Richard Couper

The sugar permeability test reflects disease activity in children and adolescents with inflammatory bowel disease

OBJECTIVES To investigate the relationship of intestinal permeability in children and adolescents with inflammatory bowel disease (IBD) to disease activity, disease extent, and response to therapy. STUDY DESIGN Patients with new and established diagnoses of IBD (12 Crohns disease [CD] and 18 ulcerative colitis [UC]) were studied. Intestinal permeability was evaluated by measuring with high-performance liquid chromatography 5-hour urinary excretion ratio of lactulose/L-rhamnose (L/Rh). RESULTS In 8 of 9 patients with active CD, the L/Rh ratio was higher than the reference range (0.006 to 0.074, n = 36). In inactive CD (n = 3) the L/Rh ratio was within the reference range. In 6 of 7 patients with active extensive UC, the L/Rh ratio was elevated. In inactive extensive UC (n = 6) the normal permeability ratio was shown. In both active CD and active extensive UC, the frequency of elevated intestinal permeability was significantly greater than values in both inactive forms. The permeability ratio was normal in 4 of 5 patients with active left-sided colitis. In 5 of 7 patients (3 CD, 4 UC), repeat permeability values entered the reference range after acute phase therapy. Two patients with persistently elevated intestinal permeability (1 CD, 1 UC) had a disease flare-up within 6 months. CONCLUSIONS Intestinal permeability is a marker of disease activity in CD and extensive UC. Serial permeability test may be useful in monitoring disease activity.

Neutrophil dysfunction in glycogen storage disease Ib: Association with Crohn's-like colitis

Two cases of patients with Crohns-like colitis and glycogen storage disease Ib have been reported previously. In the current report, chronic inflammatory bowel disease that developed in another adolescent with this glycogenosis is described, thereby corroborating the association. The neutrophil dysfunction observed in glycogen storage disease Ib is the most likely predisposing factor. Neutrophil function was investigated in our patient in an attempt to shed light on the pathogenesis of his intestinal inflammation. The patient displayed reduced neutrophil chemotaxis to zymosan-activated serum, N-formyl-methionine-phenylalanine, and Escherichia coli bacteria-derived factor and reduced intracellular killing of Staphylococcus aureus 502A. Others have found this defective bacteriocidal activity to be caused by impaired oxidative metabolism. The recent recognition of chronic inflammatory bowel disease in glycogen storage disease Ib, as well as in chronic granulomatous disease, suggests that further study of respiratory burst activity of neutrophils in Crohns disease is warranted.

Longitudinal evaluation of serum trypsinogen measurement in pancreatic-insufficient and pancreatic-sufficient patients with cystic fibrosis

We studied serial measurements of serum cationic trypsinogen in patients with cystic fibrosis to assess the predictability of changes in individuals and the value of longitudinal measurement in defining pancreatic status. Three hundred twenty-nine patients with cystic fibrosis, aged 3 days to 40 years, had serum levels of trypsinogen measured on 2 to 12 occasions for periods ranging from 1 week to 7 years. Patients were classified into three groups on the basis of 72-hour fecal fat studies performed at the time of diagnosis. Two hundred thirty-three patients had pancreatic insufficiency (PI), 78 had pancreatic sufficiency (PS), and 18 had PS at diagnosis but acquired PI during follow-up (PS-->PI). Infants with PI had greatly elevated serum trypsinogen levels that fell sharply in the first years of life, so that by age 7 years more than 95% had subnormal values; individual patient values followed a predictable course similar to previously reported cross-sectional age-related values. In patients with PS, serum trypsinogen levels generally remained within or above the normal range and, after age 10 years, were well above the upper limit for PI patients. Within-patient variance was significantly greater (p < 0.0001) in patients with PS than in those with PI who were older than 7 years of age. Changes in patients within PS-->PI generally followed the pattern seen in patients with PI, but values in older patients tended to be in the higher range. We concluded that serial measurement of serum trypsinogen is a valuable tool for monitoring the pancreatic status of patients with cystic fibrosis and PS.

Crypt fission peaks early during infancy and crypt hyperplasia broadly peaks during infancy and childhood in the small intestine of humans.

Background: Postnatal growth of the small intestine occurs by crypt hyperplasia and by the less recognised mechanism of crypt fission. How the small intestine grows is largely extrapolated from animals and is poorly described in humans. Aim: To investigate crypt fission and crypt hyperplasia as mechanisms of intestinal growth in humans. Patients and Methods: Proximal intestinal samples were taken from 3 neonates at surgical anastomosis, and duodenal biopsies were taken at endoscopy from 16 infants (mean age 0.7, range 0.3–1.7 years), 14 children (mean age 7.9, range 2.4–16.2 years), and 39 adults. Morphometric measures of villous area, crypt length (measure of crypt hyperplasia), and percentage of bifid crypts (measure of crypt fission) were assessed by a microdissection technique. Results: Mean crypt fission rates in neonates, infants, children, and adults were 7.8%, 15%, 4.9%, and 1.7%, respectively. In particular, crypt fission peaked at 18% in 5 infants from 6 to 12 months of age. Mean crypt length was 123 μm in neonates, 287 μm in infants, 277 μm in children, and 209 μm in adults. Thus, crypt hyperplasia had a broad peak during infancy and childhood. Conclusions: We conclude that crypt fission was present predominantly during infancy, and crypt hyperplasia occurred during both infancy and childhood.

Renal calcium handling in cystic fibrosis: Lack of evidence for a primary renal defect

Because cystic fibrosis (CF) epithelia have ion transport abnormalities that may in part be regulated by intracellular calcium metabolism, and the kidney is actively involved in both ion transport and calcium homeostasis, we have investigated renal calcium handling in CF. Twenty-four-hour urine collections were analyzed in 34 CF patients (age 5 to 35 years) and kidney ultrasound studies were performed in 17 CF patients (age 6 months to 23 years). Renal histologic findings at postmortem examination of 14 CF patients (age 4 months to 23 years) were compared with those of 12 patients (age 11 months to 17 years) with other chronic illnesses (6 congenital heart disease, 6 malignancy). In 30 of the 34 CF patients urinary calcium excretion was normal (less than 4 mg (0.1 mmol)/kg/24 hr). Four CF patients had hypercalciuria (calcium excretion 4.4 to 8.8 mg (0.11 to 0.22 mmol)/kg/24 hr). However, these patients had other possible explanations for hypercalciuria, such as immobilization (n = 2), increased dietary sodium load (n = 1), and glucocorticoid therapy (n = 1). None of the 17 patients examined by renal ultrasonography had nephrocalcinosis. Five CF patients had histologic evidence of sparse nephrocalcinosis at autopsy. However, 6 of 12 autopsy kidney specimens from patients with other chronic illnesses and similar preterminal events also showed nephrocalcinosis. The hypercalciuria and nephrocalcinosis in CF and other chronic debilitating diseases may be explained by factors known to affect calcium handling. Our evidence does not support a primary renal defect as the basis of hypercalciuria and nephrocalcinosis in CF.

Relationship of Hepatocyte Growth Factor in Human Umbilical Vein Serum to Gestational Age in Normal Pregnancies

Hepatocyte growth factor (HGF) is expressed in placental syncitium and fetal organs and acts as a mitogen, motogen, and morphogen in vitro, suggesting a role in fetal growth and development. We aimed to examine the correlates of serum HGF in human cord blood. HGF was measured by ELISA using recombinant human HGF and mouse MAb to recombinant human HGF (Immunology Institute, Tokyo). Umbilical vein blood was collected prospectively at 148 deliveries including 94 normal pregnancies and 54 pregnancies complicated by medical conditions, primarily diabetes mellitus and pregnancy-induced hypertension. Growth parameters, gestation, pregnancy history, and perinatal events were recorded. Sera from 54 adolescents and 32 adult controls were also analyzed. Cord HGF [0.97 (0.66-1.33) ng/mL] [median (25-75 percentile)] was higher than HGF levels in adolescent sera [0.28 (0.21-0.35) ng/mL, p< 0.0001] and adult control sera [0.23 (0.14-0.31) ng/mL, p < 0.0001]. Cord HGF correlated with gestational age (r = 0.42,p = 0.0001) in normal pregnancies, with term babies (n = 69) having higher cord HGF than babies less than 37 wk of gestation(n = 25) [1.11 (0.78-1.45), 0.78 (0.46-1.03) ng/mL, p = 0.0007]. However, there was no relationship between gestation and cord HGF in complicated pregnancies. Cord HGF did not differ at term between appropriate for gestational age babies and small for gestational age babies. There were no independent correlations between cord HGF and birth weight, birth length and placental weight. We provide evidence for the first time that cord HGF levels are high and relate to gestation in normal pregnancies. HGF may have a significant role in fetal development during pregnancy.

Serum Immunoglobulin G Directed Against Porcine Trypsin in Pancreatic Insufficient Cystic Fibrosis Patients Receiving Pancreatic Enzyme Supplements

Cystic fibrosis (CF) patients frequently malabsorb nutrients because of pancreatic failure. Standard therapy entails oral administration of porcine pancreatic enzymes, with meals. Porcine enzymes contain in excess of 25 potentially antigenic proteins. To evaluate antigenicity of one of these (porcine trypsin), we developed ELISA techniques capable of measuring total immunoglobulin G (IgG) and IgG directed against porcine trypsin in patient sera. Cross-sectional evaluation of sera from 12 controls and 41 CF patients showed that IgG directed against porcine trypsin was detectable in 12/17 CF patients receiving porcine enzymes (50.6 ± 56.0 ng/ml; range 0–154.0 ng/ml), while none was detected in controls or the 26 CF subjects not receiving enzymes. In the 17 CF patients receiving enzymes, porcine trypsin binding IgG contributed 0.85 ± 0.83% of the total IgG pool. Levels of porcine trypsin binding did not correlate with total IgG. Longitudinal evaluation was then performed in 26 CF patients, before and after commencement of enzyme therapy. Prior to commencing therapy, porcine trypsin binding IgG was undetectable in sera from 24/26 patients. Within 4.2 years of commencing therapy, 25/26 patients (96%) developed porcine trypsin binding IgG. Thus, serum IgG responses to porcine trypsin appear to be common in CF patients receiving porcine enzymes and contribute considerably to total IgG levels. Other individual enzymes in porcine extracts are likely to elicit similar antigenic response.

Pancreatic disorders and cystic fibrosis: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

The exocrine pancreas is pivotal to the digestion and absorption of nutrients. Pancreatic disorders manifest either with pain secondary to inflammation or with malabsorption secondary to acinar malfunction, paucity, or dropout. Children suffer from the full range of pancreatic disease seen in adults, and some pancreatic disorders first become apparent in childhood. The spectrum of pancreatic disease is listed below.

Australian Experience of Total Pancreatectomy and Islet Auto Transplant (TPIAT) Utilizing a Remote Isolation Center

Introduction In 2015 we performed the first TPIAT in Australia on a 7 year old paediatric patient suffering hereditary chronic pancreatitis due to a PRSS1 mutation. We have since performed a further 4 TPIAT procedures, 2 paediatric and 2 adult recipients. All 5 TPIAT procedures were performed in Adelaide, South Australia at the Women’s and Children’s Hospital (paediatric patients) or the Royal Adelaide Hospital (adult patients). The islet isolation procedure was performed at a remote isolation center, St Vincent’s Institute (SVI), Melbourne Victoria. SVI is a 1hr15min commercial flight from Adelaide or approximately 470 miles by road. Following isolation, the islets were infused back into each patient on the same day in Adelaide. Materials and Methods In the first 2 patients a total pancreatectomy, splenectomy, cholecystectomy, and biliary and enteric reconstruction was performed. In patients 3-5 the spleen was spared during the total pancreatectomy. Once removed, the pancreas was placed in preservation solution and escorted from Adelaide to Melbourne by commercial airline. Pancreatic digestion and islet isolation were performed using Serva enzyme and standard protocols. Islet infusion into the liver was performed by cannulation of the portal vein with concomitant portal vein pressure monitoring. Results The cold ischaemic time for all 5 pancreas was similar, ranging from 5hr to 5hr21min. The pancreas weights varied significantly, however this did not correlate with islet yield. Total IEQ ranged from 28,254 to 653,222 and the time from placing the islets into transplant bags through to infusion into the recipient was relatively consistent, ranging from 4-5hrs. To date, patients 1 & 3 have ceased all pre-operative pain medication and patient 4 has significantly reduced his opiate usage and is currently undergoing a controlled withdrawal and detoxification program with medical guidance to cease the remaining analgesia. Patient 5 the most recent TPIAT is in the process of weaning off her pre-operative analgesia and patient 2 suffered complications following TPIAT and is deceased. All 4 surviving patients are c-peptide positive with daily insulin requirements ranging from 10-20U and HbA1c levels of 5-8. Conclusion We have successfully completed a pilot study involving 5 patients undergoing TPIAT for the management of chronic pancreatitis. All 5 isolations were performed at a facility remote to the hospital where the total pancreatectomy and subsequent islet infusion was performed. All surviving recipients have experienced a reduction or complete resolution of their chronic pain following TPIAT with two patients no longer requiring any form of analgesia. They are all c-peptide positive, requiring minimal doses of exogenous insulin with excellent management of their diabetes. Recently, we secured additional funding to perform 6 more TPIATs with the long-term goal of establishing TPIAT as a government funded procedure for the treatment of chronic pancreatitis. The Hospital Research Foundation South Australia. MedVet Sciences South Australia. Women’s and Children’s Hospital. Table. No title available.

First Report of Successful Total Pancreatectomy and Islet Autotransplant in Australia

To the Editor:We present the first total pancreatectomy and islet autotransplant (TP-IAT) performed in Australia in a child with hereditary pancreatitis. Collaboration with interstate and international expertise enabled this procedure. The 7-year-old boy had a severely fibrosed pancreas but has achi