Cystic fibrosis liver disease in the new era of cystic fibrosis transmembrane conductance regulator (CFTR) modulators.

Cystic fibrosis liver disease (CFLD) is characterised by a wide heterogenity of manifestations and severity. It represents a major cause of morbidity in people with cystic fibrosis (PwCF), which will be of increasing relevance as survival increases in the new era of cystic fibrosis care. No medical therapy currently available has evidence to treat or prevent progression of liver disease. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators may be transformative on pulmonary, nutritional and quality of life, but direct effect on long term liver disease outcomes is not yet established. Drug-associated hepatic adverse effects may be common, and clinician familiarity with drug-monitoring recommendations is essential. Longitudinal studies are required to understand the effect of CFTR modulators on the incidence and natural history of CFLD, including with early treatment initiation, in established advanced liver disease, and post liver transplantation.

Paediatric constipation for general paediatricians: Review using a case-based and evidence-based approach.

Constipation is a common problem in childhood. The most common type of constipation is functional, accounting for 90-95% of all cases. The aim of this review is to provide clinical scenarios with treatment using evidence-based information, and management strategies and a clinical algorithm to guide the management of constipation in children. Recent guidelines and online information sites are detailed. Clinical red flags and organic causes of constipation are included. Four clinical scenarios are presented: case (1) 4-month-old child with constipation since birth and likely Hirschsprung disease; case (2) 6-month-old infant with infant dyschezia; case (3) 4-year old with functional constipation; and; case (4) 9-year old with treatment resistant constipation. Children with functional constipation need a thorough history and physical exam to rule out the presence of any 'red flags' but do not require laboratory investigations. Management includes education and demystification, disimpaction followed by maintenance therapy with oral laxatives, dietary counselling and toilet training. Treatment options differ between infants and children. Disimpaction and maintenance regimens for common laxatives are presented. On treatment failure or on suspicion of organic disease the patient should be referred for further evaluation. The radionuclide intestinal transit study (scintigraphy) is a useful modality for evaluation and planning of management in treatment-resistant children. Treatment options for treatment-resistant patients are presented. High-level evidence (meta-analyses) for pharmalogical and non-pharmalogical treatment modalities are reviewed and an algorithm for assessment and treatment are presented.

Combined liver and pancreas transplantation in two children with cystic fibrosis-First experience in Australia and New Zealand.

We report the first two pediatric patients with CF who underwent successful combined liver-pancreas transplantation in Australia and New Zealand for CF liver disease and CF-related diabetes mellitus.

Practical approach to the gastrointestinal manifestations of cystic fibrosis.

Cystic fibrosis (CF) is the most common, life-shortening, genetic illness affecting children in Australia and New Zealand. The genetic abnormality results in abnormal anion transport across the apical membrane of epithelial cells in a number of organs, including the lungs, gastrointestinal tract, liver and genito-urinary tract. Thus, CF is a multi-system disorder that requires a multi-disciplinary approach. Respiratory disease is the predominant cause of both morbidity and mortality in patients with CF. However, there are significant and clinically relevant gastrointestinal, liver, pancreatic and nutritional manifestations that must be detected and managed in a timely and structured manner. The aim of this review is to provide evidence-based information and clinical algorithms to guide the nutritional and gastrointestinal management of patients with CF.

Fulminant liver failure in a neonate.

Neonatal acute liver disease is relatively rare, with multiple different aetiologies including congenital infections, metabolic disorders, gestational alloimmune liver disease, haemophagocytic lymphohistiocytosis, and ischaemic injury. We report a case of neonatal liver failure in a preterm, growth-restricted infant, who underwent extensive investigation and was clinically diagnosed with gestational alloimmune liver disease, which was confirmed on post-mortem examination. We then discuss management of neonatal liver failure and gestational alloimmune liver disease, including maternal management in future pregnancies.

Clinical audit results in earlier nutritional intervention in malnourished children with cystic fibrosis with improved outcome.

AIM: The association between nutritional status, pulmonary function and survival in cystic fibrosis (CF) is well established. A previous case series from the Royal Children's Hospital, Melbourne (RCH), demonstrated suboptimal referral practices and highlighted the importance of early nutritional interventions in children with CF. Various qualitative changes were made to our CF service, and this study assesses the effects of these practice changes timing of gastrostomy and clinical outcome in patients who underwent gastrostomy insertion. METHOD: Clinical audit of all CF patients who had undergone gastrostomy insertion from 2002 to 2010 at Royal Children's Hospital. Clinical data, including nutritional parameters, respiratory function and survival, were collected at 2 years prior and 2 years post gastrostomy insertion. Data were compared with the previous study from 1989 to 1997. RESULTS: Patients with CF who underwent gastrostomy insertion between 2002 and 2010 (n = 22) had higher weight-for-age scores (-1.5 ± 0.68 vs. -2.67 ± 1.06; P = 0.0001) and higher forced expiratory volume in 1 s (68% ± 22 vs. 52% ± 18.5; P = 0.006), compared with the cohort from 1989 to 1997 (n = 37). These differences were maintained at 2-year follow-up. Pseudomonas aeruginosa colonisation rate was 100% in 1989-1997 vs. 41% in 2002-2010; P = 0.0001. The 2-year survival post-gastrostomy insertion improved from 70% to 100%; P = 0.004. CONCLUSION: Earlier referral of patients in the recent cohort resulted in sustained improvements in weight-for-age and lung function. Survival at 2 years post-procedure was significantly improved. This study confirms the value of clinical audits and subsequent re-evaluation of clinical services.

Can celiac serology alone be used as a marker of duodenal mucosal recovery in children with celiac disease on a gluten-free diet?

OBJECTIVES: Assessment of treatment response in children with celiac disease (CD) after commencing a strict gluten-free diet (GFD) is generally based on the resolution of clinical features and normalization of serology. Recent adult studies have shown that serologic markers do not correlate with mucosal recovery. We aimed (i) to determine whether anti-tissue transglutaminase immunoglobulin (Ig)A (tTG) and anti-deamidated gliadin peptide IgG (DGP) antibodies are sensitive and specific markers of mucosal recovery in children with CD on a GFD for at least 12 months, and (ii) to determine whether a validated dietary questionnaire of compliance can identify patients with mucosal recovery. METHODS: A total of 150 children with biopsy-proven CD were prospectively evaluated with duodenal biopsies at ≥12 months on GFD, paired with repeat tTG and DGP serology. The biopsies were reviewed in a blinded manner by two histopathologists and graded by Marsh criteria. A validated questionnaire of dietary compliance was also administered. RESULTS: Of 150 children recruited, 27 (18%) had positive serology, 97 (65%) had negative serology, and 26 (17%) had equivocal serology. Of the 97 children with negative serology, none had Marsh type 3 enteropathy. Of the 27 patients with positive serology, only 6 had Marsh type 3 changes. The sensitivity and specificity of serology as a marker of significant mucosal pathology was 75 and 85%, respectively, with a positive predictive value of 22% but a negative predictive value of 98%. Of the 129 (86%) questionnaires completed, 88% reported good or excellent compliance with a GFD (negative predictive value 97%). CONCLUSIONS: This study suggests that follow-up using two serological tests in children with CD on a GFD may obviate the need for repeat mucosal biopsy in the majority of patients. A standardized dietary questionnaire may be useful in identifying patients who require further evaluation.

Clinical patterns and outcome of early-onset inflammatory bowel disease.

We sought to determine whether extremely-early-onset childhood inflammatory bowel disease (age <6 years; 20 ulcerative colitis [UC], 8 Crohn disease [CD], 2 indeterminate, sequentially diagnosed) was clinically more severe than in older children (6-17 years; 19 UC, 39 CD, 2 indeterminate). Early-onset UC was marked by less abdominal pain at presentation, but an aggressive course with a significant reduction in weight-for-age, increased use of immunosuppressants, and more surgery. Children with early-onset CD were more likely to have bloody stools at presentation and an isolated colitis. This study supports the suggestion that inflammatory bowel disease phenotype differs in early-onset disease.

Unusual manifestations of a common gastrointestinal disorder.

We present an instructive case of a 13-year old male who presented with bilateral scrotal redness, swelling and tenderness, but with a normal testicular exam. His scrotal swelling persisted despite treatment with intravenous antibiotics, and on further history he reported 2 years of intermittent upper lip swelling. After a referral to a dermatologist, a lip biopsy showed granulomatous changes and he was referred to the gastroenterology department. A gastroscopy and colonoscopy was performed and histology confirmed non-caseating granulomas consistent with Crohn's disease (CD). Eighteen months after the diagnosis of CD he developed perianal disease with a fistula and distal anal stricture. He was successfully treated with insertion of a seton and escalation of therapy to azathioprine and infliximab. CD is a phenotypically diverse chronic inflammatory condition with an increasing incidence in Australia and other Western countries. Non-typical presentations, such as perianal manifestations or orofacial granulomatosis, can be the only presenting symptom in CD, and this highlights the importance for a high degree of clinical suspicion. Genital involvement is rare, but reported.

Contrasts and comparisons between childhood and adult onset acute pancreatitis.

Acute pancreatitis (AP) in children is an increasingly recognised clinical entity notably different from the adults with respect to incidence, aetiology, severity and outcome. Yet our current understanding and approach to the management of paediatric pancreatitis is based almost entirely on adult studies. Acute recurrent pancreatitis (ARP) in children is more likely associated with various genetic factors, some of which have been relatively well characterised and others are in an evolving phase. The aim of this review is to summarise current knowledge, highlight any recent advances and contrast the paediatric and adult forms of this condition.

Prevalence of irritable bowel syndrome and functional abdominal pain disorders in children with inflammatory bowel disease in remission.

Despite evidence of an increased prevalence of irritable bowel syndrome (IBS) in adults with inflammatory bowel disease (IBD) compared with the general population, the prevalence of IBS in children with IBD is unclear. In this review, we aimed to identify the reported prevalence of IBS or functional abdominal pain disorders (FAPDs) in children with IBD in remission. A search of three databases (MEDLINE, Embase, and PubMed) was performed to identify studies reporting the prevalence of IBS or FAPDs in pediatric patients with IBD in remission. A total of 60 studies were identified, with four eligible studies remaining following abstract screening. In children with IBD in remission, the overall prevalence of IBS ranged between 3.9 and 16.1%, and the overall prevalence of FAPDs ranged between 9.6 and 29.5%. The prevalence of FAPDs in patients in biomarker-based remission was generally higher than those in clinical remission (range 16-22.5% vs 9.6-16.7%, respectively). There is a paucity of literature reporting on the prevalence of IBS or FAPDs in children with IBD in remission. Despite the differences in criteria used to define IBD remission in the included articles, there seems to be an increased overall prevalence of IBS or FAPDs in children with IBD.

An Australian audit of vaccination status in children and adolescents with inflammatory bowel disease.

BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) are at increased risk of vaccine preventable diseases (VPD). This includes invasive pneumococcal disease and influenza. The primary aim of this study was to describe compliance with current Australian guidelines for vaccination of children and adolescents diagnosed with IBD. A secondary aim was to review the serological screening for VPD. METHODS: A random sample of patients (0-18 years at diagnosis), were selected from the Victoria Australia state based Pediatric Inflammatory Bowel Disease Register. A multi-faceted retrospective review of immunization status was undertaken, with hospital records audited, a telephone interview survey conducted with consenting parents and the vaccination history was checked against the primary care physician and Australian Childhood Immunization Register (ACIR) records. The routine primary childhood vaccinations and administration of the recommended additional influenza and pneumococcal vaccines was clarified. RESULTS: This 2007 audit reviewed the immunization status of 101 individuals on the Victorian Pediatric IBD database. Median age at diagnosis was 12.1 years, 50% were on active immunosuppressive therapy. 90% (38/42) [95% confidence intervals (CI) 77%; 97%] with complete immunization information were up-to-date with routine primary immunizations. Only 5% (5/101) [95% CI 2%; 11%] received a recommended pneumococcal vaccine booster and 10% (10/101) [95% CI 5%; 17%] had evidence of having ever received a seasonal influenza vaccine. Those living in rural Victoria (p = 0.005) and younger at the age of diagnosis (p = 0.002) were more likely to have ever received an influenza vaccine Serological testing, reviewing historical protection from VPD, identified 18% (17/94) with evidence of at least one serology sample. CONCLUSION: This study highlights poor compliance in IBD patients for additional recommended vaccines. A multi-faceted approach is required to maximize protection from VPD in this vulnerable special risk population.

Severe iron-deficiency anaemia in adolescents: consider Helicobacter pylori infection.

AIM: This article describes the association of severe iron-deficiency anaemia with Helicobacter pylori gastritis. RESULTS: We report three children who had symptomatic iron-deficiency anaemia with no obvious clinical cause and refractory to iron replacement therapy. All three underwent a diagnostic endoscopy and were found to have H. pylori gastritis. Histopathology confirmed inflammatory changes consisting of dense bands of clusters of plasma cells within the lamina propria and two of the three adolescents were noted to have numerous H. pylori in gastric crypts and glands. Two of the three cases had a urease positive test. Iron deficiency was successfully corrected following antibiotic eradication of H. pylori infection. CONCLUSIONS: This case series highlights the importance of considering H. pylori infection as a cause of refractory iron-deficiency anaemia in adolescents, even in the absence of gastrointestinal symptoms.

Is significant cystic fibrosis-related liver disease a risk factor in the development of bone mineralization abnormalities?

In order to assess the effects of significant cystic fibrosis-related liver disease (CFLD) on bone health, we compared the bone mineral status of older children and adolescents with CFLD to those with cystic fibrosis (CF) alone. Thirteen children (age range, 10-19 years) from our clinical CF services were identified with significant CFLD (9 of these 13 patients had clinical and radiological evidence of portal hypertension). This cohort was then matched by age, gender, and anthropometric measurements with equal numbers of patients with CF alone. All patients had a dual-energy X-ray absorptiometry (DEXA) scan to determine bone mineral content (BMC), bone area (BA), bone mineral density (BMD), and bone mineral apparent density (BMAD) in the region of the lumbar spine. Blood was drawn to determine serum vitamin A, D, E, and K status and liver function tests. The best forced expired volume in 1 sec (FEV1) for each patient in the 12 months around the time of the scan was also documented. Patients with CFLD had slightly worse FEV1 (82 +/- 20% vs. 91 +/- 16%, P = 0.05) and significantly higher alanine aminotransferase (65.5 +/- 35 IU/l vs. 30 +/- 20 IU/l, P = 0.01) than those with CF alone. The mean lumbar spine BA, BMC, BMD, and BMAD were not different between children with CFLD and CF. In conclusion, the presence of significant liver disease in children with CF does not appear to be an additional risk factor for the development of abnormal bone mineralization.

Autoimmune Pancreatitis and IgG4 Related Disease in Three Children.

We report 3 children who presented with fever and abdominal pain, deranged liver function tests, and on abdominal ultrasound were found to have an enlarged pancreas, substantial abdominal lymphadenopathy, and extrahepatic biliary duct dilatation. After ruling out malignancy, probable immunoglobulin G4-related disease (IgG4RD) associated with autoimmune pancreatitis was considered. This condition was first described in the adults and often mimics pancreatic cancer. It can involve multiple organs, either synchronously or metachronously, and is rarely reported in children. The disorder mostly responds to corticosteroid therapy and other immune suppression. We highlight the difficulty in diagnosing autoimmune pancreatitis/IgG4-related disease in children and illustrate the difference between pediatric and adult presentation.

Intussusceptions arising from two different sites in a child with cystic fibrosis.

Abdominal pain is common in individuals with cystic fibrosis (CF). We report on a 17-year old boy with CF and two recognized intussusceptions: the first colonic intussusception was presumed due to distal intestinal obstruction syndrome, and the second enteric one due to polypoid lesions containing heterotopic gastric mucosa. The presentation, pathology, management, and a literature review of intussusception in CF are discussed.

Factors affecting clinical outcome in gastrostomy-fed children with cystic fibrosis.

In order to assess the effects of gastrostomy feeding on nutritional status, respiratory function, and survival in children with cystic fibrosis (CF), we studied all patients undergoing gastrostomy between 1989-1997 at the Royal Children's Hospital, Melbourne. Clinical information was collected from medical records, including serial measurements of weight-for-age standard deviation scores (WAZ) and forced expired volume in 1 sec (FEV1) (percent predicted). Measurements were compared for 2 years before and 2 years after gastrostomy placement. Data on gastroesophageal reflux (GER), adherence to the gastrostomy feeding program, and sputum culture were also assessed. Of 37 children (22 male; mean age, 11.6 +/- 4.8 years; range, 3-20), 11 died during the study period (7 female, 4 male). Female patients were more likely to die within 2 years of gastrostomy placement (OR = 3.9; 95% CI, 0.72-23.2; P = 0.07). Mortality was significantly associated with a WAZ score < -2 (OR = 10.7; 95% CI, 1.07-466.6; P = 0.02) and predicted FEV1 < 50% (OR = 10.8; 95% CI, 1.07-512.9; P = 0.02) at time of gastrostomy. Patients with clinical evidence of GER (n = 11) had significantly lower weight gain after gastrostomy (delta WAZ, -0.32 +/- 0.26 vs. 0.03 +/- 0.39; P = 0.03). In conclusion, the presence of advanced lung disease, GER, and female gender were factors associated with a poor clinical outcome after gastrostomy placement.

Synopsis of recent guidelines on pancreatic exocrine insufficiency.

BACKGROUND: In recent years, three national gastroenterology societies established guidelines for the diagnosis and therapy of pancreatic exocrine insufficiency (PEI). In addition, the Cochrane Collaboration issued a review. OBJECTIVE: The purpose of this paper is to present an overview of the recommendations and concordance between the four recent published guidelines and stimulate further discussion. METHODS: A review of the Australian, German and Italian guidelines and the Cochrane review was conducted, and a synthesis was made of common statements. RESULTS: There is a high degree of agreement on almost all items within these guidelines, both in the diagnosis of PEI and in terms of therapy and approach to management of PEI. In addition, novel emerging developments are highlighted, such as the fecal elastase-1 test, which is widely used but is not suitable for measuring mild-to-moderate PEI despite its ability to positively establish the diagnosis of severe PEI. One of the few novel tests proving to be useful is the (13)C mixed-chain triglycerides (MCT) breath test. This test, albeit an excellent quantitative test, is not widely used and is rarely available. The use of this test is making it apparent that there is a difference between treating the symptoms of PEI and treating malnutrition, the broader underlying defect. This may have direct consequences for the dosing of pancreatic enzymes (pancreatin), in that the consensus starting dose of all guidelines may be too low for some patients. Although chronic pancreatitis in adults and cystic fibrosis in children account for the main evidence base used for PEI, other indications are also discussed. CONCLUSIONS: There is good concordance between recommendations provided by international groups. More prospective studies are required in many areas, including the use of pancreatic enzymes in other gastrointestinal disorders, such as celiac disease and irritable bowel syndrome (IBS). We also need to assess the feasibility of the (13)C MCT breath test. At the same time, it needs to be confirmed that higher doses of pancreatic enzymes are really necessary to not only relieve the symptoms of PEI but also treat malnutrition appropriately.

Sixty-year study of incidence of childhood ulcerative colitis finds eleven-fold increase beginning in 1990s.

BACKGROUND: We sought to define the point at which a recently noted marked increase in the incidence of ulcerative colitis (UC) had occurred in children in Victoria, Australia. METHODS: A 60-year retrospective review (1950-2009) of children age 16 years or less diagnosed with UC in the state's major pediatric centers was performed. RESULTS: In all, 342 children were diagnosed with UC (male to female ratio of 1.25:1.0, median age 10.9 years, interquartile range [IQR] 7.0, 13.2). The overall median annual incidence of UC was 0.36/10(5) children ≤ 16 years of age (IQR 0.18, 0.66). The number of reported cases increased by 11-fold during the study period (P < 0.001). This marked increase appeared to occur from the early 1990s and has yet to plateau. Children diagnosed during the last two decades were older at diagnosis (median 10 years vs. 11.6, P < 0.0001), and had higher weight- and height-for-age z scores than those diagnosed during the first 40 years (mean weight-for-age [standard deviation] 1950-1989: -0.80 [1.56] vs. 1990-2009: -0.11 [1.17], P < 0.001; mean height-for-age 1950-1989: -0.50 [1.15] vs. 1990-2009: -0.13 [1.12], P < 0.05). More recently diagnosed children also had more extensive disease (1950-1989: 52% vs. 1990-2009: 71%, P < 0.01). CONCLUSIONS: The incidence of UC has increased markedly in Victorian children since 1990. Although some of this change may be attributable to earlier diagnosis, it is unlikely that this can provide a complete explanation for this still-increasing condition.