Ranitidine, 75 mg, over-the-counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux.

BACKGROUND: The use of over-the-counter antacids has increased in children under the age of 12 years, and has been followed by an apparent increase in the use of over-the-counter histamine-2 receptor antagonists. However, the pharmacokinetic and pharmacodynamic effects of over-the-counter histamine-2 receptor antagonists in the paediatric population are largely unknown. AIM: To evaluate the pharmacokinetics and pharmacodynamics of a single dose of the over-the-counter histamine-2 receptor antagonist, ranitidine, 75 mg, in children with symptoms of gastro-oesophageal reflux disease. METHODS: Children aged between 4 and 11 years with symptoms of heartburn suspected to be due to gastro-oesophageal reflux disease were recruited at six clinical centres. Following a single dose of either oral ranitidine, 75 mg (n=19), or placebo (n=10), recording of intragastric pH and serial blood sampling were carried out for 6 h. RESULTS: The estimated pharmacokinetic parameters of ranitidine, 75 mg, were as follows: the median Cmax value of 477 ng/mL occurred within a median of 2.5 h after dosing, and the median half-life was 2.0 h. The intragastric pH began to rise approximately 30 min after dosing with ranitidine to a peak of pH; 4. The pH in the ranitidine group remained higher than that in the placebo group throughout the 6-h evaluation period. Adverse events were generally mild. CONCLUSIONS: Ranitidine, 75 mg, significantly increased the intragastric pH in children aged 4-11 years. The pharmacokinetic and pharmacodynamic profiles were similar to those in adults. Ranitidine, 75 mg, appears to be effective for the control of intragastric acidity for 5-6 h in children aged 4-11 years.

Frequency of celiac disease in individuals with Down syndrome in the United States.

Ninety-three individuals with Down syndrome (DS) were screened to investigate the prevalence of celiac disease (CD) in the United States. Five of the 93 individuals were antiendomysial antibody (EMA) positive. Of the 5 who tested positive for EMA, 4 were biopsied, 1 refused biopsy. Three of the 4 individuals biopsied manifested changes of CD on small bowel biopsy. This gives a frequency of 3.2% of confirmed CD in our DS individuals and suggests the need for periodic screening for celiac disease in this population.

Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency.

There is a correlation between pregnancy complications such as acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency. We diagnosed another fatty acid beta-oxidation defect, short-chain acyl-coenzyme A dehydrogenase deficiency, in an infant when evaluating him because his mother had acute fatty liver of pregnancy. Other beta-oxidation defects, in addition to LCHAD deficiency, should be considered in children born after pregnancies complicated by liver disease.

New developments in the pathophysiology, clinical spectrum, and diagnosis of disorders of fatty acid oxidation.

Fatty acid oxidation disorders are among the most common inborn errors of metabolism affecting infants and children. Recognition of this family of defects is critical because careful dietary monitoring, avoidance of fasting, and prompt intervention during common childhood illness can prevent catastrophic cardiac and metabolic decompensation. This review focuses on new molecular and clinical diagnostic aspects of several of these disorders. Recent papers highlight the recognition that the clinical spectrum of disorders of fatty acid oxidation goes far beyond the stereotypical Reyes-like presentation or cardiomyopathy, and now encompasses more cases of sudden infant death syndrome, fulminant hepatic failure, and severe complications during pregnancy.

Acylcarnitines in plasma and blood spots of patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase defiency.

The acylcarnitines in plasma and blood spots of 23 patients with proven deficiency of long-chain 3-hydroxyacylcoenzyme A dehydrogenase were reviewed. Long-chain 3-hydroxyacylcarnitines of C14:1, C14, C16 and C18:1 chain length, and long-chain acylcarnitines of C12, C14:1, C14, C16, C18:2 and C18:1 chain length were elevated. Acetylcarnitine was decreased. In plasma, elevation of hydroxy-C18:1 acylcarnitine over the 95th centile of controls, in combination with an elevation of two of the three acylcarnitines C14, C14:1 and hydroxy-C16, identified over 85% of patients with high specificity (less than 0.1% false positive rate). High endogenous levels of long-chain acylcarnitines in normal erythrocytes reduced the diagnostic specificity in blood spots compared with plasma samples. The results were also diagnostic in asymptomatic patients, and were not influenced by genotype. Treatment with diet low in fat and high in medium-chain triglyceride decreased all disease-specific acylcarnitines, often to normal, suggesting that this assay is useful in treatment monitoring.

Sacrosidase therapy for congenital sucrase-isomaltase deficiency.

BACKGROUND: The purpose of this study was to determine if sacrosidase, a liquid produced from Saccharomyces cerevisiae containing 6000 IU of sucrase activity per mg protein, prevented symptoms of diarrhea, abdominal cramps, gas, and bloating in patients with congenital sucrase-isomaltase deficiency (CSID) consuming a normal sucrose and carbohydrate-containing diet. METHODS: Twenty-eight children (aged 5 months to 11 years) underwent a randomized, double-blind trial consisting of two phases: 1) three sucrose breath H2 tests with three single-dose treatments (placebo, sacrosidase, and sacrosidase plus milk), and 2) a dose-response phase consisting of four multidose treatments, each for 10 days of full-strength sacrosidase, 1:10 dilution, 1:100 dilution, and 1:1000 dilution. Patients who weighed less than or equal to 15 kg received a dose of sacrosidase and those who weighed more than 15 kg received 2 ml. For the dose-response phase each patient consumed a normal diet. The number of stools and severity of symptoms were recorded daily for each concentration of sacrosidase administered and compared to a baseline period during which the patient took no sacrosidase and consumed a sucrose/starch-free diet. Data were analyzed using an ANOVA model and the nonparameter Wilcoxon signed-rank test. RESULTS: Breath H2 excretion decreased significantly when patients received sacrosidase or sacrosidase plus milk compared to placebo during sucrose breath tests. During the dose-response phase significant treatment differences were observed between the two higher concentrations and the two lower concentrations of sacrosidase for both total stools (p < 0.001) and total symptom score (p = 0.003). Higher concentrations of sacrosidase were associated with fewer stools and a greater number of formed or hard stools compared to lower concentrations and compared to the baseline period. Higher concentrations were also associated with fewer symptoms of gas, abdominal cramps, or bloating, but no differences in vomiting. The only significant adverse event was wheezing in one child with a history of asthma. CONCLUSIONS: Sacrosidase is a safe, effective, well-accepted treatment to prevent gastrointestinal symptoms in patients with CSID consuming a normal diet.

Mitochondria and childhood liver diseases.

The newly recognized mitochondrial hepatopathies should be considered in the differential diagnosis of acute and chronic liver disease in childhood. It may appear as neonatal liver failure, delayed onset liver failure in early childhood or as a multisystemic process. Comparison of features of several of the known primary mitochondrial hepatopathies is provided in Table 5. Secondary mitochondrial hepatopathies are examples of the critical importance of mitochondrial function in the pathogenesis of liver injury. Our improved understanding of the role of the mitochondria in cellular necrosis and apoptosis opens the way for development of new therapeutic approaches to several hepatic disorders. Primary mitochondrial hepatopathies (especially the respiratory chain defects) should be considered in any child with liver disease and neuromuscular involvement, multisystemic disease, lactic acidosis or rapidly progressive disease, and when hepatic steatosis is the dominant histologic finding on examination of a liver specimen. Current therapies are inadequate; improved therapeutic strategies are needed for these disorders. Some patients with respiratory chain defects limited to the liver have had successful liver transplantation. This field is in evolution and will undoubtedly provide new and important developments as the next millennium begins.

Disorders of the mitochondria.

Recent advances in our understanding of the structure and function of mitochondria have led to the recognition that inherited and acquired mitochondrial dysfunction may be responsible for diseases affecting the liver and other organ systems. Mitochondrial health may also determine hepatocyte survival in other hepatic disorders not directly related to the mitochondrion. Primary mitochondrial hepatopathies are conditions in which there are inherited defects in structure or function of the mitochondria, most of which involve the respiratory chain and oxidative phosphorylation, fatty acid oxidation, the urea cycle, and other pathways confined to mitochondria. Maternally inherited mutations or deletions of the mitochondrial genome, or putative nuclear gene mutations encoding electron transport proteins, cause defective electron transport, oxidative stress, impaired oxidative phosphorylation, and other metabolic derangements that lead to hepatic failure or chronic liver dysfunction in affected children. The mitochondrial DNA (mtDNA) depletion syndrome, which similarly leads to liver failure and neurologic abnormalities, is caused by a putative nuclear gene that controls mtDNA replication or stability. Other proven or suspected primary mitochondrial hepatopathies include Pearson's marrow-pancreas syndrome, Alpers disease, mitochondrial neurogastrointestinal encephalomyopathy syndrome, and Navajo neuropathy. Secondary mitochondrial hepatopathies are conditions in which the mitochondria are major targets during liver injury from another cause, such as metal overload, certain drugs and toxins, alcoholic liver injury, and conditions of oxidant stress. Diagnosis of mitochondrial dysfunction may be difficult with currently available tools, however, elevated blood lactate: pyruvate ratios or arterial ketone body ratios with characteristic liver histology are initial tests. Measuring respiratory chain enzyme activities, mtDNA levels, and searching for mtDNA mutations and deletions are more specific tests. Treatment of these disorders is currently empirical, involving agents that may improve the redox status of mitochondria, promote electron flow, or act as mitochondrial antioxidants. Liver transplantation has occasionally been successful in patients who lack other systemic involvement.

Gastric graft-versus-host disease: a blinded histologic study.

Acute graft-versus-host disease (GvHD) of the upper gastrointestinal (GI) tract is common after allogeneic bone marrow transplantation (BMT). However, diagnosis cannot be made on clinical presentation and endoscopic findings alone, because these are nonspecific, and histologic confirmation is often desirable. The diagnosis of gastric GvHD is often based on subtle findings with considerable potential for variability in interpretation. Evaluation of the reproducibility of diagnosis and recognition of histologic features of gastric GvHD was based on blinded review of 56 gastric biopsies (24 from patients with allogeneic BMT or unrelated umbilical cord blood transplantation and 32 control biopsies from patients who did not undergo BMT, of whom eight had active GI cytomegalovirus [CMV] infection). Histologic criteria for GvHD were apoptosis and gland destruction, sparse inflammatory infiltrate, and granular eosinophilic debris in dilated glands. Seventeen patients (22 biopsies) were judged to have clinical GvHD on the basis of skin or liver involvement and GI symptoms without other known cause. Eighteen of these 22 gastric biopsies were classified as GvHD by at least two of the three pathologists on initial review. Blinded histologic diagnosis of GvHD had a positive predictive value of 69%, a sensitivity of 82%, and specificity of 76%. False-positive results occurred in CMV gastritis, human immunodeficiency virus (HIV) infection, primary immunodeficiency, and after renal transplantation. Of individual features, granular debris in glands was a specific (94% specificity), but insensitive (41% sensitivity) marker for GvHD. Distinction between GvHD and CMV infection can be difficult, and GvHD can be confused with changes seen in HIV infection and other immunodeficiency states.

Activated eosinophils in esophagitis in children: a transmission electron microscopic study.

BACKGROUND: Esophagitis in infants and children is often characterized by eosinophilic inflammation. The underlying pathophysiologic mechanisms leading to this type of inflammation, and the role of eosinophils in the clinical expression of esophagitis, are unknown. The purpose of this study was to demonstrate the ultrastructural activation state of eosinophils in esophagitis in infants and children. METHODS: Standard transmission electron microscopy was used to examine endoscopic esophageal biopsy material from patients with and without esophagitis, as defined by standard histologic criteria. RESULTS: Twelve esophagitis and three control cases were studied. In patients with esophagitis, electron microscopy revealed numerous eosinophils throughout the mucosa and invariably demonstrated signs of activation, including inversion of core-to-matrix densities and lucency of granule core protein. Eosinophils in an activated state were seen in active diapedesis through vascular endothelium into the mucosa. Eosinophils were sometimes seen in proximity to lymphocytes. Biopsies of control patients did not demonstrate eosinophils. CONCLUSIONS: Eosinophils present in esophagitis are activated by electron microscopic criteria, and can been seen in an activated state entering into the mucosa. This suggests that eosinophils play an active role in the pathophysiology of this disorder, and that proinflammatory factors are present that selectively recruit and activate eosinophils in esophagitis in children.

Recurrence of nonalcoholic steatohepatitis in a liver transplant recipient.

A 42-year-old white man with morbid obesity and hypertriglyceridemia was noted to have nonalcoholic steatohepatitis (NASH) at the time of a laparoscopic cholecystectomy for presumed gallstone pancreatitis. His postoperative course was complicated by a 50-kg weight loss and continued right upper quadrant pain. Repeat liver biopsy revealed NASH with accompanying micronodular cirrhosis. Due to progressive fatigue, he underwent an orthotopic liver transplantation complicated by a 36-kg weight gain. Sixteen months posttransplantation, a liver biopsy revealed the recurrence of NASH. Screening for defects in fatty acid oxidation proved negative.

Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

BACKGROUND: The similarity of the hepatic pathology in acute fatty liver of pregnancy (AFLP) to that seen in children with inherited disorders of intramitochondrial fatty acid oxidation (FAO) suggests that there may be a genetic basis for some cases of AFLP. OBJECTIVE: The purpose of this study was to examine patients with AFLP and their offspring to determine if there were women with AFLP who were heterozygous for the FAO defect, long chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency. METHODS: We evaluated 12 women previously diagnosed with AFLP. Provocative fasting studies and skin biopsies for examination of their cultured skin fibroblasts were performed to search for a generalized defect in FAO both in vivo and in vitro. Cultured skin fibroblasts from AFLP patients, their children, and their husbands were also examined specifically for LCHAD activity. RESULTS: Of 12 women with a previous episode of AFLP, eight had reduced LCHAD activity consistent with being heterozygous for LCHAD deficiency. The eight heterozygotes had a total of nine pregnancies complicated by AFLP. In seven of those nine pregnancies, the women developed severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Of the nine offspring delivered from these pregnancies, four were confirmed to be affected with homozygous LCHAD deficiency. Three other deceased infants were presumed to be LCHAD-deficient based on clinical findings, postmortem examination, and confirmed heterozygote parents. The remaining two infants delivered after pregnancies complicated by AFLP had LCHAD activity in the heterozygous range and are healthy at 18 and 24 months of age. Consistent with the known autosomal recessive nature of this defect, five tested husbands of LCHAD heterozygous women with a history of AFLP and affected infants also showed reduced LCHAD activity. CONCLUSIONS: These studies indicate that a significant subgroup of women with AFLP are heterozygous for LCHAD deficiency and that careful observation of their offspring for signs of this disorder is warranted. Severe preeclampsia appears to increase the risk of AFLP in LCHAD heterozygous women.

Fecal short-chain fatty acids in patients with diarrhea-predominant irritable bowel syndrome: in vitro studies of carbohydrate fermentation.

Colonic bacterial production of short-chain fatty acids (SCFA) plays an important role in the salvage of unabsorbed carbohydrate and in colonic absorption of electrolytes and water. The objective of this study was to determine whether patients with diarrhea-predominant irritable bowel syndrome (DP-IBS) have a different pattern and rate of fermentation of carbohydrate and fiber to SCFA compared with controls. Fecal homogenates from 10 patients with DP-IBS and 10 age-matched controls were studied. SCFA were measured by gas chromatography in baseline fecal samples and in fecal homogenates in an in vitro anaerobic fermentation system after incubation with no additional substrate, lactulose, potato starch, citrus pectin, and hemicellulose over a 24-hour period. Net SCFA production rates were calculated for the first 6 h of the incubation period. Patients with DP-IBS had a consistently different pattern of less total SCFA, a lower percentage of acetate (p < 0.05), and a higher proportion of n-butyrate (p < 0.05) than controls. In stool homogenates from both controls and DP-IBS patients, lactulose fermentation resulted in the highest rate of SCFA production followed by pectin, starch, and hemicellulose. However, at all time points, the fecal homogenates from controls generated a higher concentration of total SCFA, acetate, and propionate with all substrates tested. SCFA production rates were higher in controls incubated with lactulose, starch, and hemicellulose. The fecal SCFA profile of patients with DP-IBS is characterized by lower concentrations of total SCFA, acetate, and propionate and a higher concentration and percentage of n-butyrate. Fecal flora from these patients produced less SCFA in an in vitro fermentation system in response to incubations with various carbohydrates and fibers. Differences in SCFA production by colonic bacterial flora in patients with DP-IBS may be related to the development of gastrointestinal symptoms.

Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele.

Acute fatty liver of pregnancy (AFLP) is a devastating late gestational complication with many similarities to the inherited disorders of mitochondrial fatty acid oxidation. We report the molecular defects in a woman with AFLP and her infant who subsequently was diagnosed with trifunctional protein (TFP) deficiency. We used single-stranded conformation variance and DNA sequence analyses of the human TFP alpha-subunit gene, which encodes the long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity, to demonstrate a C to T mutation (C1678T) in exon 16 present on one allele in the mother and the affected infant. This creates a premature termination codon (R524Stop) in the LCHAD domain. Using reverse transcriptase-PCR amplification of the alpha-subunit mRNA from cultured fibroblasts, we demonstrated that transcripts containing this R524Stop mutation are present at very low levels, presumably because of rapid mRNA degradation. The affected infant also had the common E474Q mutation (nucleotide G1528C) on the second allele. Thus, he is a compound heterozygote. The father and two normal siblings are heterozygous for this E474Q mutation. This initial delineation of the R524Stop mutation provides evidence of the heterogeneity of genetic defects responsible for TFP deficiency and AFLP.