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William R Treem

Publications and source records attributed to William R Treem.

9 recordsLinked to original sources
PubMed2006

Mutant neurogenin-3 in congenital malabsorptive diarrhea.

BACKGROUND: Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells and is required for endocrine-cell development in the pancreas and intestine. The NEUROG3 gene (NEUROG3) is therefore a candidate for the cause of a newly discovered autosomal recessive disorder characterized by generalized malabsorption and a paucity of enteroendocrine cells. METHODS: We screened genomic DNA from three unrelated patients with sparse enteroendocrine cells for mutations of NEUROG3. We then tested the ability of the observed mutations to alter NEUROG3 function, using in vitro and in vivo assays. RESULTS: The patients had few intestinal enteroendocrine cells positive for chromogranin A, but they had normal numbers of Paneth's, goblet, and absorptive cells. We identified two homozygous mutations in NEUROG3, both of which rendered the NEUROG3 protein unable to activate NEUROD1, a downstream target of NEUROG3, and compromised the ability of NEUROG3 to bind to an E-box element in the NEUROD1 promoter. The injection of wild-type but not mutant NEUROG3 messenger RNA into xenopus embryos induced NEUROD1 expression. CONCLUSIONS: A newly discovered disorder characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells is caused by loss-of-function mutations in NEUROG3.

Amino Acid Sequence↗
PubMed2006

Liver transplantation for non-hepatotoxic inborn errors of metabolism.

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.

Child↗
PubMed2006

Nonalcoholic fatty liver disease.

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.

Adolescent↗
PubMed2004

Prevention of secondary stroke and resolution of transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy.

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.

Adolescent↗
PubMed2004

Emerging concepts in celiac disease.

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.

Adenocarcinoma↗
PubMed2002

Prevalence of factor V G1691A (Leiden), prothrombin G20210A, and methylene tetrahydrofolate reductase C677T thrombophilic mutations in children with inflammatory bowel disease.

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.

Adolescent↗
PubMed2002

Mitochondrial fatty acid oxidation and acute fatty liver of pregnancy.

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.

Acute Disease↗