocarbons ethane and pentane have been advocated as noninvasive markers of free-radical induced lipid peroxidation in humans. In in vitro studies, the evolution of ethane and pentane as end products of n-3 and n-6 polyunsaturated fatty acids, respectively, correlates very well with other markers of lipid peroxidation and even seems to be the most sensitive test available. In laboratory animals the use of both hydrocarbons as in vivo markers of lipid peroxidation has been validated extensively. Although there are other possible sources of hydrocarbons in the body, such as protein oxidation and colonic bacterial metabolism, these apparently are of limited importance and do not interfere with the interpretation of the hydrocarbon breath test. The production of hydrocarbons relative to that of other end products of lipid peroxidation depends on variables that are difficult to control, such as the local availability of iron(II) ions and dioxygen. In addition, hydrocarbons are metabolized in the body, which especially influences the excretion of pentane. Because of the extremely low concentrations of ethane and pentane in human breath, which often are not significantly higher than those in ambient air, the hydrocarbon breath test requires a flawless technique regarding such factors as: (1) the preparation of the subject with hydrocarbon-free air to wash out ambient air hydrocarbons from the lungs, (2) the avoidance of ambient air contamination of the breath sample by using appropriate materials for sampling and storing, and (3) the procedures used to concentrate and filter the samples prior to gas chromatographic determination. For the gas chromatographic separation of hydrocarbons, open tubular capillary columns are preferred because of their high resolution capacity. Only in those settings where expired hydrocarbon levels are substantially higher than ambient air levels might washout prove to be unnecessary, at least in adults. Although many investigators have concentrated on one marker, it seems preferable to measure both ethane and pentane concurrently. The results of the hydrocarbon breath test are not influenced by prior food consumption, but both vitamin E and beta-carotene supplementation decrease hydrocarbon excretion. Nevertheless, the long-term use of a diet high in polyunsaturated fatty acids, such as in parenteral nutrition regimens, may result in increased hydrocarbon exhalation. Hydrocarbon excretion slightly increases with increasing age. Short-term increases follow physical and intellectual stress and exposure to hyperbaric dioxygen.(ABSTRACT TRUNCATED AT 400 WORDS)

S-adenosylmethionine prevents total parenteral nutrition-induced cholestasis in the rat.

Both an excess and an imbalance of amino acids have been associated with total parenteral nutrition-induced cholestasis. The present study was undertaken to further our understanding of this condition in light of observations that methyl donor amino acids may be protective. Rats were maintained on Travasol (3.4 g amino acids/24 h) and dextrose (10.2 g/24 h) with and without the "active methyl" S-adenosylmethionine at a dose of 75 mg/kg/24 h for 5 days, and compared to control rats on dextrose alone (10.2 g/24 h) with free access to rat chow. Bile flow (microliters/min) was lower (p < 0.025) in the Travasol (8.65 +/- 0.78) than in the control group (12.30 +/- 0.52) and was restored in the Travasol+S-adenosylmethionine animals (11.42 +/- 10). Furthermore, the bile acid secretory rate (mumol/h) was higher (p < 0.05) with S-adenosylmethionine (23.34 +/- 3.71) than without S-adenosylmethionine (14.16 +/- 2.19). As expected, the molar ratio of biliary cholesterol was lower (p < 0.005) in both total parenteral nutrition groups. However, in the total parenteral nutrition group without S-adenosylmethionine, there was also a decrease in the molar ratio of phospholipids which correlated well with the bile acid secretory rate. Analysis of liver plasma membranes showed that a lower activity of Na+K(+)-ATPase (mumol Pi/mg protein/h) (p < 0.005) in the Travasol animals (6.26 +/- 0.53) was restored to control values (15.20 +/- 1.43) by the addition of S-adenosylmethionine (17.07 +/- 2.87). In the three groups, a close correlation was observed between Na+K(+)-ATPase activity and bile flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver membrane composition after short-term parenteral nutrition with and without taurine in guinea pigs: the effect to taurine.

Having recently demonstrated that taurine supplementation prevents total parenteral nutrition (TPN)-induced cholestasis, we chose to use this model to examine plasma membrane composition in relation to bile formation. Male guinea pigs received daily a mixture of glucose and of the amino acid solution Travasol with or without added taurine (1.2 mM). After 3 days, bile was collected and liver plasma membrane fractions enriched in sinusoidal lateral membrane and bile canalicular membrane domains were isolated. In animals receiving TPN alone, bile flow and biliary secretory rate of bile acid and bicarbonate decreased significantly compared with controls. Although membrane ATPases (Na+K+ and Mg+) were unchanged, TPN induced an increase in the lipid to protein ratio and a decrease of polyunsaturated fatty acids, in conjunction with a higher content of diene conjugates in sinusoidal lateral membrane fractions. Taurine corrected these changes and, in addition, reduced significantly the cholesterol to phospholipid ratio in both membrane fractions. The data show that changes in liver cell membranes occur in TPN-induced cholestasis and suggest that free radical injury may play a role. As taurine prevented cholestasis as well as membrane changes, it is suggested that taurine should be added to amino acid solutions used for parenteral nutrition.

Beneficial effects of fish-oil supplements on lipids, lipoproteins, and lipoprotein lipase in patients with glycogen storage disease type I.

Glycogen storage disease type I (GSD-I) is frequently complicated by severe hyperlipoproteinemia and the increased potential risk of premature atherosclerosis. The effects of fish-oil supplementation [MaxEPA, 10 g.(1.73 m2)-1 for 3 mo] were investigated prospectively in seven hyperlipoproteinemic patients with GSD-I. Hypertriglyceridemia and hypercholesterolemia improved after 3 mo of fish-oil treatment, decreasing 49% (P < 0.005) and 23%, respectively. This was accompanied by a reduction in both low-density-lipoprotein (LDL) cholesterol (25%, P < 0.03) and apolipoprotein B (40%) and by increased high-density-lipoprotein increased (HDL) cholesterol (30%, P < 0.002) and apolipoprotein A-I (31%, P < 0.05). Low pretreatment ratios of HDL to total cholesterol and HDL to LDL, indicators of elevated atherosclerosis risk, increased significantly (P < 0.05). Plasma lipoprotein profile as well as lipoprotein composition [triglyceride (TG) enrichment and cholesteryl depletion] improved. Reduced TG concentrations were due to enhanced fat catabolism, as evidenced by the significantly increased hepatic and extrahepatic lipoprotein lipase activity (P < 0.05). Withdrawal of fish oil for 3 mo was associated with a return to pretreatment abnormalities in plasma lipids and lipoproteins. Fish-oil supplementation thus improves the hyperlipoproteinemia in GSD-I and may significantly reduce the risk of premature atherosclerotic cardiovascular disease.

Prolonged pH monitoring is of limited usefulness for gastroesophageal reflux.

OBJECTIVE: To assess the diagnostic value of pH monitoring. DESIGN: A prospective study. SETTING: Pediatric university hospital serving as a secondary and tertiary referral center. PARTICIPANTS: Thirty-eight infants, aged 1 to 12 months, and 26 children, aged 13 months to 18 years, admitted during a 2-year period because of clinically significant gastroesophageal reflux (GER). INTERVENTIONS: Prolonged (20-hour) pH monitoring as well as endoscopy and biopsy of the esophagus were carried out in all patients who, on the basis of clinical data, were classified as having mild, moderate, or severe GER disease. RESULTS: In the infant group, results of prolonged pH monitoring were abnormal in 34 (89.5%). In the older group, results were abnormal in less than half (11 [42.3%]) of the cases. In both groups, pH monitoring data did not correlate with the severity of GER disease or of esophagitis. Severity of GER disease was not predictive of esophagitis. CONCLUSIONS: (1) Endoscopy and biopsy of the esophagus should be the first procedures whenever there are clinical findings of moderate to severe GER disease. (2) Monitoring of pH should be restricted to those patients without a clear-cut history of GER disease.

The hydrocarbon breath test in the study of lipid peroxidation: principles and practice.

Lipid peroxidation has gained increasing interest in recent years as one of the more prominent features of free radical-induced damage in biology. The study of lipid peroxidation might increase our understanding of the etiology and pathophysiology of a great number of diseases. Ethane and pentane are among the numerous end-products of lipid peroxidation and although they represent only a small and possibly variable proportion of the total amount of peroxidized polyunsaturated fatty acids, their determination in head space or exhaled breath enables accurate assessment of oxidative stress both in vitro and in vivo. To date, the number of studies utilizing the hydrocarbon breath test as a marker of lipid peroxidation in humans is small. Technical difficulties are among the main reasons for the limited use of this method. An appropriate washout period, the use of the right materials, the scrupulous avoidance of air contamination, adequate preinjection concentrations of the samples, and a sensitive gas chromatographic technique enable the accurate and reproducible measurement of hydrocarbons in human breath. The hydrocarbon breath test provides a noninvasive and extremely sensitive instrument for the assessment of oxidative stress status in adults as well as in children.

Intraluminal and intracellular phases of fat absorption are impaired in essential fatty acid deficiency.

The structure and function of enterocyte membranes are particularly sensitive to the degree of fatty acid saturation. The objective of the present study was to assess intestinal fat transport in essential fatty acid (EFA)-deficient animal models. Both the digestive and absorptive phases leading to the formation and the secretion of triglyceride (TG)-rich lipoproteins were investigated. After an intraduodenal fat infusion, the percentage increase of plasma TG over fasting values was examined over a period of 4 h in two groups of control and EFA-deficient rats. Lower values at 1 and 2 h (P less than 0.05) were observed in EFA-deficient rats, suggesting fat malabsorption. Likewise, postprandial chylomicronemia was diminished. In a separate group of rats, EFA deficiency was associated with reduced TG and chylomicron-TG transport into lymph. Although pancreatic lipase activity did not change (47.1 vs. 46.2 mumol free fatty acids.mg protein-1.h-1), bile flow was decreased over the 8-h period of collection. Concomitantly, a significant decline (nmol.min-1.g liver-1, P less than 0.05) was discernible in the biliary secretory rate of bile salts (14.09 +/- 2.13 vs. 35.09 +/- 3.73), phospholipids (7.01 +/- 0.61 vs. 11.79 +/- 1.65) and cholesterol (0.19 +/- 0.01 vs. 0.83 +/- 0.06). In vitro studies, utilizing everted sacs incubated with mixed micelles, revealed that EFA-deficient jejunal segments of rats incorporated and esterified less [14C]oleic acid (21 and 32%, respectively). Moreover, the synthesis and secretion of TG-rich lipoproteins were found markedly reduced in mouse jejunal explant cultures. We conclude that EFA deficiency modifies both the intraluminal and intracellular phases of fat absorption.

Pneumatosis and pneumoperitoneum in chronic idiopathic intestinal pseudoobstruction.

Chronic idiopathic intestinal pseudoobstruction is a diagnosis of exclusion for the rare patient with severe small bowel atony without any demonstrable organic cause. The very poor prognosis associated with this disease has been somewhat improved with the advent of parenteral nutrition; nevertheless, these patients follow a stormy course characterized by malnutrition, recurrent obstruction, infection, hemorrhage, and perforation. We describe a 16-year-old boy with this disease who presented to us with vague abdominal pain and pneumoperitoneum. Laparotomy showed pneumatosis cystoides intestinalis without intestinal perforation. The presence of free air in the abdominal cavity is an almost pathognomonic sign of intestinal perforation. Pneumatosis cystoides intestinalis is one of the very few nonsurgical causes of pneumoperitoneum. Beyond the neonatal period, in which it is the hallmark of necrotizing enterocolitis, it has been described in patients with severe obstructive lung disease, in collagenous disorders, and in the short-bowel syndrome. In the present case, it may have resulted from chronic intestinal distension, allowing air under pressure to dissect through the bowel wall. The challenge of such a unique association of conditions lies in the avoidance of unnecessary surgery in a chronic, essentially nonsurgical disease while avoiding unnecessary delay in a possibly acute surgical event.