HEPATIC FIBROSIS AND SURVIVAL IN BILIARY ATRESIA
Viraine S Weerasooriya, Frances V White, Ross W Shepherd, Pediatrics, Washington University, St. Louis, MO; Pathology/Immunology, Washington University, St. Louis, MO; Pediatrics, Washington University, St. Louis, MO
Poor outcome in Biliary Atresia (BA) after the Kasai portoenterostomy (KP) has been related to age at the time of KP. We aimed to study whether the degree of hepatic fibrosis at the time of KP correlated with age, and if hepatic fibrosis was a determining factor in survival of the native liver.
Methods:
A pathologist (FW) blindly evaluated liver wedge biopsies taken from 30 cases from 1991-2001 for degree of fibrosis (Mild, Moderate, Severe) using Trichrome and H&E stained slides. Descriptive factors, age (days) at surgery, and outcome measures including bilirubin levels, and survival of native liver (months) were obtained by chart review. Pearson Correlation, Kaplan-Meier survival analysis, and Cox Regression were used to analyze the data.
Results:
Although the age of the patient and degree of fibrosis directly correlated at the KP (p=0.02), fibrosis had a greater influence on survival than age in this study. Survival was significantly worse with severe (nodular) fibrosis compared to those with mild or moderate fibrosis (Fig.). Using Cox regression, the only independent predictor of survival was the conjugated bilirubin level 3 months after surgery.
Figure. Proportion o...Image Tools
Conclusion:
Severe hepatic fibrosis decreases survival after the KP, and may explain why in other studies age at surgery is a predictor of survival. This finding requires confirmation in larger prospective cohort studies. The degree of fibrosis may eventually be used as a predictor for the need of liver transplantation. Further characterization of mechanisms of fibrogenesis in BA is also needed, as this may lead to innovative therapies and improve outcome.
RECOMBINANT FACTOR VIIA IMPROVES COAGULOPATHY DUE TO LIVER FAILURE
Jeffrey B Brown, Deborah L Brown, Karan M Emerick, Estella M Alonso, Gastroenterology, Hepatology, and Nutrition, Childrens Memorial Hospital, Northwestern University, Chicago, IL; Hematology and Oncology, Childrens Memorial Hospital, Northwestern University, Chicago, IL
Background:
Coagulopathy is an important cause of morbidity and mortality in patients with liver failure. Standard therapies used to support coagulation, including fresh frozen plasma (FFP), cryoprecipitate, and platelets, are frequently insufficient in preventing bleeding and can lead to iatrogenic complications such as volume overload and blood borne infection. We report our experience using Recombinant Factor VIIa (rFVIIa) as a safe adjunct to traditional therapies for coagulopathy due to hepatic synthetic failure.
Methods:
A retrospective review of in-patient pharmacy records from 4/2000 to 12/2001 identified 14 patients who were treated with rFVIIa for coagulopathy due to liver disease. The mean initial dose used was 85.2 ± 13.9 mcg/kg. The medical records of these patients were reviewed to identify patient demographics, indications for therapy, immediate response to rFVIIa infusion, and patient outcome. Mean prothrombin time (PT) results before and after therapy were compared by paired t-test.
Results:
The indication for rFVIIa in all 14 patients was on-going coagulopathy despite treatment with FFP. The mean PT at initial presentation was 37.4 seconds, with a range of 23.9 to > 60 seconds (INR 3.30 to > 15.3). 8 patients had coagulopathy due to acute liver failure and 6 due to chronic end stage liver disease. Administration of the first dose of rFVIIa resulted in correction of the PT from a mean of 29.4 ± 4.3 seconds prior to therapy to 13.6 ± 2.4 seconds (p < 0.0001) at 1 hour after infusion and 20.1 ± 5.5 seconds (p = 0.0011) at 6 hours after infusion. On-going rFVIIa therapy resulted in sustained improvement in the PT, with mean values for the following 3 days ranging from 18 to 20 seconds. 7/14 patients had clinically significant bleeding despite maximal therapy with FFP and platelets. The remaining 7 were treated empirically for refractory coagulopathy to limit the risk of spontaneous hemorrhage. Of the 7 with bleeding, 6 had subjective improvement, with 2 of these being successfully weaned to < 15% of their original FFP support. Thromboembolic or other adverse events related to rFVIIa were not observed.
Conclusions:
rFVIIa can be a useful adjuvant for coagulopathy and bleeding associated with liver failure. Patients in this series experienced a significant improvement in PT during the first 6 hours after infusion. No thrombotic complications were seen. Prospective studies will be necessary to better define clinical indications, efficacy, and cost-effectiveness of this treatment.
BARTONELLA HENSELAE IS ASSOCIATED WITH HEARTBURN, ABDOMINAL PAIN, SKIN RASH, MESENTERIC ADENITIS, GASTRITIS AND DUODENITIS
Martin D Fried, Janet Schairer, Gaye Madigan, Aswine Bal, Pediatrics, Jersey Shore Medical Center, Neptune, NJ
Purpose-
To investigate Bartonella henselae (B. henselae) as a pathogen associated with gastritis and duodenitis in children and adolescents.
Methods-
From July 2001 through March 2002, ten patients between the ages of 7 and 16 years presented with a history of cat scratches, chronic abdominal pain, esophageal heartburn for at least two months, a striae-like skin rash, mesenteric adenitis (greater than one cm in diameter) on CT scan of the abdomen and a positive Immunoglobulin G titer (1:64 or higher) for B. henselae. Endoscopy assessed the gastrointestinal mucosa for inflammation and biopsies were examined for H. pylori by microscopy and for B. henselae by polymerase chain reaction (PCR).
Results-
Biopsies were PCR positive for B. henselae DNA in all with chronic abdominal pain, heartburn, positive Immunoglobulin G titers for B. henselae, skin rash and mesenteric adenitis. Chronic gastritis and or chronic duodenitis was found in all and associated with the detection of B. henselae DNA in the GI tract at the site of the inflammation.
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Conclusion-
Bartonella henselae appears to be associated with a striae-like skin rash, abdominal pain, heartburn, gastritis, duodenitis and mesenteric adenitis in the pediatric population.
FLUCTUATION OF LEVELS OF TRANSGLUTAMINASE AUTOANTIBODIES IN GENETICALLY AT-RISK CHILDREN IN RELATION TO A POSITIVE CELIAC DISEASE BIOPSY
Edwin Liu, Fei Bao, Kathy J Barriga, Dongmei Miao, Liping Yu, Henry A Erlich, Joel E Haas, Edward J Hoffenberg, Marian J Rewers, George S Eisenbarth, Section of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital, Denver, CO; Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, CO; Department of Pediatrics, Immunology and Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO
With the development of quantitative transglutaminase autoantibody assays large scale screening for celiac disease is now practical. Relatively large numbers of asymptomatic children and adults express transglutaminase autoantibodies. It is not uncommon however to identify a child whose intestinal biopsy is negative. This has led to the suggestion that these sensitive autoantibody assays may have a low positive predictive value with the gold standard of celiac disease on biopsy. Our analysis of cohorts of genetically at risk children suggests an alternative explanation, namely that the celiac disease process fluctuates as reflected by the levels of transglutaminase autoantibodies and that levels of these autoantibodies are highly correlated with biopsy results at the time of biopsy. We have prospectively followed two genetically at risk cohorts of children, patients with type 1A diabetes and children from the general population HLA typed at birth and expressing DQ2. Once transglutaminase autoantibodies appeared they remained in most individuals above the 100th percentile of normal controls (index >0.05, n=184 samples). Despite remaining positive, the levels fluctuated dramatically (10 to 100 fold) with repeat sampling between 3 months and 1 year. Twenty of 21 children whose transglutaminase autoantibody level exceeded an index of 0.5 at the time of the biopsy had biopsy-confirmed celiac disease. Of the children with a negative biopsy (n=11), only 1 had a transglutaminase autoantibody level greater than 0.5 at the time of biopsy, despite having markedly higher transglutaminase levels greater than 0.5 months prior to the biopsy (the reason for scheduling the biopsy). Those with transglutaminase autoantibody levels greater than 0.5 at the time of biopsy were more likely to have a positive small bowel biopsy than those with levels less than or equal to 0.5 (20/21 or 95% biopsy positive compared to 3/13 or 23% (p<0.0001)). Of those with indeterminate biopsies, 1 of 4 had a transglutaminase autoantibody level greater than 0.5. This fluctuation in antibody may reflect the relapsing and remitting nature of many autoimmune diseases. We recommend in asymptomatic children who are screened for celiac disease to obtain a confirmatory transglutaminase autoantibody level immediately prior to biopsy to decrease the probability of false negative biopsies.
SELENIUM AND VITAMIN E DEFICIENCIES ALTER INTESTINAL EPITHELIAL CELL FUNCTION IN MICE INFECTED WITH HELIGMOSOMOIDES POLYGYRUS
Karla J Au Yeung, Kathleen B Madden, Allan Smith, Joseph F Urban, Orville Levander, Aiping Zhao, Terez Shea-Donohue, Pediatrics, Walter Reed Army Medical Center, Washington, DC; Pediatrics, Uniformed Services University of Health Sciences, Bethesda, MD; BHNRC, NRFL, USDA-ARS, Beltsville, MD
Worldwide, GI nematode infections are a major source of morbidity in childhood, often exacerbated by malnutrition. Selenium (Se) and Vitamin E (VE) deficiency (Se-/VE-) alter resistance to viral infections in mice. The effects of nutritional deficiencies on the host response to nematode infection are unknown. Th2 cytokines are induced by Heligmosomoides polygyrus (Hp) infection and expulsion is dependent on IL-4.
Aim:
To determine the effect of nutritional deficiencies on immune and intestinal epithelial cell function in mice infected with Hp.
Methods:
Balb/c mice were fed continuously a control diet (Se+/VE+) or deficient diet (Se-/VE-) and inoculated with Hp. Eggs and adult worm recovery were used as indices of resistance to infection and fecundity, respectively. Sections of stripped mucosae were mounted in Ussing chambers to measure tissue permeability and changes in chloride secretion to acetylcholine (ACH) and sodium-linked absorption of glucose. Serum concentrations of IFNγ and IL-4 were measured by the Cincinnati cytokine capture assay.
Results:
In Se-/VE- mice, resistance to Hp was reduced and fecundity was increased; however, the ability of Hp to elevate IL-4 was unimpaired. The Se-/VE- diet alone did not significantly alter intestinal epithelial cell function or permeability. Hp infection inhibited secretion in response to ACH and this effect was unchanged by Se-/VE-. In contrast, Hp- induced inhibition of glucose absorption was absent in Se-/VE- mice.
Conclusion:
Se/VE deficient mice have reduced resistance to Hp infection despite induction of Th2 cytokines. Se-/VE- mice showed enhanced absorption of glucose even during Hp infection. Increased fluid in the lumen is critical to worm expulsion. Thus, nutritional status is an important factor in the functional response to enteric infection and deficiencies can supercede the effects of Th2 cytokine upregulation.
Supported by USDA-ARS CRIS 1235-51000-039 (OL), NIH AI/DK49316 (TSD)
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OBESE CHILDREN HAVE IMPAIRED QUALITY OF LIFE
Jeffrey B Schwimmer, Tasha M Burwinkle, James W Varni, Pediatrics, UCSD; Center for Child Health Outcomes, Children's Hospital and Health Center; Psychiatry, UCSD, San Diego, CA
Aim:
To describe the Health Related Quality of Life (HRQOL) of obese children. We hypothesize that obese childen have low HRQOL.
Background:
Childhood obesity is the most common nutritional disorder in the United States. HRQOL is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity. While other studies have demonstrated that obese children have lower self-esteem, the HRQOL of obese children has not been previously studied.
Method:
The PedsQL™ 4.0 is a validated 23-item instrument encompassing physical functioning, emotional functioning, social functioning, and school functioning. PedsQL™ 4.0 was self-administered to obese subjects (newly referred patients to Gastroenterology or Nutrition for management of obesity). Obesity was defined as Body Mass Index (BMI) > 95th percentile for age and sex. PedsQL™ scores of obese children were compared with a reference population of 401 healthy, normal weight children. Impaired HRQOL was defined as a score > 1 SD below the reference mean.
Result:
93 consecutive obese subjects were enrolled (50 M, 43F; age: 12.2 ±3.0 years; BMI: 35.2 ±9.6; BMI Z-score: 2.46 ±0.37; ethnicity: Hispanic 50%, White 32%, Black 8%, Other 10%). Obese children were 5.8 (3.6-9.5) times more likely to have low total PedsQL™ score compared to normal weight children. All measures of quality of life were substantially lower in the obese children even after controlling for sex, ethnicity, and co-morbid conditions.
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Conclusion:
HRQOL is significantly lower in obese children compared to normal weight children. The impairment occurs in all domains and is as severe as previously reported HRQOL in children with cancer receiving chemotherapy. Parents, teachers, and physicians need to be aware of the physical and psychosocial consequences of childhood obesity in order to provide appropriate care including increased social and emotional support.
A MODEL FOR MONITORING ANTIMICROBIAL RESISTANCE IN HELICOBACTER PYLORI INFECTION IN THE U.S.
Benjamin D Gold, William M Duck, Jan M Pruckler, Qunsheng Song, Alana Sulka, Bala Swaminathan, Jeremy Sobel, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Foodborne and Diarrheal Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA
Helicobacter pylori (Hp) infection causes gastritis, duodenal ulcers, and is associated with gastric cancer. Eradication therapy entails multi-antimicrobial dosing regimens given for ∼ 2 weeks. Cross sectional studies worldwide suggest an overall increase in Hp drug resistance. The Hp Antimicrobial Resistance Monitoring Project (HARP) is the only prospective, multi-center U.S. network tracking regional and national prevalence rates of Hp resistance. In 1998, 11 U.S. medical centers began submitting Hp isolates obtained at diagnostic EGD to CDC for antimicrobial resistance testing. Each isolate is linked to a case report form with clinical and epidemiologic data. Susceptibility testing was performed using agar dilution, with validated quality control strains and standardized break points (NCCLS). Univariate analysis was performed (SAS version 8.2). 352 Hp isolates were submitted by participating sites, 12/98 to 5/01. Susceptibility testing was performed on 325 isolates; 99 isolates (30.5%) were resistant to 1 antimicrobial, and 15 (4.6%) were resistant to 2 agents; 73 (22.5%) were resistant to metronidazole (MET), 24 (7.4%) to clarithromycin (CLA), and 2 (0.6%) to amoxicillin (AMOX). Of 15 isolates resistant to 2 antimicrobials, 1 (6.6%) was resistant to CLA and AMOX and 14 (93.3%) were resistant to CLA and MET. 194 patients (63.0%) were male and 114 (37.0%) were female, median age was 58 range, (3-94), 122 (40.3%) were white, 165 (54.5%) were black, and 10 (3.3%) were Asian. In univariate analysis, factors associated with infection by resistant Hp were: antacid use in 12 months preceding EGD (OR=1.8, 95%CI, 1.1-3.1); ZantacR or TumsR use 30 days preceding EGD (OR=2.7, 95% CI, 1.2-6.1 and OR=3.3, 95% CI, 1.3-8.8, respectively); non-white race (OR=1.7, 95% CI, >1.0-2.7); earnings > $30,000/yr; (OR=1.8, 95% CI, 1.1-3.2); and residence in rural or farm area (OR=3.5, 95% CI, 1.2-10.8). Hp antimicrobial resistance to CLA, AMOX, and MET is prevalent at HARP project sites and associated with preceding antacid use. Expanding HARP sites to increase population and geographic representativeness will enhance monitoring Hp resistance on a regional and national level, and, help clarify risk factors associated with Hp resistance in the U.S.
POSSIBLE ROLE OF ISCHEMIA-REPERFUSION INJURY IN ACUTE PANCREATITIS AFTER SCOLIOSIS SURGERY
Devendra I Mehta, Zhaoping He, Dabney Kirk, Shah Suken, Tonb Dalal, Kolketty Stacey, Miller Freeman, Alfred I duPont Hospital for Children, Department of Pediatrics, Thomas Jefferson University, Wilmington, DE, USA
Acute pancreatitis (AP) complicates the postoperative course after posterior spinal fusion in up to 18% of children and adolescents. Though mostly mild, significant morbidity and occasional mortality from hemorrhagic pancreatitis has been reported. The mechanism is unknown, though AP is associated with prolonged aortic clamping in bypass surgery. METHOD: In a prospective study, we enrolled 39 patients undergoing posterior spinal fusion for neuromuscular scoliosis. Cytokines IL-6, IL-8, and TNFα were obtained immediately postoperatively and daily 1 post operatively in 21 cases. Intraoperative blood loss and duration of hypotension were recorded. Gastric Tonometry was used to obtain gastric mucosal pCO2 at 30 minute intervals, and the gap above end tidal pCo2 used to estimate duration of splanchnic hypoperfusion intraoperatively (greater or less than 60 minutes). Acute pancreatitis was diagnosed based on threefold increase in amylase, elevation of lipase, and clinical symptoms, and the length of stay (LOS) recorded. RESULTS: 4/21 patients developed acute pancreatitis days 3 to 5. The LOS in days was significantly longer in the AP group ( 36 +/- 14 vs control 5 +/- 2, P<0.05). Intraoperative blood loss in mls was also increased in the AP group 4,850 +/- 2315 vs control 1,332 +/-617, P<0.05), though no significant systemic hypotension was noted. The immediate post-operative TNFα levels, in pg/ml were higher in AP 11.88+/-8.03 vs control 5.72+/-3.36 p<0.05, though no difference was seen in IL-6 or IL-8, or TNFα levels day 1. Gastric tonometry was only completed in 12/21 cases due to intermittent sump tube obstruction. 2/12 developed acute pancreatitis. The duration of splanchnic hypoperfusion was greater than 60 minutes in both cases of acute pancreatitis, vs 4/10 controls ( P<0.05 Chi). CONCLUSION. Posterior spinal fusion is associated with prolonged splanchnic hypoperfusion. AP is associated with increased blood loss, TNFα levels, and greater than 60 minute splanchnic hypoperfusion. The cytokine profile in the immediately postoperative period is similar to that seen after ischemia/reperfusion from prolonged aortic clamping, and is predictive of subsequent AP. If confirmed early intervention may be possible in those at risk.
© 2002 Lippincott Williams & Wilkins, Inc.