Ranjana Gokhale

Clinical Aspects and Pathophysiology of Inflammatory Bowel Disease

SUMMARY The chronic inflammatory bowel diseases (IBD), Crohns disease and ulcerative colitis, are recognized as important causes of gastrointestinal disease in children and adults. In this review we delineate the clinical manifestations and diagnostic features of IBD. In addition, we summarize important recent advances in our understanding of the immune mediators of intestinal inflammation. This information has led to new therapeutic approaches in IBD. Further, we discuss the considerable data that point to the significance of genetic factors in the development of IBD and the genetic loci which have been implicated through genomewide searches. The commensal bacterial flora also appears to be a critical element, particularly in regards to Crohns disease, although the precise role of the bacteria in the disease manifestations remains unclear. Current investigations promise to yield fresh insights in these areas.

Bone mineral density assessment in children with inflammatory bowel disease

BACKGROUND & AIMS Children with inflammatory bowel disease (IBD) are at risk for osteoporosis because of undernutrition, delayed puberty, and prolonged corticosteroid use. The aim of this study was to compare bone mineral density (BMD) in children with IBD with that in normal children and to assess the effects of nutritional and hormonal factors and corticosteroid dosages on BMD. METHODS One hundred sixty-two subjects (99 with IBD and 63 healthy sibling controls) were enrolled. Patients underwent anthropometric assessment, pubertal staging, bone age radiography, and BMD assessment by dual energy x-ray absorptiometry of the lumbar spine, femoral neck, and radius. Laboratory evaluations included serum calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone, osteocalcin, urinary N-telopeptides, albumin, insulin-like growth factor I, and testosterone or estradiol. Cumulative corticosteroid doses were calculated. RESULTS BMD Z scores at the lumbar spine and femoral neck were lower in patients with IBD, and lower in those with Crohns disease compared with those with ulcerative colitis. Low BMD persisted after correction for bone age in girls with Crohns disease (lumbar spine, P = 0.004; femoral neck, P = 0.002). Cumulative corticosteroid dose was a significant predictor of reduced BMD. BMD did not correlate with measures of calcium homeostasis, except elevated serum phosphate and urine calcium levels in girls. CONCLUSIONS Low BMD occurs in children with IBD (more in Crohns disease than in ulcerative colitis), especially pubertal and postpubertal girls. Cumulative corticosteroid dose is a predictor of low BMD, but other factors in Crohns disease remain undetermined.

6-mercaptopurine metabolite levels in children with inflammatory bowel disease.

Objectives Some authors suggest that efficacy of 6-mercaptopurine (6-MP) in patients with inflammatory bowel disease correlates with circulating 6-thioguanine (6-TG) levels more than 235 pmol/8 × 10 8 red blood cells. The authors evaluated the relation between 6-MP metabolite levels and disease activity in children and adolescents with inflammatory bowel disease. Methods Clinical status and hematologic and hepatic parameters were determined in 101 children with inflammatory bowel diseasefrom a single center and compared with 6-MP metabolite levels. Results There was a trend for higher 6-TG levels among patients in remission than among those with active disease (217 vs. 173); however the difference was not statistically significant (P = 0.09). The likelihood of therapeutic response did not increase significantly at 6-TG levels greater than 235 pmol/8 × 10 8 red blood cells (odds ratio 1.7;P = 0.1). In the current study, 58% of patients in remission had 6-TG levels less than 235. However, serial measurements of 6-MP metabolite levels in 50 patients with active disease showed that increasing 6-TG levels correlated significantly with disease remission in patients followed up longitudinally (P = 0.04). Leukopenia was significantly associated with high 6-TG levels (P = 0.03) but not with clinical response (P = 0.2). Conclusions These data suggest that the target range of 6-TG levels previously described by others did not apply to 58% of the pediatric patients with IBD in remission. However, serial monitoring of 6-MP metabolite levels in individual patients with active disease should allow dose escalation and induction of remission while minimizing the risk of toxicity.

Use of barbiturates in the treatment of cyclic vomiting during childhood

BACKGROUND Cyclic vomiting is an uncommon disorder that can be described as recurrent, self-limiting, fairly uniform episodes of intractable nausea and vomiting with no identifiable organic cause, separated by symptom-free intervals. There is no established therapeutic regimen for this disorder. METHODS Fourteen children referred to the Pediatric Gastroenterology Clinic were diagnosed with cyclic vomiting from May 1984 to January 1995. Vomiting, the predominant symptom, was present in all children and was severe enough to require hospitalization in 11. Associated symptoms included abdominal ain, headache, nausea, aura, and fever. Diagnostic studies were done to rule out organic causes as indicated in individual patients. Daily phenobarbital was prescribed in all 14 patients. The dose ranged from 30 to 120 mg/hs, (mean 2 mg.kg-1.day-1), with a median dose of 60 mg/hs [corrected]. Prior therapy with propranolol (3 patients) and butalbital (2 patients) had been ineffective. RESULTS Eleven patients had complete resolution of their symptoms, and 3 patients had marked improvement in their symptoms with infrequent attacks of reduced severity. The only side effects associated with long-term phenobarbital therapy were behavioral in nature, namely hyperactivity and disruptive behavior at school. CONCLUSIONS The results of our series of 14 patients, all of whom received barbiturates, support the usefulness of this therapeutic approach. Hence we feel that daily low-dose phenobarbital therapy is a safe and effective therapy in preventing episodes of cyclic vomiting in children.

Thalidomide use and outcomes in pediatric patients with Crohn disease refractory to infliximab and adalimumab.

Objective: The aim of the study was to evaluate thalidomide as rescue therapy for pediatric patients with severe refractory Crohn disease (CD) who failed to respond to antitumor necrosis factor (TNF) biologic agents. Patients and Methods: A computerized database was used to identify children with CD who had failed conventional immunosuppression therapy and received thalidomide rescue therapy. Twelve patients, mean age at diagnosis 10 years, were identified. Eight children had disease localized to the ileum and colon and 4 to the gastroduodenal area and colon. Five cases were complicated by strictures and 7 by fistulae. Previous drug therapy included azathioprine/6-mercaptopurine (11/12), methotrexate (7/12), and anti-TNF biologics (12/12). Outcome measures were Harvey-Bradshaw Index, change in prednisone dose, hospitalizations, bowel resections, and incision and drainage procedures. Laboratory evaluations were calculated before and after 1 to 6 months of thalidomide. Results: Mean Harvey-Bradshaw Index score improved from 11.8 to 3.9 (P = 0.0004), mean prednisone dose decreased from 13.9 to 2.3 mg/day (P = 0.001), mean number of hospitalizations decreased from 6.3 to 1.3 (P = 0.002), and erythrocyte sedimentation rate decreased from 35 to 14 mm/h (P = 0.02). The surgery rate pre-thalidomide was 0.031 and on thalidomide was 0.004. Of the 7 patients with fistulae, 5 had complete fistula closure, 1 had partial closure, and 1 showed no improvement. Adverse reactions that resulted in discontinuation of thalidomide are as follows: 42% peripheral neuropathy, 17% worsening of the CD, 8% dizziness, and 8% allergic reaction. All 5 patients who developed peripheral neuropathy had clinical resolution of the neurologic symptoms within 2 to 3 months after stopping thalidomide. Conclusions: Thalidomide is a potentially effective rescue therapy for severe refractory CD in children who fail to respond to anti-TNF medications.

Assessment of growth and nutrition

Growth is a dynamic process that is characterized by physiological changes in an individual from infancy into adulthood. Growth should be monitored sequentially and is an important tool in the early detection of chronic disease in children. Growth occurs in three phases: infancy, childhood and puberty (adolescence). The adequacy of nutritional status can be assessed by anthropometric measurements that include height, weight and body composition as well as laboratory evaluations. Individual patients can then be compared to normative or expected values. Impaired growth and nutritional status can be seen in a variety of gastrointestinal disorders and are described in this chapter.

Can You Teach a Teen New Tricks? Problem Solving Skills Training Improves Oral Medication Adherence in Pediatric Patients with Inflammatory Bowel Disease Participating in a Randomized Trial.

Background:Medication nonadherence is associated with higher disease activity, greater health care utilization, and lower health-related quality of life in pediatric inflammatory bowel diseases (IBD). Problem solving skills training (PSST) is a useful tool to improve adherence in patients with chronic diseases but has not been fully investigated in IBD. This study assessed feasibility, acceptability, and preliminary efficacy of PSST in pediatric IBD. Methods:Recruitment occurred during outpatient clinic appointments. After completion of baseline questionnaires, families were randomized to a treatment group or wait-list comparison group. The treatment group received either 2 or 4 PSST sessions. Youth health-related quality of life was assessed at 3 time points, and electronic monitoring of oral medication adherence occurred for the study duration. Results:Seventy-six youth (ages 11–18 years) on an oral IBD maintenance medication participated. High retention (86%) and treatment fidelity rates (95%) supported feasibility. High satisfaction ratings (mean values ≥4.2 on 1–5 scale) supported intervention acceptability. Modest increases in adherence occurred after 2 PSST sessions among those with imperfect baseline adherence (d = 0.41, P < 0.10). Significant increases in adherence after 2 PSST sessions were documented for participants aged 16 to 18 years (d = 0.95, P < 0.05). Improvements in health-related quality of life occurred after 2 PSST sessions. No added benefit of 4 sessions on adherence was documented (d = 0.05, P > 0.05). Conclusions:Phone-delivered PSST was feasible and acceptable. Efficacy estimates were similar to those of lengthier interventions conducted in other chronic illness populations. Older adolescents benefited more from the intervention than their younger counterparts.

Inflammatory Bowel Disease in Children and Adolescents

The chronic inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are increasingly being recognized as a cause of chronic gastrointestinal disease in children and adolescents. About 20% of all patients with IBD develop symptoms during childhood (1) with about 5% being diagnosed before 10 yr of age (2). Comprehensive studies from Scotland have reported a 4.4-fold increase in pediatric CD between 1968-1988. No such trend has been noted for UC (3,4).

Manifestations of Cow's-milk Protein Intolerance in Preterm Infants

Objectives: Cows-milk protein intolerance (CMPI) is poorly recognized in preterm infants. This study examined the clinical events that preceded the diagnosis of CMPI in preterm infants. Methods: This was a retrospective study of infants in a level-III neonatal intensive care unit of those who received parenteral nutrition (PN) support during a 12-month period. Parameters assessed included birth weight (g), diagnosis, duration and frequency on PN, type of enteral feeds at initiation, and achievement of enteral autonomy. CMPI was diagnosed based on persistent feeding intolerance that resolved after change of feeds from intact protein to a protein hydrolysate or crystalline amino acid formula. Results: Three hundred forty-eight infants with birth weight (median/range) 1618 g (425–5110) received PN. Fifty-one (14%) infants required multiple courses of PN, and 19 of 348 (5%) were diagnosed with CMPI. The requirement for multiple courses on PN versus single course was associated with a high likelihood of CMPI: 14 of 51 versus 5 of 297, P < 0.001. Nine of the 14 infants identified with CMPI were initially diagnosed with necrotizing enterocolitis (NEC) after a median duration of 22 days (19–57) on intact protein feeds. After recovery from NEC, they had persistent feeding intolerance including recurrence of “NEC-like illness” (N = 3) that resolved after change of feeds to a protein hydrolysate or crystalline amino acid formula. Conclusions: The requirement for multiple courses of PN because of persistent feeding intolerance after recovery from NEC and recurrence of “NEC-like illness” may be a manifestation of CMPI in preterm infants.

Hermansky-Pudlak Syndrome: Severe Colitis and Good Response to Infliximab

JPGN Volume 51, N 13.9 EU/mL (<21 EU/mL), and protoplasmic-staining anti-neutrophil cytoplasmic antibodies 33 EU/mL (<12.1 EU/mL). Because of H ermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease with a relatively higher prevalence of 1:8000 in people of Puerto Rican descent, which was first described in 1959. HPS consists of tyrosine-positive oculocutaneous albinism with nystagmus, variable skin hypopigmentation, a platelet storage pool deficiency resulting in a bleeding diathesis due to decreased or absent platelet dense bodies, and ceroid deposition within the reticuloendothelial system. Seven genotypes have been described in HPS. HPS 1 and HPS 4 genotypes have been implicated in patients with severe pulmonary fibrosis, which usually presents in the third decade of life, and granulomatous colitis (1). Case reports of HPS in adults with gastrointestinal complications related to chronic granulomatous colitis, including fistulization and perineal disease, have been described (2). The majority of the cases failed to respond to conventional treatment of Crohn disease and required surgery. We report the first pediatric patient with HPS and severe granulomatous colitis who responded to infliximab.