ABSTRACTObjectives:α‐1‐Antitrypsin (A1AT) deficiency is a common genetic disease with an unpredictable and highly variable course. The Childhood Liver Disease Research and Education Network is a National Institutes of Health, multicenter, longitudinal consortium studying pediatric liver diseases, with the objective of prospectively defining natural history and identifying disease modifiers.Methods:Longitudinal, cohort study of A1AT patients' birth through 25 years diagnosed as having liver disease, type PIZZ or PISZ. Medical history, physical examination, laboratory, imaging, and standardized survey tool data were collected during the provision of standard of care.Results:In the present report of the cohort at baseline, 269 subjects were enrolled between November 2008 and October 2012 (208 with their native livers and 61 postliver transplant). Subjects with mild disease (native livers and no portal hypertension [PHT]) compared to severe disease (with PHT or postliver transplant) were not different in age at presentation. A total of 57% of subjects with mild disease and 76% with severe disease were jaundiced at presentation (P = 0.0024). A total of 29% of subjects with native livers had PHT, but age at diagnosis and growth were not different between the no‐PHT and PHT groups (P > 0.05). Subjects with native livers and PHT were more likely to have elevated bilirubin, ALT, AST, INR, and GGTP than the no‐PHT group (P << 0.001), but overlap was large. Chemistries alone could not identify PHT.Conclusions:Many subjects with A1AT presenting with elevated liver tests and jaundice improve spontaneously. Subjects with PHT have few symptoms and normal growth. Longitudinal cohort follow‐up will identify genetic and environmental disease modifiers.

Objectives To determine short-term outcome for children with acute liver failure (ALF) as it relates to cause, clinical status, and patient demographics and to determine prognostic factors.Study design A prospective, multicenter case study collecting demographic, clinical, laboratory, and short-term outcome data on children from birth to 18 years with ALF. Patients without encephalopathy were included if the prothrombin time and international normalized ratio remained ?:20 seconds and/or > 2, respectively, despite vitamin K. Primary outcome measures 3 weeks after study entry were death, death after transplantation, alive with native liver, and alive with transplanted organ.Results The cause of ALF in 348 children included acute acetaminophen toxicity (14%), metabolic disease (10%), autoimmune liver disease (6%), non-acetaminophen drug-related hepatotoxicity (5%), infections (6%), other diagnosed conditions (10%); 49% were indeterminate. Outcome varied between patient sub-groups; 20% with non-acetaminophen ALF died or underwent liver transplantation and never had clinical encephalopathy.Conclusions Causes of ALF in children differ from in adults. Clinical encephalopathy may not be present in children. The high percentage of indeterminate cases provides an opportunity for investigation.

Background: Children with short bowel syndrome (SBS) who have central venous catheters (CVC) placed for total parenteral nutrition (TPN) are at risk for thrombotic complications. The purpose of this study was to assess for independent risk factors for thrombosis in TPN-dependent children with SBS. Methods: Over a 2 year period, 22 children were assessed whose diagnoses included necrotizing enterocolitis, Hirschsprung's disease, malrotation with volvulus, gastroschisis, ileal or jejunal atresias, and intestinal dysmotility disorders associated with SBS. Serum protein C (PC), prothrombin time, chemistry panels, and nutritional indices were measured. Patients were followed for the occurrence of CVC thrombosis, deep venous thrombosis and pulmonary embolism. Clinical data were then analyzed with respect to PC, thrombotic events and amount of small bowel remaining at the time of their initial surgeries. Results: 19/22 children (86%) had catheter related thromboses, as demonstrated by angiographic evidence for clots, obstruction of CVC flow that responded to urokinase or heparin, or required removal of the catheter. 12/22 patients (55%) had deep venous thrombotic episodes; 3/11 (27%) of children were studied with lung scans and had multiple perfusion defects consistent with pulmonary emboli. 18/22 (82%) patients had a PC level of less than 65% of normal; 7/11 (64%) patients with <60cm of small bowel had PC<60 and 4/5 patients with >60cm of small bowel had PC>60. PC levels did not correlate with laboratory evidence of hepatic synthetic function (PT, albumin, glucose, cholesterol), cholestasis (total bilirubin, alkaline phosphatase), hepatitis (AST, ALT), or nutritional status (phosphorus, total calcium, total protein, magnesium, weight/height, or percent of ideal body weight). Conclusion: Children with SBS often have CVC related thrombotic events, deep venous thrombosis, and pulmonary emboli as a consequence of having low PC. Low PC were not explained by decreased hepatic synthesis of PC, nor poor nutritional status. Whether low PC levels were a primary contributing factor to the development of SBS in these children requires further investigation.

The safety and efficacy of olsalazine sodium was compared to sulfasalazine over 3 months in a multicenter, randomized, double-blind study of 56 children with mild to moderate ulcerative colitis. Twenty-eight children received 30 mg/kg/day of olsalazine (maximum, 2 g/day) and 28 received 60 mg/kg/day of sulfasalazine (maximum, 4 g/day). Side effects were frequent in both groups. Eleven of 28 patients (39%) on olsalazine reported headache, nausea, vomiting, rash, pruritus, increased diarrhea, and/or fever. Thirteen of 28 on sulfasalazine (46%) reported similar side effects and/or neutropenia, and four patients had the drug stopped because of an adverse reaction. After 3 months, 11 of 28 (39%) on olsalazine were asymptomatic or clinically improved, compared to 22 of 28 (79%) on sulfasalazine (p = 0.006). In addition, 10 of 28 patients on olsalazine versus one on sulfasalazine required prednisone because of lack of response or worsening of colitis (p = 0.005). The dose of olsalazine used in this clinical trial was thought to be equivalent to a standard dose of sulfasalazine, but fewer patients on olsalazine improved and a greater number had progression of symptoms when compared to sulfasalazine. Although side effects were slightly less frequent for olsalazine, the number of patients was too small to detect a clinically significant difference.

Pediatric Gastroenterology and Nutrition, Oakland Children's Hospital, Oakland; and ˆUniversity of Southern California School of Medicine and Childrens Hospital of Los Angeles, Los Angeles, California, U.S.A. Address correspondence and reprint requests to E. E. Gleghorn at Division of Pediatric Gastroenterology, Oakland Children's Hospital, 747 52nd St., Oakland, CA 94707, U.S.A. Manuscript received September 3, 1991; revisions received June 16, 1992; July 21, 1992; final revision accepted July 22, 1992.

Measurement of fecal alpha-1-antitrypsin (A1AT) excretion has been demonstrated to be a reliable, non-invasive test for protein-losing enteropathy in humans. The unique biologic properties of A1AT allow it to serve as a natural marker for loss of serum protein into the gut. Our laboratory has recently purified rat A1AT and raised antibody to rat A1AT. The biological and chemical characteristics of human and rat A1AT are very similar. We performed the following initial experiment to establish whether measurement of fecal A1AT also detects intestinal damage in rats. Adult Sprague-Dawley rats were given either a single, intraperitoneal injection of 40 mg/kg of bleomycin or an equal volume injection of sterile saline. Bleomycin has known toxic effects upon the gastrointestinal tract. Stools were collected for 5 days following the injection and assayed for A1AT content by rocket immunoelectrophoresis. Mean fecal A1AT±SD (mg/g dry stool) are given below for each day following injection: Our data indicate that intraperitoneal bleomycin resulted in elevated fecal A1AT excretion. Conclusions: 1) fecal A1AT is a useful marker for intestinal damage in rats, and 2) the toxic gastrointestinal effects of various drugs and treatments administered to rats can be monitored by fecal AlAT.

The prevalence of colic with respect to the type of milk feeding in the first 17 weeks of life was assessed by questioning the parents of 964 healthy infants aged 2 to 52 weeks. There was a similar prevalence of colic in infants fed human milk (20%), formula (19%), and formula-supplemented human milk (21%). Intestinal damage, determined by measuring random fecal alpha 1-antitrypsin concentrations in 206 infants aged 2 to 17 weeks and fecal hemoglobin concentrations in 200 of these, was not more likely in infants with colic at the time of study. The occurrence of adverse reactions at the time of introduction of fresh whole cow's milk into the diet of previously colicky infants was uncommon. Our results suggest that dietary protein hypersensitivity is probably not the cause of colic in most healthy young infants.

Fecal alkaline phosphatase excretion was evaluated as a marker for intestinal damage in rats. Animals received either intraperitoneal bleomycin or saline. Controls were pair-fed with animals in the bleomycin group throughout the study. Both groups demonstrated similar patterns of fecal alkaline phosphatase excretion. There was, however, marked daily variability of fecal enzymatic activity. Fecal alkaline phosphatase excretion was largely composed of intestinal alkaline phosphatase, which was characterized by enzymatic inhibition with L-phenylalanine. Dietary intake as well as daily fecal output and protein excretion were reduced immediately following bleomycin injections and gradually increased to baseline values by 7 days. It appeared that both the direct toxic effects of bleomycin and dietary intake influenced fecal alkaline phosphatase excretion. Routine clinical application of this assay may be limited because of the number of factors which may affect its excretion.

be an additive but not the main cause of the disease. Other undetected factor(s) might be involved. Because no further study was conducted, we do not have any evidence of impaired vitamin K absorption in these infants; such a possibility should be defined in the future. Komazawa a~ showed that orally administered vitamin K was less well absorbed in infants, with or without hepatic dysfunction, compared with healthy adults. The outcome in our infants was unfavorable (Table). Our observations support the concept that vitamin K prophylaxis is exclusively breast-fed infants is necessary.9.10 A recent study suggested that breast-fed babies who received vitamin K at birth did not have vitamin K deficiency at 1 month of age. 12 However, this study was criticized because the number of infants studied was small 13 and the report did not address the issue of vitamin K deficiency in breast-fed infants who do not receive prophylaxis. 9 In Japan, oral administration of vitamin K two or three times during the first month of life is being studied in an effort to prevent vitamin K deficiency, 1 but a final conclusion has not been reached.

"The appropriate age at which unheated, whole cow's milk (WCM) can be safely introduced into the infant diet is unknown and remains an area of controversy" (AAP Committee on Nutrition, 1983). Previous studies suggest that WCM is associated with an induced enteropathy in some infants, especially those under 6 months of age. However, the prevalence of intestinal damage which might result from WCM feedings has not been established in older infants. To examine this issue, we compared enteric protein and blood excretion in 332 healthy 6-12 month old infants fed breast milk (B), formula (F), or WCM in addition to solids. Fecal alpha-l-antitrypsin (FAlAT), a marker for enteric protein loss, and fecal hemoglobin (FH) concentrations were measured in random samples by radial immunodiffusion. Mean FAlAT (mg/g dry stool) ± SD are presented below:All above values are within the normal range (Gastroenterology 80:776, 1981). FAlAT did not change with age. Only 6 infants had measurable FH loss (≥3 mg/g dry stool). Diet was not a factor in FH loss.Although the biological significance of the differences observed in FAlAT excretion is conjectural, we conclude that subclinical intestinal damage is infrequent in WCM-fed healthy infants over 6 months of age.

Fecal alpha 1-antitrypsin excretion, a noninvasive indicator of protein-losing enteropathy, was correlated with clinical disease activity in pediatric patients with Crohn's disease. Disease activity was defined as the sum of 11 abnormal clinical parameters which were adapted from previously published disease activity scoring methods. Each patient was also given a subjective clinical rating when evaluated. In addition, four different devised disease activity scoring methods were correlated retrospectively with subjective clinical ratings for hospitalized patients. A total of 125 random fecal alpha 1-antitrypsin determinations were performed on 22 patients. Ninety-six percent of clinically active episodes of Crohn's disease were associated with elevated fetal alpha 1-antitrypsin (p less than 0.001). The degree of elevation was found not to correlate directly with the severity of assessed disease activity or site of intestinal involvement. A direct linear relationship was demonstrated between 23 paired random fecal alpha 1-antitrypsin and intestinal alpha 1-antitrypsin clearance assays (r = 0.93). There was a high, and remarkably similar, degree of correlation with each of the four different derived activity scoring methods and simple subjective ratings (r = 0.89-0.93). We conclude that: (a) fecal alpha 1-antitrypsin excretion may be helpful in assessing the presence or absence of Crohn's disease activity by providing an objective and specific indicator of intestinal damage; and (b) it appears that a simple subjective rating score is as clinically useful as other previously devised activity indices.

An infant with gastroschisis is presented whoseepisodes of apparent postoperative sepsis were due to milk protein hypersensitivity. Young infants with intestinal damage and increased mucosal permeability to potential antigens may be at risk for developing dietary hypersensitivity reactions.

Random fecal α-1-antitrypsin (R-FA1AT) was monitored for 4 to 22 months in 18 children with Crohn's disease aged 7 to 17 years. Excess R-FA1AT indicates abnormal fecal loss of serum protein (Clin. Res. 28 (1):97A, 1980). The relationship between the number of abnormal clinical findings (ACF) and R-FAlAT was evaluated. Eleven parameters were selected to assess disease activity (abdominal pain, weight loss, fever, diarrhea, extra-intestinal symptoms, Hgb, ESR, WBC, albumin, hematochezia, and abdominal mass). Elevated R-FA1AT was associated with high ACF (X2p<0.001). Patients had 5.7±1.7 ACF when R-FA1AT was ≥3.4 (mg/gm dry stool) (X of normal + 3SD) compared to 1.4±1.0 when R-FA1AT was <3.4 (p<0.001). With treatment ACF fell from 5.9±1.3 to 0.9±0.8 (p<0.001), and R-FA1AT decreased from 10.3±5.0 to 1.7±0.7 (p<0.001). R-FA1AT became abnormal in 2 patients prior to an increase in ACF upon relapse. Two children still had abnormal R-FA1AT despite declining ACF in early remission. We conclude that R-FA1AT is an objective, sensitive, and noninvasive marker for activity of Crohn's disease.

Eighteen pediatric oncology inpatients had 21 Hickman right atrial catheters placed for total venous access; 16 patients received parenteral nutrition. Mean duration of catheterization was 43 +/- 29 (SD) days. Four catheters had to be removed for infection or clotting. The catheter-related sepsis rate was 10%. Serious catheter-related complications were no more frequent in this population than in patients receiving only parenteral nutrition via Broviac or pediatric Broviac catheters.

*From the Department of Radiology, University of Southern California School of Medicine, Los Angeles, California †From the Department of Pediatrics, Childrens Hospital of Los Angeles and University of Southern California School of Medicine, Los Angeles, California

IN A ONE-YEAR PERIOD, we observed lactic acidosis in five oncology patients in association with the use of total parenteral nutrition. There are multiple previous reports of lactic acidosis in patients with cancer, usually leukemia or lymphoma. 1,2 The association with TPN has been noted in two adult patients and has been described in one pediatric patient receiving 10% glucose infusion. :~ ~ The relatively high risk for lactic acidosis in pediatric patients with advanced cancer when receiving TPN has not been previously stressed.