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BACKGROUND. Many infants are switched between multiple formula preparations early in life because of perceived abnormalities in stooling pattern as well as gastrointestinal symptoms. OBJECTIVE. To investigate the relationship between the type of formula consumed and the stooling characteristics and gastrointestinal symptoms of young infants. METHODS. Healthy 1-month-old infants were fed one of four commercial formula preparations (Enfamil, Enfamil with Iron, ProSobee, and Nutramigen) for 12 to 14 days in a prospective double-blinded (parent/physician) fashion. Parents completed a daily diary of stool characteristics as well as severity of spitting, gas, and crying for the last 7 days of the study period. A breast-fed infant group was studied as well. RESULTS. Two hundred eighty five infants were enrolled and 238 completed the study. Infants receiving breast milk or Nutramigen had twice as many stools as other formula groups (P < .001). Infants receiving ProSobee had hard/firm stools more often than breast-fed or other formula-fed groups (P < .00001). Watery stools were more common in infants fed Nutramigen than other formula groups (P < .04). Green stools were more common in 12 mg/L iron preparations (Enfamil with iron, ProSobee, Nutramigen) than in those with 1 mg/L (Enfamil, breast milk) (P < .00001). Spitting, gassiness, and crying were of equal severity in all formula groups. CONCLUSIONS. The interpretation of stool frequency, color, and consistency must take into account the infant's formula type as significant variations in normal infants occur. Parental education on the range of infant stooling characteristics as well as the common occurrence of spitting, gas, and crying may alleviate concern for formula intolerance and underlying gastrointestinal disease. [ABSTRACT FROM AUTHOR]

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.

Background: The latest estimate of the prevalence of inflammatory bowel disease (IBD) in the United States was based on 2009 data, which indicates a need for an up-to-date re-estimation. The objectives of this study were to investigate the prevalence of all forms of IBD including ulcerative colitis (UC), Crohn's disease (CD), and IBD unspecified (IBDU)., Methods: Pediatric (age 2-17) and adult (age ≥18) IBD patients were identified from 2 large claims databases. For each year between 2007 and 2016, prevalence was calculated per 100,000 population and standardized based on the 2016 national Census. A fixed-effects meta-analytical model was used for overall prevalence., Results: The pediatric prevalence of IBD overall increased by 133%, from 33.0/100,000 in 2007 to 77.0/100,000 in 2016. Among children, CD was twice as prevalent as UC (45.9 vs 21.6). Prevalence was higher in boys than girls for all forms of IBD, in contrast to the adult population where the prevalence was higher in women than men. We also found that the 10-17 age subgroup was the major contributor to the rising pediatric IBD prevalence. For adults, the prevalence of IBD overall increased by 123%, from 214.9 in 2007 to 478.4 in 2016. The prevalence rates of UC and CD were similar (181.1 vs 197.7) in 2016., Conclusions: Inflammatory bowel disease continues to affect a substantial proportion of the US population. In 2016, 1 in 209 adults and 1 in 1299 children aged 2-17 were affected by IBD. Prevalence of IBD has been increasing compared with previously published 2009 data., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials., Aims: This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH., Methods: This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic., Results: Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules., Conclusions: This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH., (© 2019 John Wiley & Sons Ltd.)

Aim: To determine if packed red blood cell transfusions contribute to the development of parenteral nutrition associated liver disease., Methods: A retrospective chart review of 49 premature infants on parenteral nutrition for > 30 d who received packed red blood cell (PRBC) transfusions was performed. Parenteral nutrition associated liver disease was primarily defined by direct bilirubin (db) > 2.0 mg/dL. A high transfusion cohort was defined as receiving > 75 mL packed red blood cells (the median value). Kaplan-Meier plots estimated the median volume of packed red blood cells received in order to develop parenteral nutrition associated liver disease., Results: Parenteral nutritional associated liver disease (PNALD) was noted in 21 (43%) infants based on db. Among the 27 high transfusion infants, PNALD was present in 17 (64%) based on elevated direct bilirubin which was significantly greater than the low transfusion recipients. About 50% of the infants, who were transfused 101-125 mL packed red blood cells, developed PNALD based on elevation of direct bilirubin. All infants who were transfused more than 200 mL of packed red blood cells developed PNALD. Similar results were seen when using elevation of aspartate transaminase or alanine transaminase to define PNALD., Conclusion: In this retrospective, pilot study there was a statistically significant correlation between the volume of PRBC transfusions received by premature infants and the development of PNALD., Competing Interests: Conflict-of-interest statement: None of the authors involved in this study have any conflicts of interest.

The proton pump inhibitor, rabeprazole, has been studied in children for the treatment of gastroesophageal reflux disease (GERD). In adults, rabeprazole is indicated for Helicobacter pylori eradication in combination with amoxicillin and clarithromycin. Nonlinear mixed effects modeling was conducted to estimate pharmacokinetic (PK) parameters for rabeprazole and its thioether metabolite from 336 subjects, 35% of whom were children 1-11 years with GERD from phase I and III studies. A 2-compartment disposition model with a transit absorption model provided the best fit for rabeprazole PK. The steady-state area under the concentration-time curves given several candidate doses were simulated to identify a dose per each body weight group that is comparable to a 20 mg twice-daily dose in adults, which is the recommended dose for treatment of H. pylori in adults. Simulations provided the following recommended twice-daily weight-based doses for children ≥1 year and <16 years: 10 mg for 6-10 kg, 15 mg for 10-30 kg, and 20 mg for ≥30 kg., (© 2015, The American College of Clinical Pharmacology.)

Objectives: ω-3 Fatty acids (FAs), natural ligands for the peroxisome proliferator-activated receptor-α (PPAR-α), attenuate parenteral nutrition-associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω-3 FAs are still unknown. The aim of this study was to determine the effects of ω-3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR-α and microsomal triglyceride transfer protein (MTP) in this experimental setting., Methods: 129S1/SvImJ wild-type or 129S4/SvJaePparatm/Gonz/J PPAR-α knockout mice were fed chow and water (controls); oral, fat-free PN solution only (PN-O); PN-O plus intraperitoneal (IP) ω-6 FA-predominant supplements (PN-ω-6); or PN-O plus IP ω-3 FA (PN-ω-3). Control and PN-O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR-α messenger RNA were assessed after 19 days., Results: In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN-O and PN-ω-6 groups accumulated significantly greater amounts of TG when compared with PN-ω-3 mice. Studies in PPAR-α null animals showed that PN feeding increases hepatic TG as in wild-type mice. PPAR-α null mice in the PN-O and PN-ω-6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω-3 FAs., Conclusions: PN induces TG accumulation (steatosis) in wild-type and PPAR-α null mice. In PN-fed wild-type and PPAR-α null mice given IP ω-3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω-3 FAs results from PPAR-α-independent pathways., (© 2013 American Society for Parenteral and Enteral Nutrition.)

Background: Barrett esophagus (BE) is a premalignant condition that develops due to prolonged gastroesophageal reflux disease (GERD). In some but not all cases, BE progresses to Barrett-associated adenocarcinoma. p27 is a tumor-suppressor protein that regulates the cell's division cycle and appears to be frequently inactivated in Barrett-associated adenocarcinoma due to increased degradation or cytoplasmic mislocalization. Reduced or mislocalized p27 would remove it from its nuclear targets and result in increased proliferation. Although bile acid and hydrochloric acid (HCl) are linked to the pathogenesis of BE, not every patient with BE has a history of GERD. Eosinophilic esophagitis mimics GERD, but eosinophil granule proteins, known to mediate inflammation, have not been linked to BE. It was unknown whether mediators of esophagitis affect p27 expression and/or localization in normal esophageal cells. We assessed the effects of bile acid, HCl, and eosinophil granule proteins on p27 protein expression, localization, and its ability to regulate cell proliferation., Materials and Methods: Human esophageal epithelial (HET-1A) cells were incubated with chenodeoxycholic acid (CDC), HCl, and eosinophil granule proteins (major basic protein, MBP; and eosinophil peroxidase, EPO). Cell viability analysis, immunoblot, immunofluorescence microscopy, and flow cytometric analysis were performed., Results: Exposure of HET-1A cells to CDC, HCl, MBP, and EPO did not affect total p27 levels. CDC, HCl, MBP, and EPO caused mislocalization of p27 from the nucleus to the cytoplasm. Flow cytometry showed that CDC exposure also increased HET-1A cell proliferation., Conclusions: Mislocalization of p27 caused by mediators of GERD or eosinophilic esophagitis may serve as an early marker of increased cell proliferation, which may contribute to the risk for esophageal dysplasia.

Pediatric liver transplant patients are now routinely surviving 10 years or more. Beyond the first year after transplant, surgical biliary or vascular complications are rare, and the incidence of acute rejection episodes falls precipitously. Attention is turning to minimizing the toxicity of immunosuppressive regimens and their potential negative impact on growth, bone health, cognitive development, renal function, and quality of life. Innovative combinations of immunosuppressive medications are being used as initial management after transplantation to minimize acute rejection and allow rapid weaning of corticosteroids and reduction in maintenance levels of calcineurin inhibitors. The substitution of potentially less toxic immunosuppressive agents, such as mycophenolate mofetil and rapamycin, is being studied in patients who develop renal dysfunction. A major current emphasis is on defining the natural history of long-term graft injury and elucidating histopathologic changes that mimic autoimmune chronic active hepatitis but are likely a form of chronic rejection due to production by the recipient of antibodies to foreign graft antigens. As patients survive longer, we are seeing various forms of immune dysregulation engendered by the presence of the graft and chronic immunosuppression of the host. By defining the resulting patterns of graft injury and understanding their immunopathogenesis, we can devise rational adjustments in immunosuppression that will preserve graft function and maximize graft life.

Enteroendocrine cell dysgenesis was observed in 3 patients with intestinal failure of unknown cause. Enteroendocrine cell dysgenesis is a congenitally acquired life-threatening malabsorptive condition with a unique clinical phenotype paired with a histologically identifiable disease pattern. Two cases were first presented at the Ninth International Small Bowel Transplantation Symposium, Brussels 2005, and were subsequently published (N Engl J Med 2006;355:270). We now present the histopathologic and immunohistochemical findings of the gastric antrum, small bowel, and colon in greater detail. The clinical phenotype of the patients was unusual in that the affected patients demonstrated profound malabsorption of all nutrients, except water, from birth. The small intestine in each patient demonstrated almost no abnormality, except a near absence of endocrine cells in the mucosa. The colon appeared similarly affected. Known causes of congenital malabsorption, inflammatory, and infectious causes of diarrhea were excluded. The defect is secondary to point mutations in NEUROG3, which result in an arrest of endocrine cell development in the small intestine and colon. This work describes the pathologic characterization of enteroendocrine cell dysgenesis using routine techniques. The pattern of injury is distinct from other histopathologically assessed congenital malabsorptive conditions such as microvillus inclusion disease, tufting enteropathy, and abetalipoproteinemia. It is also easily distinguished from inflammatory conditions such as food allergy, gluten-sensitive enteropathy, autoimmune enteropathy, IPEX (immune dysfunction, polyendocrinopathy, enteropathy, and X-linked inheritance), and inflammatory bowel disease. The histopathology of disease is similar to what has been found transiently in a single patient with autoimmune polyglandular syndrome type I.

Hepatic-based inborn errors of metabolism are targets for treatment with liver transplantation in children, in whom the metabolic defect causes irreversible damage to the liver. However, certain metabolic defects originate with enzyme deficiencies localized in the liver but then give rise to toxic intermediates that damage extrahepatic organs without any significant compromise of general liver function. Here, the rationale of using liver transplantation to replace an organ that is functioning normally except for a specific metabolic pathway raises difficult questions about indications for transplantation, timing, amount of replacement tissue needed to correct the defect, and whether heterozygote parents are suitable living donors for liver transplantation in their affected children. This review explores these questions and others, including the role of hepatocyte transplantation, in this select group of disorders. Until the promise of specific gene or enzyme replacement therapy is realized, liver and hepatocyte transplantation offers the best chance of achieving metabolic control in these challenging patients.

NAFLD likely is the most common liver disease in children and is responsible for significant progression to cirrhosis, portal hypertension, and the need for liver transplantation in adults and even in some adolescents. Early diagnosis and lifestyle interventions appear to be our best hope for controlling progression of disease. The pediatrician is responsible for screening all obese children with measurement of aminotransferases. Those with elevated enzymes (particularly ALT) for longer than 3 months, in the absence of markers of hepatitis B or C, autoimmune chronic active hepatitis, Wilson's disease, hemochromatosis, or alpha-1-antitrypsin deficiency, should follow up with an abdominal ultrasound. In patients with a BMI in the morbidly obese range, an ultrasound to search for a diffusely echogenic liver should be performed even if the liver enzymes are normal. Findings suggestive of NAFLD should prompt the institution of appropriate dietary and exercise regimens. If these are unsuccessful after a 3-month trial, the patient should be referred to a pediatric gastroenterologist and hepatologist for further work-up and treatment, preferably in the context of a controlled therapeutic trial. Only by aggressively engaging this current epidemic will we be able to decrease the mounting human cost of NAFLD.

Purpose of Review: There has been an explosion in knowledge about celiac disease (CD) in the last decade based on the availability of serologic screening tests and the elucidation of some of the important disease susceptibility genes. What has been discovered is that CD is among the most common inherited diseases with a worldwide prevalence of almost 1% of the population. Also, there has been a tremendous expansion of the possible clinical presentations in patients with CD, many of them predominantly or even exclusively extraintestinal. Over the last year, both the North American Society of Pediatric Gastroenterology and Nutrition, and the NIH, through the mechanism of a consensus development conference held in May 2004, have published guidelines outlining the current state of knowledge and the areas where more research is needed., Recent Findings: This review will stress the most recent findings in CD in the areas of genetics, pathogenesis, epidemiology, screening and diagnosis, and natural history. It will stress the importance of HLA DQ2 and DQ8 as disease susceptibility genes, and the interaction of the environmental triggers (gliadins and glutenins) with these gene products to trigger the immunologic response in the gut that is responsible for the pattern of injury. Recent reports that stress the importance of screening high-risk groups (i.e. siblings of index cases and first degree relatives, patients with Type I diabetes, patients with Downs syndrome, patients with IgA deficiency) will be highlighted. The identification of the most sensitive and specific screening tests will be summarized with an explanation of special situations that affect the interpretation of these tests. Finally, the long-term morbidities associated with CD will be characterized supporting the case for early diagnosis and treatment., Summary: The implications of these recent findings are of tremendous importance for both pediatricians and internists. Screening of high-risk groups, and of patients with the common symptoms of irritable bowel syndrome, iron deficiency anemia, unexplained arthritis, and even chronic elevations of aminotransferases is becoming the accepted standard of practice. Much research remains to be done to further refine our understanding of CD, and to devise more effective strategies for treatment, compliance, and prevention of long-term complications.

Objective: Transfusions prevent secondary stroke in children with sickle cell anemia (SCA) but also cause iron overload. Alternatives for stroke prophylaxis with effective therapy to reduce iron burden are needed., Study Design: For 35 children with SCA and stroke, transfusions were prospectively discontinued. Hydroxyurea was prescribed for stroke prophylaxis, and phlebotomy removed excess iron. Initial patients discontinued transfusions before hydroxyurea therapy, but later patients overlapped transfusions with hydroxyurea until tolerating full-dose therapy., Results: Children received hydroxyurea for 42 +/- 30 months (range, 3-104 months). Hydroxyurea (26.7 +/- 4.8 mg/kg per day) led to mild neutropenia (3.9 +/- 2.3 x 10(9)/L) with significant increases in hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin. Stroke recurrence rate was 5.7 events per 100 patient-years, but children receiving overlapping hydroxyurea therapy had only 3.6 events per 100 patient-years. For 26 children with >6 months of phlebotomy, 14,311 +/- 12,459 mL blood (315 +/- 214 mL/kg) was removed, with serum ferritin decreasing from a median of 2722 to 298 ng/mL. Among patients completing phlebotomy, liver biopsy documented normal histology and no excess iron deposition., Conclusions: For children with SCA and stroke, hydroxyurea effectively prevents secondary stroke and serial phlebotomy leads to complete resolution of transfusional iron overload.

Background: Patients with inflammatory bowel disease (IBD) have an increased incidence of thromboembolic events. This risk may be caused by an increased frequency of thrombophilic mutations such as factor V Leiden G1691A (FVL), prothrombin G20210A (PT), or methylene tetrahydrofolate reductase C667T (MTHFR). Prevalence rates of heterozygous mutations in FVL, PT, and MTHFR are reported for whites (1.8%, 1.3%, 26.6%, respectively), blacks (0.8%, 0.3%, and 12.4%, respectively), and Hispanics (1.2%, 2.4%, and 41.5%, respectively). We sought to determine the prevalence of these thrombophilic mutations in a large cohort of children with IBD., Methods: Children aged 21 years or younger with IBD were genotyped for FVL, PT, and MTHFR mutations by polymerase chain reaction amplification and restriction enzyme digestion. Prevalence rates were compared with established rates in the respective populations., Results: Of 92 patients enrolled, 89 (62 with Crohn disease, 24 with ulcerative colitis, and 3 with indeterminate colitis) had genotype results available. The mean age was 13.3 +/- 4.2 years (range, 2-21 years). Statistical analysis was performed on 89 FVL, PT, and MTHFR allele pairs. Polymerase chain reaction genotyping identified 5 patients with heterozygous FVL mutations, 3 patients heterozygous for the PT mutation, and 36 patients heterozygous and 4 patients homozygous for the MTHFR mutation. The thrombophilic allele mutation frequencies in our sample were not significantly different from predicted weighted average values: FVL, 2.8% versus 1.5%; PT, 1.7% versus 1.1%; and MTHFR, 24.7% versus 24.4%. In 24 patients with a family history of thrombosis, 1 was heterozygous for FVL and for MTHFR, 1 was heterozygous for FVL and homozygous for MTHFR, 2 were heterozygous for PT, and 9 were heterozygous MTHFR. There was no significant correlation between family history of thrombosis and presence of a thrombophilic mutation. The four patients with homozygous mutations for MTHFR, two of whom also were heterozygous for FVL, did not have either a personal history of thrombosis or a family history of thrombotic events. Two patients had thrombotic events without mutations in these genotypes: one had protein S deficiency and the other had no identifiable cause., Conclusions: The presence of genetic mutations that predispose to hypercoagulable states does not appear to correlate with the prevalence of IBD or to thromboembolic events in patients with IBD. There was no statistical difference between the proportions of the mutated allele frequency in our study patients and the general population.

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.

Accumulation of micro- and macrovesicular fat in hepatocytes is the hallmark of several liver diseases of pregnancy, including acute fatty liver of pregnancy (AFLP) and severe pre-eclampsia. While the exact origin of AFLP is not known, this pathologic finding and its similarity to the hepatopathology found in infants and children with inborn errors of mitochondrial fatty acid-oxidation suggests a common pathogenesis. Over the last few years, the incidence of AFLP and other severe complications of pregnancy have been found to be increased in women who carry a fetus with a defect in fatty acid oxidation, and who are themselves carriers of a genetic mutation that partially compromises their own intramitochondrial fatty acid oxidation pathway. This article reviews evidence that links AFLP with both genetic and acquired factors that compromise intramitochondrial fatty acid oxidation. Based on this review, recommendations are offered for obstetric, perinatal, and neonatal management of affected mothers and infants.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Previous work has suggested that the interleukin-1 (IL-1) receptor antagonist, IL-1ra, may regulate mucosal inflammation in inflammatory bowel disease. The present study assessed the relationship of mucosal IL-1ra levels to histologic severity of inflammation and the related proinflammatory cytokines IL-1 beta and IL-6 in children with inflammatory bowel disease. Colonic biopsy specimens from 29 patients with ulcerative colitis, 27 with Crohn's disease, and 24 noninflammatory control subjects were assayed for IL-1ra, IL-1 beta, and IL-6 by enzyme-linked immunosorbent assay. Histologic activity was graded as none, mild, moderate, or severe. Mucosal IL-1 beta levels, but not IL-1ra levels, were significantly elevated in moderate/severely inflamed biopsies from patients with either ulcerative colitis (p < 0.01) or Crohn's disease (p < 0.001) compared with those with none/mild inflammation. The mucosal molar ratio of IL-1ra/IL-1 beta was significantly lower for moderate/severe inflammation compared with none/mild inflammation for patients with ulcerative colitis (p < 0.05) and Crohn's disease (p < 0.01). The mucosal IL-1ra/IL-1 beta ratio was similar in controls to none/mild inflamed biopsies from subjects with either ulcerative colitis or Crohn's disease. Our observations suggest that increasing mucosal inflammation in inflammatory bowel disease in children is associated with a decrease in the "normal" effective IL-1ra/IL-1 beta ratio in which IL-1ra predominates. The importance of this abnormality to the pathogenesis of inflammatory bowel disease awaits further study.

Advances in the ability to treat primary causes of chronic liver disease in the adolescent have highlighted the importance of making a prompt diagnosis. Using a case study, this article reviews the clinical findings suggestive of chronic liver disease and the causes responsible in the adolescent. As the case evolves, an efficient strategy for diagnosing each possibility is presented and therapeutic modalities are reviewed.

Purpose: Emergency surgery for fulminant colitis is often complicated by high-dose steroid therapy, poor nutrition, and psychologic maladjustment. Cyclosporine is effective for fulminant ulcerative colitis in adults, resulting in avoidance of immediate surgery in 75 percent of patients and a 55 percent long-term remission rate. Over the last five years, we studied the effectiveness of cyclosporine in children with fulminant colitis., Methods: Fourteen patients with ulcerative colitis (age, 7-20 years) received cyclosporine after satisfying the following criteria: 1) greater than five bloody diarrheal stools per day; 2) severe abdominal pain; 3) no improvement after ten days of bowel rest, 4) intravenous methylprednisolone (1-2 mg/kg/day); and 5) parenteral nutrition. Treatment was begun with oral cyclosporine (4.6-9.6 mg/kg/day), and the dose was adjusted to achieve whole blood trough levels measured with a monoclonal radioimmunoassay between 150 and 300 ng/ml. If improved, patients were discharged on oral cyclosporine, prednisone, and a regular diet., Results: Eleven of 14 patients (78 percent) responded within two to nine days and were able to consume a normal diet, had three or less soft stools per day, and had no pain. One did not respond after ten days and underwent an ileal pouch-anal anastomosis procedure. Two patients elected surgery after 20 days of therapy and a partial response. Of 11 patients who left the hospital, 4 had recurrent symptoms after 2 to 11 months of taking therapeutic doses of cyclosporine and 3 flare ups while weaning from cyclosporine after 4 to 8 months. Three patients have been weaned from cyclosporine after 8 to 13 months and have remained in remission from six months to five years. One patient is about to complete a six-month course of cyclosporine. Overall ten (72 percent) have undergone surgery, including 7 of 11 who responded initially to cyclosporine and left the hospital. Weight (P < 0.001), albumin (P < 0.01), erythrocyte sedimentation rate (P > 0.05), and prednisone dose (P < 0.001) improved significantly in the seven patients on cyclosporine who responded initially, left the hospital, and subsequently underwent surgery., Conclusions: Cyclosporine is effective in achieving clinical remission in 80 percent of children with refractory fulminant colitis; however, within one year, most initial responders will require colectomy because of a flare up of the disease. In a majority of patients, the role of cyclosporine therapy is to rapidly ameliorate symptoms and prevent precipitous colectomy, improve nutrition and psychologic adaptation, and reduce the steroid dose leading to surgery in a well-prepared patient.