Altered polyamine metabolism in cystic fibrosis

Children with cystic fibrosis excreted elevated urinary levels of all three polyamines--putrescine, spermidine, and spermine. Heterozygote parents excreted intermediate concentrations of the polyamines, but not levels significantly different from levels in normal controls. Patients with cystic fibrosis who were administered a tracer amount of [14C]spermidine excreted 11--13% of the radiolabel within 72 hr whereas normal controls excreted 60--76% of the radiolabel within 72 hr. Spermine excretion was positively correlated with increased pathology as assessed by the National Institutes of Health (NIH) clinical score, whereas urinary putrescine and spermidine levels were negatively correlated with increased pathology.     

Energy metabolism in infants with cystic fibrosis

OBJECTIVE: To determine whether a defect in energy metabolism exists in infants with cystic fibrosis (CF). DESIGN: Unselected, newly-diagnosed subjects with CF (n = 46) and 24 healthy infants aged <20 weeks had measurements of resting energy expenditure (REE), total energy expenditure (TEE) (n = 25), and body composition. Metabolizable energy intake (MEI) was calculated. Genotype, energy intake, and pancreatic status was determined in all subjects with CF, and 24 underwent bronchial lavage. RESULTS: At diagnosis, infants with CF detected by newborn screening had significant anthropometric deficits (mean [SD] z-weight = 0.5 [1.0], z-length = 0.7 [1.3]) associated with pancreatic insufficiency. Their REE, TEE, or MEI (absolute measurements, per unit body weight or fat-free mass) were not increased. No relationship between REE, TEE, or MEI and Delta F(508) genotype, and no proportional differences in individual components of MEI between subjects with CF and controls, or between subjects with CF who were homozygotes or compound heterozygotes for Delta F(508) were observed. REE and TEE were not correlated with bronchial infection or inflammation. CONCLUSION: Growth impairment during the first weeks of life in infants with CF is associated with pancreatic insufficiency. However, there is no evidence for a defect of energy metabolism related to Delta F(508), and in infants with CF, minimal lung disease is unaccompanied by increased energy expenditure.     

Consensus on the diagnosis and management of changes in carbohydrate metabolism in cystic fibrosis

Abnormal glucose tolerance and diabetes mellitus are a common complication of cystic fibrosis (CF). Cystic fibrosis related diabetes (CFRD) is due to decreased insulin secretion, secondary to pancreatic insufficiency. Patients with CFRD have increased morbidity and mortality and are subject to the same microvascular complications as patients with other types of diabetes. Prompt diagnosis and aggressive management of CFRD is important.A consensus conference on CFRD was held in Madrid in May 2000to define the current standards for the diagnosis and management of this disease in Spain.     

Aspects of bile acid metabolism in cystic fibrosis

Previous reports have indicated that cystic fibrosis (CF) patients with pancreatic enzyme insufficiency have a raised faecal bile acid output. In this study, 18 out of 29 CF patients and 2 out of the 4 non-CF patients with pancreatic enzyme insufficiency had raised faecal bile acid levels. In the CF patients no correlation was found between faecal bile acid and faecal fat excretion, but an inverse relation was shown between faecal bile acid values and age. Those CF patients with overt liver disease tended to have the lowest faecal bile acid values.Duodenal aspiration in 5 CF patients and in one non-CF patient with pancreatic enzyme insufficiency (Shwachman-Diamond syndrome), produced very small fluid volumes. Duodenal fluid mean total bile acid concentrations were within normal limits. Estimation of serum bile acids in these 6 patients showed that 3 patients had raised serum bile acid values.It is suggested that excessive chronic faecal bile acid loss may produce a contraction of the bile acid pool, and lead eventually to a reduction of intraduodenal bile acid concentrations. Measures which curtail faecal bile acid loss may have a particular significance in the management of CF.     

Complex saccharide metabolism in cystic fibrosis fibroblasts.

There are several reports of secretory and other abnormalities present in cultured fibroblasts from patients with cystic fibrosis (CF). We have, therefore, investigated aspects of complex saccharide synthesis and secretion by such cells compared with fibroblasts derived from heterozygous (HZ) parents and from normal (N) children. The main glycosaminoglycans produced by skin fibroblasts during in vitro culture were hyaluronic acid, heparan sulfates, and dermatan sulfate-like materials. Using double-label experiments with D-[3H]- or [14c]glucosamine and analyzing the products by ion exchange chromatography, it was shown for five CF, two HZ, and four N lines that these polysaccharides were secreted into the medium in approximately similar proportions to each other. Moreover, experiments in which three CF, nine HZ, and three N lines were grown in log phase for up to 5 days in the presence of [35S]sulfate and [3H]glucosamine indicate that, during such a period, CF fibroblasts do not secrete complex carbohydrates at rates significantly different from N or HZ cells. Neither do such cells shown an abnormal intracellular accumulation of complex carbohydrates. The latter observation was further confirmed by preparing whole cell autoradiographs during growth of six CF, two HZ, and three N lines in the presence of D-[3H]glucosamine and, subsequently, after addition of unlabeled medium.     

Carbohydrate tolerance in cystic fibrosis is closely linked to pancreatic exocrine function

We evaluated carbohydrate tolerance in nine thin cystic fibrosis (CF) patients and in six controls, measuring responsiveness to the following insulinotropic secretagogues: oral glucose, IV glucose, and IV tolbutamide. Glucose responses segregated patients into two groups: Group I with normal carbohydrate tolerance associated with normal to slightly increased insulin responses, and Group II with impaired carbohydrate tolerance associated with insulinopenia. This latter group included one patient with frank diabetes. The CF patients demonstrated a significant positive correlation between insulin secretion, in response to each secretagogue, and pancreatic exocrine function as measured by serum pancreatic amylase isoenzyme concentration. Pancreatic alpha-cell function, as reflected by basal plasma glucagon concentrations, also correlated well with exocrine function in the CF patients, excluding the diabetic individual. The enteroinsular axis of the CF group was intact as reflected by normal plasma gastric inhibitory polypeptide concentrations in Group I and by elevated levels, basally and in response to oral glucose, in the insulinopenic Group II patients. Furthermore, those patients with impaired tolerance demonstrated a greater magnitude of insulinopenia compared to controls following IV glucose and possibly IV tolbutamide, than following oral glucose. Thus, these data suggest that loss of carbohydrate tolerance in patients with CF, like that seen with classical chronic pancreatitis, 1) parallels the loss of exocrine function, 2) is associated with appropriate enteroinsular signaling, and 3) can be detected earlier or more easily following testing with direct IV secretagogues than following oral glucose stimulation.     

Enhanced drug metabolism in young children with cystic fibrosis

The effect of cystic fibrosis on caffeine metabolism was studied in young children using the caffeine breath test. Eight children with cystic fibrosis aged 2-6 years and nine age matched controls were studied on a single occasion, and the cumulative percentage of labelled caffeine exhaled as carbon dioxide measured over two hours. This was significantly higher in the patients with cystic fibrosis than in controls, suggesting an increase in the CYP1A2 metabolic pathway in the former. The fact that these were young children with minimal lung and liver disease suggests that enhanced drug metabolism in children with cystic fibrosis is hereditary rather than secondary to lung and liver damage.     

Secular changes in anthropometric data in cystic fibrosis patients

The aim of this study was to study the secular changes in anthropometric data over calendar time in patients with cystic fibrosis (CF). Growth curves were constructed for 270 patients based on height and weight registrations from the medical files. Height, body mass index (BMI), magnitude of pubertal peak height velocity (PHV) and age at PHV were analysed for possible secular changes from the 1960s to the 1990s. There was a significant change in height over calendar time in only 1 of 12 age groups. BMI showed a significant increase in 10- and 15-y-old boys and girls and in 5-y-old girls. The magnitude of PHV changed significantly over time, whereas age at PHV was constant. No significant changes in height and age at PHV over calendar time were observed; this was probably due to a selection bias since the oldest patients, who survived to be part of the present investigation, represented milder forms of the disease. The increase in BMI and change in magnitude of PHV over calendar time may reflect the improvement in treatment leading to a better survival and clinical status through puberty. The increase in BMI and change in magnitude of PHV were sufficient to overcome the selection bias from older patients with milder disease.     

Assessment of hepatic function in cystic fibrosis by lidocaine metabolism

BACKGROUND: To determine hepatic drug metabolism in patients with cystic fibrosis, as measured by monoethylglycinexylidide formation after lidocaine injection and indocyanine green (ICG) clearance. METHODS: The following study is a case-control study, which included 19 patients with cystic fibrosis and 13 control subjects. Serum monoethylglycinexylidide concentration was measured after intravenous injection of 1 mg/kg (maximum, 50 mg) lidocaine. Indocyanine green (0.5 mg/kg) was injected concomitantly, and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half-life, and hepatic blood flow. RESULTS: Monoethylglycinexylidide formation was decreased in patients with cystic fibrosis compared with controls (39.4+/-16.9 microg/L versus 70.3+/-45.7 microg/L, mean +/- SD, respectively, P < 0.02). Indocyanine green half-life (4.6+/-2.7 min versus 3.0+/-1.0 min), volume of distribution (8.6+/-5.5 L versus 8.3+/-3.4 L), and hepatic blood flow (10.9+/-5.9 ml x kg(-1) x min(-1) versus 7.4+/-2.0 ml x kg(-1) x min(-1)) were similar in both groups. CONCLUSION: Monoethylglycinexylidide formation after lidocaine injection is impaired in patients with cystic fibrosis. This impairment may have clinical implications when using hepatically metabolized medications in patients with cystic fibrosis.     

Skeletal muscle metabolism in cystic fibrosis and primary ciliary dyskinesia

Previous studies have reported differences in muscle function and metabolism between patients with cystic fibrosis (CF) and healthy controls (HC), but it is currently unknown whether these abnormalities are specific to CF or also seen in other airway diseases. In this study, we used magnetic resonance spectroscopy (MRS) during exercise to assess muscle metabolism in CF patients. Twenty patients with CF and 20 age, gender, and habitual activity-matched HCs and a respiratory disease comparison group with primary ciliary dyskinesia (PCD; n = 10) were studied. Phosphorus MRS (P-MRS) was used to characterize muscle bioenergetic metabolism at rest and after high-, moderate-, and low-intensity exercise. CF patients exhibited lower resting ATP/phosphocreatine (PCr) ratio and significantly higher end-exercise pH values compared with both HC and PCD patients. Both CF and PCD patients demonstrated significantly slower PCr recovery time constants after high-intensity exercise. Our results suggest that not only there are specific abnormalities of muscle metabolism in CF patients but also there is a nonspecific impact of respiratory disease on muscle function.     

Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis

We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.     

Aldosterone metabolism and transepithelial potential difference in normal and cystic fibrosis subjects

The transepithelial potential difference (PD) is raised across cystic fibrosis (CF) respiratory epithelia. This raised voltage reflects active sodium absorption across a relatively chloride impermeable membrane. Because relatively little is known about the regulation of the rate of sodium absorption across mammalian airways, we assessed the possible contribution of aldosterone to the PD in normal and CF respiratory epithelia. Aldosterone excretion in five CF patients was 12.2 +/- 0.9 micrograms/24 h, a mean value not different from normal control subjects (13.6 +/- 1.5 micrograms/24 h, n = 5). Despite similar aldosterone excretion rates, nasal PD was more than 2-fold greater in the CF patients (-53.6 +/- 6.4 mV) than normal subjects (-21.3 +/- 1.4 mV). The effect of an aldosterone antagonist, spironolactone, on aldosterone excretion and nasal and rectal PD was evaluated in four CF patients and five normal subjects. During spironolactone administration, aldosterone excretion increased (2- to 4-fold) and rectal PD decreased in both groups. However, nasal PD was unchanged in each group (CF = -52.1 +/- 4.3 mV pre, -53.6 +/- 1.4 mV during; normal = -21.2 +/- 3.1 mV pre, -21.6 +/- 3.2 mV during). We conclude that neither increased aldosterone secretion rates nor organ sensitivity to aldosterone can account for the abnormally raised PD that characterizes the respiratory epithelium of subjects with CF.     

Impact of lung inflammation on bone metabolism in adolescents with cystic fibrosis

Deficits in bone mineral density resulting in premature osteopenia and osteoporosis have been documented in cystic fibrosis patients for over 20 years. A high incidence of fractures and kyphosis in the continually increasing adult patient population and in post-lung transplant patients has highlighted the problems associated with poor bone health.The aetiology of osteoporosis in CF is multifactorial but centres on an uncoupling in the normal balance between bone formation and resorption. Delayed puberty, malabsorption and reduced weight-bearing exercise can result in inadequate bone mineral accretion in childhood and adolescence. Corticosteroid use and pro-inflammatory cytokines associated with infective respiratory exacerbations can accelerate bone loss.Dual energy X-ray absorptiometry is the most commonly available technique to measure bone mineral density. All patients should be scanned at least every 2 years from adolescence. The treatment of established disease with bisphosphonates shows encouraging early results.     

Assessment of selected bone metabolism marker concentrations in children with cystic fibrosis

Aim: The aim of this study was to assess bone formation and resorption processes and bone metabolism regulators, such as osteoprotegerin and fetuin-A in children with cystic fibrosis. Material and methods: We examined 45 children with cystic fibrosis aged 5-13 years treated at the Institute of Mother and Child in Warsaw. The control group consisted of 35 healthy children in the same synage range without any diseases which may influence bone metabolism. We determined serum calcium and phosphate levels by colorimetric methods, vitamin D3 by the chemiluminiscence method and bone metabolism markers (osteocalcin, 5b isoenzyme of tartrate-resistant acid phosphatase, osteoprotegerin, fetuin-A) by immunoenzymatic methods. Results: Mean serum concentrations of calcium and phosphate in the studied children were within the reference ranges. However, the level of 25-hydroxyvitamin D3 was significantly lower in patients with cystic fibrosis compared to the controls (19.3±7.6 vs 25.2±8.9 ng/ml, p<0.01). In cystic fibrosis children we observed a statistically significant lower concentration of osteocalcin (81.9±28.9 vs 97.9±28.6 ng/ ml, p<0.01) and similar activity of 5b isoenzyme of tartrate-resistant acid phosphatase (12.5±2.9 vs 13.4±3.5 U/L) as compared to healthy peers. Mean serum concentration of osteoprotegerin in patients with CF was significantly lower than in the control children (4.1±0.98 vs 4.59±0.86 pmol/l, p<0.05). Serum concentration of fetuin-A was comparable in both groups of children. Conclusions: In children with cystic fibrosis changes in the profile of bone metabolism markers were observed. Even patients with CF who are clinically stable and supplemented with vitamins are at risk of osteopenia and osteoporosis in their later life. Therefore, they should be under a comprehensive medical and nutritional care in order to achieve their optimal peak bone mass.