William R. Treem

Primary Carnitine Deficiency Due to a Failure of Carnitine Transport in Kidney, Muscle, and Fibroblasts

CARNITINE (β-hydroxy-γ-trimethylaminobutyric acid) is an essential cofactor for the oxidation of fatty acids by mitochondria. It serves to carry long-chain fatty acids in the form of their acyl-car...

Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.

Background and Objectives: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. Methods: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. Results: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean ± SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 ± 10.4, 32.2 ± 12.7, and 47.8 ± 14.9, respectively (P < 0.001 for all comparisons). Mean ± SD PCDAI for inactive disease after treatment was 5.2 ± 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of ≥30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of ≥12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. Conclusions: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of ≥30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

Characterization of symptoms in children with recurrent abdominal pain: resemblance to irritable bowel syndrome.

We sought to prospectively characterize and compare the symptoms of children ≥ 5 years of age with recurrent abdominal pain to previously established criteria for irritable bowel syndrome (IBS) in adults. For all eligible subjects, a detailed questionnaire concerning characteristics of abdominal pain and defecatory pattern was completed at presentation. In addition, a battery of screening tests was performed and additional evaluation was done at the discretion of their physician. In all, 227 subjects fulfilled the entrance criteria, but 56 were sub-sequently excluded because of diagnoses of inflammatory bowel disease (nine cases), lactose malabsorption (46 cases), or celiac disease (one case). Of the remaining 171 patients, 117 had IBS symptoms. In the IBS subjects, lower abdominal discomfort (p < 0.001), cramping pain (p < 0.0009), and increased flatus (p < 0.0003) were more common, whereas dyspeptic symptoms such as epigastric discomfort (p < 0.003), pain radiating to the chest (p < 0.009), and regurgitation (p < 0.02) were more common in the non-IBS subjects. Our study not only confirms the clinical heterogeneity of children with recurrent abdominal pain but also concomitantly demonstrates that most children with this disorder have symptoms that fulfill the standardized criteria for IBS in adults. The identification of subgroups of children with recurrent abdominal pain can provide a framework for the diagnosis of functional bowel disease as well as establish the need for invasive and expensive tests.

Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease

BACKGROUND Intestinal and peripheral blood mononuclear cell interleukin 6 (IL-6) production in inflammatory bowel disease might present an increased quantity of IL-6 into the systemic circulation. The aim of the present study was to examine the relationship of circulatory IL-6 to the clinical and laboratory expression of inflammatory bowel disease in children. METHODS Sera were obtained from 26 children with ulcerative colitis, 49 with Crohns disease, and 29 control patients. Serum functional IL-6 was measured by a bioassay and antigenic IL-6 by enzyme linked immunosorbent assay. RESULTS Functional and antigenic serum IL-6 levels were higher in Crohns disease than in ulcerative colitis or controls (P < 0.0001) and higher in ulcerative colitis than controls (P < 0.04). In Crohns disease affecting the colon, functional and antigenic serum IL-6 levels were greater than in disease limited to the small bowel (P < 0.002). Increasing disease severity was reflected by increasing antigenic but not functional IL-6 levels in both Crohns disease (P < 0.001) and ulcerative colitis (P < 0.02). Serum antigenic IL-6 levels were related to acute phase reactants in both diseases (P < 0.001) whereas functional levels were not. CONCLUSIONS Our results underscore the importance of using both functional and antigenic methodologies in examining the relationship of circulating cytokines to the clinical manifestations of inflammatory bowel disease.

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

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

Fecal Short-chain Fatty Acids in Children with Inflammatory Bowel Disease

SummaryNutrition of colonic epithelial cells (colonocytes) is maintained by luminal short-chain fatty acids (SCFAs), chiefly by n-butyrate. The importance of SCFAs for the maintenance of colonic epithelium has been demonstrated in animal models of colitis produced by rectal instillation of an inhibitor of SCFA oxidation and in patients with diversion colitis in whom a segment of colonic epithelium was deprived of contact with luminal SCFAs. We measured fecal SCFAs and lactate in children with ulcerative colitis (UC; n = 17) and with Crohns disease with ileocolonic involvement (CD; n = 22) and age-matched controls (n = 12) by a vacuum-distillation, gas chromatographic method. Fecal SCFA concentrations were correlated with scores of clinical disease activity. Patients with UC and CD had a decrease in the fecal concentration of acetate (p < 0.05) and an increase in n-butyrate (p < 0.01) compared with controls. No significant changes in fecal lactate were seen. A comparison of inactive- or mild-UC patients with moderateor severe-UC patients yielded major differences in SCFA concentrations with n-butyrate increased in inactive and mild UC well above control values and total SCFA and acetate decreased in moderate and severe UC below control levels. Raised concentrations of fecal n-butyrate may reflect impaired utilization of this SCFA in the colon of patients with mild UC and Crohns disease with colonic involvement. Whether this defect is primary or secondary to inhibitors in the colonic lumen, due to impaired transport of n-butyrate into the cell or defective metabolism within the cell, or specific to inflammatory bowel disease remains to be explored.

Cyclosporine for the treatment of fulminant ulcerative colitis in children: Immediate response, long-term results, and impact on surgery

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.

Chronic recurrent multifocal osteomyelitis associated with chronic inflammatory bowel disease in children.

Chronic recurrent multifocal osteomyelitis(CRMO) is a rare disease of children characterized byaseptic inflammation of the long bones and clavicles. Noinfectious etiology has been identified, and CRMO has been associated with a number of autoimmunediseases (including Wegeners granulomatosis andpsoriasis). The relationship between CRMO andinflammatory bowel disease is poorly described. Throughan internet bulletin board subscribed to by 500pediatric gastroenterologists, we identified sixinflammatory bowel disease patients (two with ulcerativecolitis, four with Crohns colitis) with confirmed CRMO. In all cases, onset of the bony lesionspreceded the onset of bowel symptoms by as much as fiveyears. Immunosuppressive therapy for the bowel diseasegenerally resulted in improvement of the bone inflammation. Chronic recurrrent multifocalosteomyelitis should be considered in any inflammatorybowel disease patient with unexplained bone pain orareas of uptake on bone scan. CRMO may be a rareextraintestinal manifestation of inflammatory bowel disease;alternatively, certain individuals may be geneticallypredisposed to the development of bothdiseases.

Congenital sucrase-isomaltase deficiency

Congenital sucrase-isomaltase deficiency is a disorder that affects a persons ability to digest certain sugars. People with this condition cannot break down the sugars sucrose and maltose. Sucrose (a sugar found in fruits, and also known as table sugar) and maltose (the sugar found in grains) are called disaccharides because they are made of two simple sugars. Disaccharides are broken down into simple sugars during digestion. Sucrose is broken down into glucose and another simple sugar called fructose, and maltose is broken down into two glucose molecules. People with congenital sucraseisomaltase deficiency cannot break down the sugars sucrose and maltose, and other compounds made from these sugar molecules (carbohydrates).

Gastroesophageal Reflux in the Older Child: Presentation, Response to Treatment and Long-Term Follow-Up

Much attention has been focused on the natural history of gastroesophageal reflux (GER) in neurologically normal infants which generally resolves by two years of age. In contrast, little is known of the outcome of GER diagnosed in normal older children. The charts of 32 children (21 males) without neurologic or esophageal anatomic abnormalities, age 3.5 to 16 years (mean = 9.8) at the time of diagnosis, were reviewed. Diagnosis was based on suggestive presenting symptoms and evaluation of prolonged intraesophageal pH monitoring. Esophagitis was diagnosed by histologic criteria in 16 of the 32 patients. Medical treatment consisted of prokinetic agents (metoclopramide, bethanechol) and H2-receptor antagonists. After a one to eight year follow-up period (mean ± SD - 3.4 ± 2.1), the symptoms in 13 children had resolved or were sufficiently improved to discontinue medication. In 13 patients, symptoms were improved but medication was required for adequate control. Four children were symptomatic without improvement in spite of medical therapy and two others required fundoplication for continued severe symptoms and refractory esophagitis. In summary, less than 50% of otherwise normal older children with GER undergo spontaneous resolution of marked improvement in symptoms and the remainder require continued long-term medical and/or surgical management.