Outcomes of patients with cystic fibrosis undergoing lung transplantation with and without cystic fibrosis-associated liver cirrhosis.

People with severe cystic fibrosis (CF) lung disease with co-existent CF-associated liver disease (CFLD) are often excluded from consideration of sole lung transplantation, largely because of the concerns that they will subsequently develop hepatic decompensation. This retrospective cohort study aimed at determining whether patients with severe cirrhosis caused by CFLD have any differences in perioperative and relevant post-transplant outcomes compared to CF patients without CFLD when undergoing sole lung transplantation. Six patients with CFLD were matched with 18 CF patients without CFLD undergoing sole lung transplant at the same institution. There were no differences in total operative time or intra-operative requirements for cardiopulmonary bypass or blood products. Over a period of five yr post-transplant, no differences were observed between the two groups in body mass index, six-min walk, lung function, and survival. None of the CFLD subjects developed variceal bleeding; however, one developed hepatocellular and renal failure at four yr post-transplant and is being assessed for liver-kidney transplant. One additional patient with CFLD required repeat lung transplantation for bronchiolitis obliterans syndrome. This study provides evidence that CF patients with liver cirrhosis caused by CFLD can safely be considered for sole lung transplantation provided there is no evidence of significant hepatocellular dysfunction with decompensated cirrhosis or hepatic synthetic failure.

Cystic fibrosis modifier genes related to Pseudomonas aeruginosa infection.

Cystic fibrosis (CF) is one of the most common life-shortening genetic disorders, and the CF transmembrane conductance regulator (CFTR) is the major causal gene. However, a substantial clinical variability among patients with identical CFTR genotypes suggests the presence of modifier genes. We tested the effect of four genes involved in Pseudomonas aeruginosa infection. Analysis of a primary cohort detected eight candidate polymorphisms that were genotyped in the secondary cohort of 1579 patients; lung function and age at first infection with P. aeruginosa were considered as the phenotypes. Both additive and codominant models were considered, adjusting for confounding variables but not for multiple comparisons. In the secondary cohort, heme oxygenase-1 (HMOX1) rs2071749 had the most significant effect on lung function in the pediatric group (P=0.01; P(corrected)=0.03), and complement factor 3 (C3) rs11569393 and HMOX1 rs2071746 in the adult groups (P=0.03 for both variants; P(corrected)=0.16, 0.09). No polymorphism of complement factor B (CFB) or toll-like receptor 4 (TLR4) had a significant modifying effect on lung function in either group. We have identified two genes that showed nominal association with disease severity among CF patients. However, because of the multiple comparisons made, further studies are required to confirm the interaction between these modifying genes and CFTR.

Does the Macroduct collection system reliably define sweat chloride concentration in subjects with intermediate results?

OBJECTIVES: The sweat test remains the current diagnostic gold standard for CF disease. Many CF testing centres have switched from the Gibson and Cooke to the Macroduct. Since the validity and sensitivity of Macroduct has not been tested in patients with intermediate sweat chloride concentrations, we compared both methods simultaneously including subjects expected to have intermediate results. DESIGN AND METHODS: We prospectively evaluated controls, obligate heterozygotes, patients with CF and with an uncertain diagnosis of CF (congenital absence of the vas deferens, pancreatitis and sinopulmonary disease). RESULTS: We assessed 82 subjects (3.7-60.1 years); 14 healthy controls, 7 obligate heterozygotes, 20 CF (15 pancreatic insufficient, 5 pancreatic sufficient), and 41 with unproven diagnosis. Mean test difference was close to 0 (95% CI+/-20 mmol/L) and test values were highly correlated (r=0.93, p < or =0.0001). Discrepancies between the two testing methods occurred in 22% of subjects. CONCLUSION: Sweat chloride measured by Macroduct highly correlates with Gibson and Cooke for concentrations in all ranges, including the intermediate range. This study reveals the limitations of sweat testing for excluding a diagnosis of CF since 38% of subjects had intermediate range results.

Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS.

Pancreatic exocrine and bone marrow dysfunctions are considered to be universal features of Shwachman-Diamond syndrome (SDS) whereas the associated skeletal dysplasia is variable and not consistently observed. The genetic defect in SDS has recently been identified; causative mutations have been shown in the SBDS gene. The aims of this study were to characterize the nature, frequency, and age-related changes of radiographic skeletal abnormalities in patients with SBDS mutations and to assess genotype-phenotype correlation. Fifteen patients (mean age 9.7 years) with a clinical diagnosis of SDS and documented SBDS gene mutations were included. Review of their skeletal radiographs showed abnormalities in all patients. The skeletal changes were variable, even in patients with identical genotypes. The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia. There was a tendency towards normalization of the epiphyseal maturation defect and progression of the metaphyseal changes with age. The results suggest that the characteristic skeletal changes are present in all patients with SDS and SBDS mutations, but their severity and localization varies with age. No phenotype-genotype correlation was observed.

Treatment of vitamin K deficiency in cystic fibrosis: Effectiveness of a daily fat-soluble vitamin combination.

OBJECTIVE: Patients with cystic fibrosis (CF) and pancreatic insufficiency (PI) commonly have vitamin K deficiency, and those with CF-associated liver disease (CFLD) have universal vitamin K deficiency. We evaluated the effectiveness of an oral fat-soluble vitamin combination (ADEKs) to treat patients with vitamin K deficiency. STUDY DESIGN: Patients with PI and CF (mean age, 15 years; range, 0.6 to 46 years) including 6 with advanced CFLD were prospectively enrolled in a study of a fat-soluble vitamin combination taken on a daily basis. None had received vitamin K supplementation for at least 4 months before the study. Fat-soluble vitamin combination supplementation was given for a minimum of 4 months; the mean vitamin K intake was 0.18 mg/d (SD = 0.1, range, 0 to 0.3). The primary outcome was change in plasma PIVKA-II (prothrombin in vitamin K absence). RESULTS: Before supplementation 58 (81%) of 72 patients had abnormal PIVKA-II levels (>2.9 ng/mL). After supplementation 29 (40%) had abnormal PIVKA-II levels (P =.001). All 6 patients with advanced CFLD had abnormal PIVKA-II levels (median, range of 20.8, 5.5 to 55 ng/mL) before treatment, which corrected to normal in 50% (4.1, 2.1 to 65 ng/mL). Four patients, 2 with CFLD, had a prolonged prothrombin time (>13.5 seconds) at both time periods. CONCLUSIONS: An oral fat-soluble vitamin combination with a modest amount of vitamin K can, as a daily supplement, improve the PIVKA-II levels in patients with PI and CF.

Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. A genomewide scan of families with SDS was terminated at approximately 50% completion, with the identification of chromosome 7 markers that showed linkage with the disease. Finer mapping revealed significant linkage across a broad interval that included the centromere. The maximum two-point LOD score was 8.7, with D7S473, at a recombination fraction of 0. The maximum multipoint LOD score was 10, in the interval between D7S499 and D7S482 (5.4 cM on the female map and 0 cM on the male map), a region delimited by recombinant events detected in affected children. Evidence from all 15 of the multiplex families analyzed provided support for the linkage, consistent with a single locus for SDS. However, the presence of several different mutations is suggested by the heterogeneity of disease-associated haplotypes in the candidate region.

Challenges in the dietary treatment of cystic fibrosis related diabetes mellitus.

Cystic fibrosis related diabetes mellitus is an increasingly recognized problem as survival in patients with cystic fibrosis improves. In a 5 year retrospective study of 627 children and adults attending Toronto cystic fibrosis clinics, we identified 57 (9%) patients with cystic fibrosis related diabetes mellitus; four (1.3%) of 301 children (<18 years) and 53 (16%) of 326 adults. The development of this complication of cystic fibrosis is associated with increased mortality, deteriorations in both respiratory and nutritional status, and the development of late microvascular, but not macrovascular, diabetic complications. Unfortunately, systematic review of the literature provides few well designed studies that provide sound evidence for clinical practice. Recommendations are therefore often based on anecdote, rather than physiological or outcomes research. Dietary therapy combines the principles of the dietary management of both cystic fibrosis and diabetes mellitus, but emphasizes the need for a high energy diet (> 100% of recommended daily intake) in patients with cystic fibrosis related diabetes mellitus. The importance of calories from fat is emphasized, with no restriction on total carbohydrate intake. Insulin intake mirrors carbohydrate intake. Routine dietary therapy is straightforward, but challenges occur due to both complications of cystic fibrosis and advancing disease. If a patient with cystic fibrosis related diabetes mellitus is malnourished, overnight enteral tube feeding is often used, with an adjusted insulin regimen. There is a great need for both physiological and outcomes research to provide sound scientific evidence for the dietary treatment of cystic fibrosis related diabetes mellitus.

Pancreatic aspects of cystic fibrosis and other inherited causes of pancreatic dysfunction.

Causes of pancreatic dysfunction in childhood can be divided into two general categories: (1) hereditary conditions that directly affect the pancreas and (2) acquired disorders in which loss of pancreatic function is a secondary phenomenon. This article discusses genotypes and phenotypes, clinical features, Shwachman-Diamond syndrome, isolated enzyme deficiencies, and other topics.

Segregation analysis in Shwachman-Diamond syndrome: evidence for recessive inheritance.

Shwachman-Diamond syndrome is a rare disorder of unknown cause. Reports have indicated the occurrence of affected siblings, but formal segregation analysis has not been performed. In families collected for genetic studies, the mean paternal age and mean difference in parental ages were found to be consistent with the general population. We determined estimates of segregation proportion in a cohort of 84 patients with complete sibship data under the assumption of complete ascertainment, using the Li and Mantel estimator, and of single ascertainment with the Davie modification. A third estimate was also computed with the expectation-maximization (EM) algorithm. All three estimates supported an autosomal recessive mode of inheritance, but complete ascertainment was found to be unlikely. Although there are no overt signs of disease in adult carriers (parents), the use of serum trypsinogen levels to indicate exocrine pancreatic dysfunction was evaluated as a potential measure for heterozygote expression. No consistent differences were found in levels between parents and a normal control population. Although genetic heterogeneity cannot be excluded, our results indicate that simulation and genetic analyses of Shwachman-Diamond syndrome should consider a recessive model of inheritance.

Pathogenesis of malnutrition in cystic fibrosis, and its treatment.

PATHOGENESIS: We have developed a model of the pathogenesis of malnutrition in cystic fibrosis. It consists of the relationship between nutrient balance and nutrient requirement. The validation has been conducted with respect to energy, but the same general principals can be applied to any nutrient. A patient with CF either loses weight or fails to grow normally if their absorbed energy intake is less than their total daily energy expenditure. Multiple factors have the potential to contribute to reduced energy intake including, anorexia, gastroeosophageal (GE) reflux leading to vomiting and hence food loss, as well as maldigestion. Another more recently recognized source of energy loss, is glucosuria as a result of CF related diabetes (CFRD). Conversely, lung inflammation appears to be related to increases in resting metabolic rate (RMR). Acute exacerbations of the chronic lung disease increases RMR which returns to a basal level some weeks after the inflammation is treated. In clinically stable patients with CF, RMR rises in a quadratic fashion as lung function falls. When FEV(1)is >85% predicted RMR is not different from controls, but it rises in a curvilinear fashion as FEV(1)falls. Initially it appears that patients adapt to their increased RMR by reducing their activity so their total daily energy expenditure (TDEE) is often no higher than controls. But this is by no means always the case. Furthermore good lung care requires CF patients to be involved in aerobic activities, hence their TDEE would rise. Although there has been considerable interest as to whether the genetic defect has an energy wasting effect, it appears genetic factors have little or no effect on RMR. TREATMENT: This starts with making an energy diagnosis. First, a 3 day faecal fat balance study is conducted. This provides information with regard to intake as well as to maldigestion. In addition a history of GE reflux is sought, since it can readily be treated with H(2)-blockers. If significant fat malabsorption exists, efforts are made to improve pancreatic enzyme dose and function. The possibility of CFRD also needs to be considered. We measure the RMR of the patient using open circuit indirect calorimetry. Recommendations for diet therapy are based on estimated TDEE, which is determined from RMR taking into account faecal losses. Diet therapy places the emphasis on increasing the fat content of the diet. We have conducted a study to determine whether or not oral supplements help increase TDEE and they did not; they merely replaced food energy. Conversely, nocturnal gastrostomy supplemental feeding, while reducing voluntary food energy intake by about 20%, does result in a significant increase in total daily energy intake. Our target is to achieve a completely normal nutritional status. Long term follow-up of these patients has shown significantly better survival in patients who achieve normal nutritional status. The advent of lung transplantation has added another dimension. In our experience, following a successful lung transplant, most patients no longer need their supplemental gastrostomy feeding. SUMMARY: Our clinic policy is to encourage a high fat diet (35-40% total energy) and our patients grow normally in height and weight until their lung disease deteriorates significantly. Patients who develop a negative energy balance seldom if ever respond to diet therapy and hence are candidates for supplemental nocturnal gastrostomy feeds. Gastrostomy fed patients constitute 3 to 5% of our total CF population of approximately 590 patients.

Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar.

OBJECTIVES: With the use of clinical data from a large international cohort, we evaluated and compared affected siblings and isolated cases. STUDY DESIGN: Data from 116 families were collected, and patients conforming to our predetermined diagnostic criteria were analyzed. Phenotypic manifestations of affected siblings and singletons were compared with the use of t tests, Wilcoxon scores, and chi2 analysis. RESULTS: Eighty-eight patients (33 female, 55 male; median age 5.20 years) fulfilled our predetermined diagnostic criteria for Shwachman syndrome; 63 patients were isolated cases, and 25 affected siblings were from 12 multiplex families. Steatorrhea was present in 86% (57 of 66), and 91% (78 of 86) displayed a low serum trypsinogen concentration. Patients older than 4 years more often had pancreatic sufficiency. Neutropenia occurred in 98%, anemia in 42%, and thrombocytopenia in 34%. Myelodysplasia or cytogenetic abnormalities were reported in 7 patients. Short stature with normal nutritional status was a prominent feature. CONCLUSIONS: Clinical features among patients with Shwachman syndrome varied between patients and with age. Similarities in phenotype between isolated cases and affected sibling sets support the hypothesis that Shwachman syndrome is a single disease entity.

Exclusion of linkage of Shwachman-Diamond syndrome to chromosome regions 6q and 12q implicated by a de novo translocation.

Shwachman-Diamond syndrome is a rare genetic disorder of unknown pathogenesis involving exocrine pancreatic insufficiency and hematological and skeletal abnormalities. There is broad clinical variability; the extent of heterogeneity is unknown but comparisons within a large cohort of patients show no striking differences between patients of families with single or multiple affected offspring. Segregation analysis of a cohort of 69 families has suggested an autosomal recessive mode of inheritance. A single constitutional de novo chromosome rearrangement was reported in a Japanese patient involving a balanced translocation, t(6;12)(q16.2;q21.2), thereby suggesting possible loci for a genetic defect. Evenly spaced microsatellite markers spanning 26-32 cM intervals from D6S1056 to D6S304 and D12S375 to D12S346 were analyzed for linkage in members of 13 Shwachman-Diamond syndrome families with two or three affected children. Two-point lod scores were calculated for each marker under assumptions of recessive inheritance and complete penetrance. Negative lod scores indicated exclusion of both chromosome regions. Further, affected sibs were discordant for inheritance of chromosomes in most families based on constructed haplotypes. The cytogenetic abnormality is not associated with most cases of Shwachman-Diamond syndrome.

Synergistic effects of cAMP- and calcium-mediated amylase secretion in isolated pancreatic acini from cystic fibrosis mice.

We evaluated pancreatic enzyme secretory response to secretagogues (cAMP- and Ca2+-mediating) involved in exocytosis and in chloride channel activation in an exon 10 knockout cystic fibrosis (CF) mouse model. Experiments were performed in isolated pancreatic acini from liquid-fed Cftr-/- mice (5-6 wk of age) and age-matched Cftr+/+ controls fed a solid or liquid diet. BrcAMP and forskolin alone induced higher amylase secretion (% initial amylase content) in the Cftr+/+ acini than carbachol (p < 0.05). Carbachol and BrcAMP or BrcAMP and forskolin, given in combination, produced additive effects on enzyme secretion in the Cftr+/+ acini. Ca2+- and cAMP-mediated amylase secretion in isolated pancreatic acini from the Cftr-/- mice was no different to that observed in the age- and diet-matched Cftr+/+ animals. However, Cftr-/- pancreatic acini showed a significantly greater amylase response to the combination of BrcAMP and carbachol than the sum of the individual responses in separate experiments (p < 0.05). The amylase response was not different in acini from solid-fed or liquid-fed Cftr+/+ controls. In summary, this study suggests that cystic fibrosis transmembrane conductance regulator is not essential for enzyme secretion as evidenced by no reduction in cAMP-mediated amylase secretion in Cftr-/- mice. The results in Cftr+/+ acini suggest pancreatic enzyme secretion is mediated via multiple intracellular pathways acting in parallel and probably converge at a distal step in the secretory process. However, Cftr-/- pancreatic acini exhibited a synergistic secretory response following stimulation by BrcAMP plus carbachol. The enhanced secretory response may partially contribute to the development of pancreatic dysfunction in CF patients by facilitating occlusion of digestive enzymes in the secretory canaliculus of the pancreatic acini.

Management of fibrosing pancreatitis in children presenting with obstructive jaundice.

BACKGROUND: Children with fibrosing pancreatitis are conventionally treated surgically to relieve common bile duct (CBD) obstruction caused by pancreatic compression. Residual pancreatic function has not been formally tested in these patients. AIMS: To evaluate the usefulness of non-surgical temporary drainage in children with fibrosing pancreatitis and to assess pancreatic function after resolution of their CBD obstruction. PATIENTS: Four children (1.5-13 years; three girls). METHODS AND RESULTS: Abdominal sonography and computed tomography revealed diffuse enlargement of the pancreas, predominantly the head. The CBD was dilated due to compression by the head of the pancreas. Pancreatic biopsy specimens obtained in three patients showed notable acinar cell atrophy and extensive fibrosis. Cystic fibrosis was excluded. No other cause of pancreatitis was identified. Pancreatic tissue from one patient contained viral DNA sequences for parvovirus B19 detected by polymerase chain reaction; serum IgM to parvovirus was positive. Three patients had temporary drainage of the CBD and one patient underwent a choledochojejunostomy. Serial imaging studies revealed resolution of the CBD obstruction with reduction in pancreatic size. Exocrine pancreatic function deteriorated. Three patients developed pancreatic insufficiency within two to four months of presentation. The fourth patient has notably diminished pancreatic function, but remains pancreatic sufficient. None has diabetes mellitus. CONCLUSIONS: Temporary drainage of the CBD obstruction is recommended in fibrosing pancreatitis in children along with close monitoring of the clinical course, before considering surgery.

Impact of protein deprivation on protein and DNA synthesis in the developing rat pancreas.

The metabolic effects of protein malnutrition on growth and development of the exocrine pancreas are largely unknown. The aim of the present study was to evaluate the effects of protein malnutrition on pancreatic protein and DNA synthesis during postnatal development. Rat dams and their offspring were fed a protein-deficient diet (6% casein) or a control diet (25% casein) during gestation, lactation and after weaning. Pancreatic protein and DNA synthesis were measured in vitro at postnatal ages 1, 3, 10, 23, 36 and 60 days, by assessing [3H]leucine and [3H]thymidine incorporation in freshly isolated acini. Different patterns of protein synthesis were seen in the two groups. At birth, pancreatic protein synthesis was low in both control and malnourished animals. At day 3, protein synthesis in the control acini increased 10-fold while synthesis in acini of the malnourished animal group was only 50% of age-matched control values. No differences in protein synthesis were detected between the control and malnourished groups between 10 and 36 days of age. At 60 days (adulthood), acinar protein synthesis declined in the control-fed rats, but a significant increase was observed in the malnourished animals (p < 0. 0005). At birth, DNA synthesis was high in the acini from both control and malnourished animals. The low-protein diet induced a slight reduction in DNA synthesis at day 3, without altering the general pattern during later stages of development. In conclusion, protein deprivation has variable effects on pancreatic protein and DNA synthesis at different stages of postnatal development. Furthermore, the mechanisms of control within acini appear to be intrinsically regulated.

Uncertainty in the diagnosis of cystic fibrosis: possible role of in vivo nasal potential difference measurements.

The diagnosis of cystic fibrosis (CF) is not always certain, despite extensive clinical evaluation, multiple sweat chloride tests, and genotype analysis. We hypothesized that nasal transepithelial potential difference measurements have a useful role in this situation. In 11 patients without an established diagnosis of CF, results of simultaneous nasal potential difference (PD) and sweat chloride measurements were compared with those from control subjects, obligate CF heterozygotes, and patients with a confirmed diagnosis of CF. Two patients conformed to the PD profile for CF patients, whereas nine had values corresponding to those of the healthy control subjects. Subsequently the 5-thymidine (IVS8-5T) CF gene variant was identified in the two patients with abnormal PD measurements.

A position paper of the North American Society for Pediatric Gastroenterology and Nutrition. Pediatric gastroenterology Workforce Survey and future supply and demand.

BACKGROUND: The North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) performed a Workforce Survey to determine the current number and distribution of pediatric gastroenterologists in the United States and Canada and to estimate the supply and demand in the future in the United States. METHODS: The response rate was more than 90%. There were 624 pediatric gastroenterologists in the United States, and 48 in Canada. RESULTS: There were 2.4 pediatric gastroenterologists per million population in the United States, ranging from 3.1 per million in the Northeast to 1.9 per million in the West, and 1.6 per million in Canada. In the United States, fewer than 5 pediatric gastroenterologists retire each year, but more than 40 fellows per year complete training. In the United States, 30% of pediatric gastroenterologists believe there is already an excess supply; only 12% believe there is a shortage (p < 0.001). CONCLUSIONS: If the number of fellows who complete training each year remains unchanged, in 10 years there will be more than 950 pediatric gastroenterologists in the United States (3.3 per million population). At the same time, if the demand for pediatric gastroenterologists remains 2.4 per million population, there will be a demand for only 675. If these assumptions are correct, it is necessary to reduce the number of fellows to be trained. Although it is difficult to predict future workforce needs reliably, we recommend that the number of fellowship positions in training programs in the United States be reduced by 50% to 75%. Changes in health care in the coming years will be challenging, and effective planning is necessary for pediatric gastroenterologists to achieve their clinical, research, and educational missions.