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.

Double-blind placebo-controlled trial of amitriptyline for the treatment of irritable bowel syndrome in adolescents.

OBJECTIVES: To determine the efficacy of amitriptyline (AMI) in treating irritable bowel syndrome (IBS) in adolescents. STUDY DESIGN: Adolescents 12 to 18 years with newly diagnosed IBS were surveyed with a symptom checklist, pain rating scale, visual analog scale, and IBS quality of life (QOL) questionnaire. Subjects were randomized in a double-blinded fashion to receive AMI or placebo, and again completed surveys at 2, 6, 10, and 13 weeks. RESULTS: Thirty-three patients (24 female) were enrolled. Patients receiving AMI were more likely to experience improvement from baseline in overall QOL at 6, 10, and 13 weeks (P = .019, .004, and .013). Patients receiving AMI were also more likely to experience a reduction in IBS-associated diarrhea at 6 and 10 weeks (P = .029 for both), a reduction in periumbilical pain at 10 weeks (P = .018), and a reduction in right lower quadrant pain at 6, 10, and 13 weeks (P = .014, .039, and .004). CONCLUSION: AMI significantly improves overall QOL in adolescents with IBS and should be a therapeutic option for adolescents with this disorder.

Isoniazid-related hepatic failure in children: a survey of liver transplantation centers.

BACKGROUND: Isoniazid (INH) therapy for tuberculosis carries a known risk for hepatoxicity, and leads to hepatic failure in a small subset of patients. This incidence has been described for adults, but is uncertain in children. Our aim was to estimate the incidence of pediatric referrals for INH-related liver failure, and to describe the characteristics and outcomes of these patients. METHODS: The 84 U.S. centers performing pediatric liver transplants between 1987 and 1997 were surveyed regarding patients with INH-induced liver failure. Additional transplant statistics were obtained from the United Network for Organ Sharing. Estimates of the number of children taking preventive INH were derived from a nationwide public health database. RESULTS: Twenty cases of INH-related liver failure were found during a 10-year period. Four patients (20%) recovered spontaneously; 10 (50%) underwent orthotopic liver transplantation (OLT), while six (30%) died awaiting OLT. Mean age at presentation was 9.8 years (range 1.3-17). Mean length of INH therapy was 3.3 months (range 0.5-9). Notably, five patients seen for symptoms of hepatitis were initially told not to stop treatment. INH-associated liver failure accounted for 0.2% (8 of 4679) of all pediatric OLTs, and 14% (8/56) of transplants for drug hepatoxicity. The estimated incidence of liver failure was up to 3.2/100,000 for children on prophylactic INH. CONCLUSIONS: While INH-associated liver failure in children is rare, discontinuation at the onset of symptoms does not assure recovery. This indicates a need for increased awareness of hepatotoxicity risk, expanded biochemical monitoring for children receiving INH, and prompt withdrawal in symptomatic patients.

Oral tacrolimus for steroid-dependent and steroid-resistant ulcerative colitis in children.

PURPOSE: To evaluate tacrolimus in 3 situations: for the induction of remission in children with severe steroid-resistant ulcerative colitis (UC); for steroid sparing in children with steroid-dependent UC in whom treatment with other immunosuppressants fails; and for the maintenance of remission in children with steroid-dependent and steroid-resistant UC. PATIENTS AND METHODS: We retrospectively evaluated 18 consecutive patients (13 with pancolitis) who were treated with oral tacrolimus at our institution from May 1999 to October 2005. Nine patients had steroid-resistant UC and 9 patients were steroid-dependent. We started patients initially on tacrolimus 0.2 mg/kg divided twice daily, with a goal plasma trough level of 10 to 15 ng/mL for the first 2 weeks, and then titrated doses to achieve plasma levels between 7 and 12 ng/mL after induction. RESULTS: Of the 18 patients in this study, 17 showed a positive response to tacrolimus therapy (ie, cessation of diarrhea and other symptoms) and 5 showed a prolonged response to tacrolimus. The mean time from initiation of tacrolimus therapy until response was 8.5 days. The mean duration of response was 260 days. Eleven of 18 patients required colectomy, including all of the patients with steroid-resistant UC, but only 2 of 9 who were steroid-dependent. The mean time from initiation of tacrolimus until colectomy was 392 days. CONCLUSIONS: It is possible that tacrolimus may benefit selected patients with steroid-dependent UC, including those who are intolerant of 6-mercaptopurine or azathioprine. Conversely, patients with steroid-resistant UC are unlikely to sustain a prolonged clinical response to tacrolimus and seem to require colectomy eventually. Careful considerations of risk versus benefit, as well as close monitoring for adverse effects, are essential in all patients.

Choline deficiency is associated with increased risk for venous catheter thrombosis.

BACKGROUND: Patients with intestinal failure who require long-term parenteral nutrition (PN) develop catheter thrombosis as a complication. This patient group may also develop choline deficiency because of a defect in the hepatic transsulfuration pathway in the setting of malabsorption. This study was undertaken to determine whether choline deficiency is a risk factor for development of catheter thrombosis. METHODS: Plasma free and phospholipid-bound choline concentrations were measured in a group of 41 patients that required long-term PN. Episodes of catheter thrombosis from onset of PN to the time of blood testing were recorded. RESULTS: Sixteen (39%) patients developed catheter thrombosis, and 5 of these had recurrent catheter thrombosis. Plasma free choline was 7.7 +/- 2.7 nmol/mL in patients with no history of catheter thrombosis and 6.2 +/- 1.7 nmol/mL in patients with previous catheter thrombosis (p = .076 by Wilcoxon rank-sum test). The partial correlation between plasma free choline concentration and the frequency of clots after controlling for catheter duration was r = -0.33 (p = .038). The relative risk for catheter thrombosis in subjects with a plasma free choline concentration <8 nmol/mL was 10.0, 95% confidence interval (1.134-88.167). Plasma phospholipid-bound choline concentration was 2191.7 +/- 679.0 nmol/mL in patients with previous catheter thrombosis and 2103.3 +/- 531.2 nmol/mL in patients without history of catheter thrombosis (p = NS). CONCLUSION: Choline deficiency is a significant risk factor for development of catheter thrombosis in patients with intestinal failure who require PN.

Irritable bowel syndrome and nonspecific diarrhea in infancy and childhood--relationship with juice carbohydrate malabsorption.

Lactose intolerance and malabsorbed carbohydrate present in some fruitjuice may trigger symptoms commonly seen in irritable bowel syndrome. In a two-site study, 28 subjects 9 months to 18 years old (mean 6.9 +/- 5.9 years) with significant intake of apple juice or pear nectar (> 6 oz a day) with the diagnoses of irritable bowel syndrome, functional abdominal pain, or chronic nonspecific diarrhea were recruited. Breath hydrogen tolerance tests utilizing lactose, sucrose, and apple juice in the amount they typically consumed were positive in 32%, 0%, and 50%, respectively. Subjects were asked to refrain from the ingestion ofjuice for 1 month: 13 of the 28 (46%) subjects improved while 15 (54%) showed no change in their symptoms. In fact, none consuming 6 to 12 oz of apple or pear juice daily improved, 27% of those consuming 12 to 16 oz improved, and 91% of those consuming > 16 oz improved (P < 0.02). Subjects were then given comparable amounts of white grape juice for 1 year. The initial symptoms did not recur in any of the subjects who initially responded to the juice-free diet. Of the 15 subjects who did not respond to the juice-free diet, seven became asymptomatic. Overall, 20 subjects (71%) were asymptomatic, and eight (29%) had no change in their symptoms. Some individuals with irritable bowel syndrome have their symptoms based on their malabsorption of carbohydrates present in apple juice and pear nectar and may improve with adequate choices of fruit juice such as changing to white grape juice.

Postinfectious gastroparesis: a case series of three adolescent females.

Postinfectious gastroparesis (PIGP) is a subgroup of idiopathic gastroparesis rarely reported in adolescents. This study describes 3 adolescent females with severe PIGP, who each underwent extensive workup prior to referral to a pediatric gastroenterologist. PIGP may be an underrecognized disorder in pediatrics, particularly in adolescents, and if untreated, can lead to significant morbidity.

Long-term nutrition and predictors of growth and weight gain following pediatric intestinal transplantation.

BACKGROUND: Advances in intestinal transplantation (ITx) have resulted in improved survival and the opportunity to examine nutritional outcomes. The aim of this study was to describe detailed, long-term nutritional results and identify positive predictors of growth and weight gain following pediatric ITx. METHODS: A single-center retrospective, Institutional Review Board-approved review of a prospective database was conducted. Inclusion criteria were ITx recipients 18 years or younger with survival of 6 months or more. Outcomes included anthropometric measurements and biochemical markers at 6, 12, 24, 36, and 48 months post-ITx. More than 25 ITx-related variables were analyzed as potential predictors of growth and weight gain. Statistical analysis was performed using chi-square test, t test, and analysis of variance. RESULTS: Between November 1991 and April 2007, 50 children received 55 ITx; 33 patients met eligibility criteria. Median age at ITx was 2.2 years, follow-up time was 3.8 years, and time from ITx to cessation of total parenteral nutrition was 31 days. The most common micronutrient deficiencies post-ITx were zinc, iron, and copper. Serum protein levels improved significantly over time. Weight gain occurred within 6 months and vertical growth within 12 months, although limited catch-up growth was seen. Early predictors of weight gain and growth included shorter hospitalization and absence of rejection. Long-term predictors were low steroid dosage, infrequent hospitalization, and the use of peptide-based formulas. CONCLUSIONS: This represents one of the largest and most comprehensive long-term studies on nutritional outcomes in pediatric ITx. Overall, positive growth and weight gain were seen as were micronutrient deficiencies. Numerous long-term nutritional challenges exist which require a multidisciplinary approach and future prospective studies.

Predictors of survival following liver transplantation in infants: a single-center analysis of more than 200 cases.

BACKGROUND: Infants (<12 months) who require liver transplantation (LTx) represent a particularly challenging and understudied group of patients. METHODS: This retrospective study aimed to describe a large single-center experience of infants who received isolated LTx, illustrate important differences in infants versus older children, and identify pretransplant factors which influence survival. More than 25 pre-LTx demographic, laboratory, and operative variables were analyzed using the Log-rank test and Cox proportional hazards model. RESULTS: Between 1984 and 2006, 216 LTx were performed in 186 infants with a mean follow-up time of 62 months. Median age at LTx was 9 months, the majority had cholestatic liver disease, were hospitalized pre-LTx, and received whole grafts. Leading indications for re-LTx (n=30) included vascular complications (43%) and graft nonfunction (40%), whereas leading causes of death were sepsis and multiorgan failure. One-, 5-, and 10-year graft and patient survivals were 75%/72%/68% and 79%/77%/75%, respectively. Relative to older pediatric recipients, infants had worse overall patient survival (P=0.05). The following were significant univariate predictors of graft loss: age less than 6 months and reduced cadaveric grafts; and of patient loss: age less than 6 months, calculated CrCl less than 90, pre-LTx hospitalization, pre-LTx mechanical ventilation, repeat LTx, infants transplanted for reasons other than cholestatic liver disease, and patients transplanted between 1984 and 1994. CONCLUSIONS: Long-term outcomes for infants undergoing LTx are excellent and have improved over time. As the largest, single-center analysis of LTx in infants, this study elucidates a unique set of predictors that can aid in medical decision making.

Resolution of hypophosphatemia is associated with recovery of hepatic function in children with fulminant hepatic failure.

Fulminant hepatic failure (FHF) is a rare but often fatal disease in children. Clinical and laboratory predictors of liver regeneration and recovery, however, have not been well established. We hypothesized that hypophosphatemia may indicate recovery of liver synthetic function in children with FHF. We retrospectively reviewed the medical records of children with FHF who were admitted to UCLA and recovered hepatic function either spontaneously or by liver transplantation (LTx). Serum phosphate (Ph) and prothrombin time or international normalized ratio (INR) were compared over the patient's clinical course. Records of 39 children who spontaneously recovered experienced profound hypophosphatemia that resolved as liver synthetic function improved. Similar patterns were seen in the 84 children who recovered after LTx. We found that hypophosphatemia precedes the recovery of liver synthetic function in children with FHF who recovered with or without transplantation, and that Ph levels return to normal as liver synthetic function improves. These data suggest that hypophosphatemia may be a useful laboratory indicator of recovering liver function in children with FHF.

Varicella in pediatric liver transplant patients: a retrospective analysis of treatment and outcome.

BACKGROUND: Varicella is a common childhood disease that can cause morbidity and mortality among immunosuppressed patients. There have been few previous studies monitoring the course of pediatric liver transplant patients with acute varicella. The aim of this study was to evaluate the treatment, outcomes, and complications of pediatric liver transplant patients admitted with acute varicella infection. METHODS: A retrospective chart review was carried out based on discharge diagnoses of orthotopic liver transplant and varicella among pediatric patients (age range, birth-18 years) admitted to the UCLA Medical Center between 1985 and 2001. RESULTS: Five hundred fifty-six pediatric patients received liver transplantations between 1985 and 2001. Twenty-two of these patients were admitted to the UCLA Medical Center with varicella (11 females, 11 males). No patients were treated on an outpatient basis. Mean age of the patients was 6 years (range, 1-16 years). None of these patients received the varicella vaccine before hospitalization. On admission, 5 of 22 patients (23%) had received varicella zoster immunoglobulin within 96 hours of exposure. The mean length of hospitalization was 6 days (range, 2-11 days). All immunosuppression dosages were reduced during the admissions. None of the patients had been treated with high-dose corticosteroids for acute rejection before the onset of the varicella infection. Patients were treated until defervescence with intravenous acyclovir and until their varicella lesions crusted. Patients were discharged with oral acyclovir to complete a 10-day course (including the intravenous treatment). No patients had complications from the varicella infection. A complication of an elevated serum creatinine for one patient was noted with the intravenous acyclovir treatment. This patient had associated headache and nausea that resolved when the creatinine level returned to normal. CONCLUSIONS: There were no complications or dissemination of varicella infection among our pediatric liver transplant patients. Further prospective randomized trials are required to evaluate the management of pediatric liver transplant patients infected with varicella.

Long-term parenteral nutritional support and intestinal adaptation in children with short bowel syndrome: a 25-year experience.

OBJECTIVE: To analyze the outcome of children with short bowel syndrome (SBS) who required long-term parenteral nutrition (PN). STUDY DESIGN: Retrospective analysis of children (n=78) with SBS who required PN >3 months from 1975 to 2000. STATISTICS: univariate analysis, Kaplan-Meier method, and Cox proportional regression model were used. RESULTS: We identified 78 patients. Survival was better with small bowel length (SBL) >38 cm, intact ileocecal valve (ICV), intact colon, takedown surgery after ostomy (all P <.01), and primary anastomosis (P <.001). PN-associated early persistent cholestatic jaundice (P <.001) and SBL of <15 cm (P <.01) were associated with a higher mortality. Intestinal adaptation was less likely if SBL <15 cm (P <.05), ICV was removed, colonic resection was done (both P <.001), >50% of colon was resected (P <.05), and primary anastomosis could not be accomplished (P <.01). Survival was 73% (57), and 77% (44) of survivors had intestinal adaptation. CONCLUSIONS: SBL, intact ICV, intestinal continuity, and preservation of the colon are important factors for survival and adaptation. Adaptation usually occurred within the first 3 years. Need for long-term PN does not preclude achieving productive adulthood. Patients with ICV even with <15 cm of SBL and patients with SBL >15 cm without ICV have a chance of intestinal adaptation.

Late-onset bacteremia in uncomplicated pediatric liver-transplant recipients after a febrile episode.

The aim of this study was to analyze the incidence and risk factors of bacteremia after a febrile episode in uncomplicated pediatric recipients more than 2 months after liver transplantation, which has not previously been studied. This cross-sectional study was conducted over a 4-year period. Patients with known risk factors for sepsis at the time of admission were excluded from the study. Seventy-one patients were hospitalized on 128 occasions, with bacteremia occurring in the case of 11 admissions (8.6%). No laboratory tests were predictive of bacteremia. The bacteremic group most frequently presented with ill appearance ( P<0.001), lethargy ( P<0.01), decreased physical activity, and a history of early-onset bacteremia after transplantation and segmental graft ( P<0.05). This study identified a significant incidence of bacteremia in uncomplicated patients many months after liver transplantation.