Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis

The impact of pre-diabetes on clinical status was retrospectively studied in 38 cystic fibrosis (CF) patients with diabetes mellitus (DM) and 38 non-diabetic CF patients (control patients), matched in pairs for age, sex, and chronicPseudomonas aeruginosa lung infection. Quarterly parameters of CF clinical status were collected for 6 years prior to the diagnosis of DM in the index case. Compared to the control patients, decreases in body weight, body mass index (BMI), forced expiratory volume in 1s (FEV₁), and forced vital capacity (FVC) and an increase in the daily intake of pancreatic enzyme capsules were found in the pre-diabetic patients. Statistically significant differences in body weight, BMI, FEV₁, FVC, and intake of pancreatic enzyme capsules between pre-diabetic and control patients emerged 4, 4, 1.25, 3 and 4.5 years prior to the diagnosis of DM, respectively. The number of lung infections did not differ between the two groups of patients. Thus, when DM develops in CF patients, an insidious decline in overall clinical status is observed for years prior to its diagnosis. Whether clinical deterioration in CF leads to DM, or pre-diabetes results in declining CF clinical status is presently unknown. Accumulating evidence suggests that the latter may be the case since insulin therapy seems to improve lung function in CF.     

Faecal immunoreactive lipase: a simple diagnostic test for cystic fibrosis

The study evaluates faecal immunoreactive lipase (IRL) measurement in spot stool samples as an index of exocrine pancreatic function in patients with cystic fibrosis (CF). Stool samples (211) from 183 healthy volunteers (age range: 2 days–14.2 years) showed a normal log distribution of IRL values with a median concentration of 71.4 μg/g (range: 0.53–4160 μg/g). In 156 stool samples from 58 patients with proven CF, the median IRL concentration of 0.4 μg/g (range: 0.003–107 μg/g) was significantly lower (P < 0.001) than that of normal controls. In healthy controls, IRL levels were age related with significantly higher levels (P < 0.001) shortly after birth compared to older children. Stimulation of the exocrine pancreas by oral milk feeding resulted in a significant (P < 0.001) increase in a faecal IRL concentration. Faecal IRL concentrations in meconium were very low and of the same magnitude as in patients with CF. Conclusion Faecal IRL determination had a high diagnostic sensitivity (87%) and excellent diagnostic specificity (97%) in patients with CF. A negative test result (PV_neg: 99%) virtually excluded CF under screening conditions. Received: 20 January 1997 / Accepted in revised form: 22 August 1997     

Detection and follow up of exocrine pancreatic insufficiency in cystic fibrosis: a review

Pancreatic function testing is particularly difficult when the degree of remaining function has to be quantified. Detection of pancreatic insufficiency can suggest the diagnosis of cystic fibrosis (CF). It is, however; also important to follow the degree of pancreatic insufficiency in CF since its function can decline with age. Adaptation of pancreatic enzyme replacement therapy on residual function is necessary. Different tests with their advantages and disadvantages are critically reviewed in this article with respect to specificity, sensitivity, performance and cost-effectiveness. Conclusion Elastase-1 detection in faeces is probably the easiest test for the detection of pancreatic insufficiency in cystic fibrosis. For clinical follow-up tests, measuring the fat assimilation such as steatocrit and breath tests are more suited. Received: 25 November 1999 / Accepted: 8 March 2000     

Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor

Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1–5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.     

Induced sputum nitrites correlate with FEV1 in children with cystic fibrosis

Aim: To determine the difference in the levels of nitrites in induced sputum of children with cystic fibrosis (CF) and controls. Furthermore, to evaluate the association between induced sputum nitrites and lung function in children with CF. Methods: Nitrites, cell differentials, white blood cell count, were estimated in induced sputum of 20 children with CF and 10 age‐matched healthy controls. Nitrites in induced sputum samples were measured using the Greiss assay. Lung function was ascertained by spirometry. Results: We observed high levels of nitrites in CF (184.8 ± 11.07 μM/L) versus controls (56.4 ± 5.7 μM/L) (p < 0.01). A positive correlation between neturophil percent and nitrites, white blood cell count and nitrites (p < 0.05) in children with CF was observed. Sputum nitrites correlated negatively with FEV₁ (p < 0.05) in children with CF. Conclusion: Induced sputum nitrite could serve as a useful non invasive marker for assessing the degree of inflammation in the airways of children with CF.     

Effect of exocrine pancreatic function on resting energy expenditure in cystic fibrosis

AIM: To prove the hypothesis that exocrine pancreatic function determines resting energy expenditure (REE) in cystic fibrosis (CF). METHOD: Thirty-eight CF individuals, 9-34 (19.98 +/- 1.0) years, were divided into three groups: Six pancreatic sufficient patients (PS; group A), 21 pancreatic insufficient patients (PI), whose pulmonary function was comparable to that of group A (group B1) and 11 PI patients, whose pulmonary function was significantly worse than that of group A (group B2). REE was estimated by indirect calorimetry. Predicted REE was based on Schofield equations. Measured REE was expressed as % of the predicted. BMI, BMI z-scores, serum albumin, cholesterol and triglycerides levels were related to REE. Results were expressed as mean +/- standard error. RESULTS: Groups B1 and B2 had significantly higher REE% (111.7 +/- 2.75% and 119.94 +/- 3.8, respectively) as opposed to group A (98.9 +/- 3.81%; p = 0.022 and 0.035, respectively) whose REE% was similar to that predicted. REE% between group B1 and B2 was not statistically significant. In groups A, B1 and B, mean FEV1% was 86.33 +/- 10.1%, 90.24 +/- 4.39%, 44.54 +/- 3.47%, respectively, mean BMI was 25.6 +/- 2.06, 19.48 +/- 0.64 and 20.09 +/- 8.8, respectively, BMI z-scores were 0.75 +/- 0.51, -0.52 +/- 0.24 and -1.07 +/- 0.37, respectively. Significant correlation was demonstrated between REE%, BMI z-scores and cholesterol levels in group A. CONCLUSION: Clinically stable CF patients, who had comparable pulmonary function, exhibited increased REE% only in the presence of exocrine pancreatic insufficiency. REE% strongly correlated with BMI z-scores in pancreatic sufficiency. These findings support the hypothesis that pancreatic rather than pulmonary function may determine nutritional status as well as REE in CF.     

Association of vitamin A status with lung function in children and adolescents with cystic fibrosis

Importance:Vitamin A(or retinol)has considerable antioxidative and anti-inflammatory attributes and it may have protective effects on the respiratory health of ...     

Relationship between impulse oscillometry and spirometric indices in cystic fibrosis children

Background: The aim of our retrospective study was to determine the relationship between impulse oscillometry ( IOS) data and spirometric tests in cystic fibrosis (CF) children.
Methods : Thirty CF children aged 4–19 years have performed lung function tests (LFT). A subset of 15 patients repeated LFT on five separate occasions. IOS parameters were respiratory resistance (Rrs), reactance (Xrs) and impedance at 5 Hz (R5, X5, Zr) and the resonant frequency (Fres). Spirometry indices (SI) included forced expiratory volume in 1 sec (FEV₁), forced expiratory flow during the middle half of FVC (FEF_25–75) and forced vital capacity (FVC).
Results: An inverse relationship was observed between raw values of R5, Zr, Fres and SI respectively, and X5 correlated positively with SI. Although significant, these correlations were poor. Receiver operating characteristic curves (ROC) were constructed to identify cutoff points for IOS parameters to discriminate between children according to predefined FEV₁ thresholds (percent predicted), generally used to categorize the level of lung function impairment. No acceptable cutoff points can be found for IOS parameters. Trends analyses in the subgroup of 15 patients showed a significant decline of FEV₁ between the first and the fifth evaluation. None of the IOS indices demonstrated a consistent tendency, apart from a slight decrease of Fres.
Conclusion: IOS measurements presented an insufficient sensitivity to detect and follow bronchial obstruction in CF patients.     

Myocardial fibrosis — a rare complication in patients with cystic fibrosis

We report a 10-month-old male infant who was admitted to our hospital with a history of failure to thrive and bulky stools. On examination, he was dystrophic and had a protruding abdomen, but he was well oxygenated and his lungs were clear on auscultation. A tachycardia of 145 beats per min and radiological evidence of cardiomegaly indicated involvement of the heart, but an ECG failed to show signs of myocarditis or cardiac hypertrophy. An elevated sweat chloride concentration of 141 mEq/l confirmed the diagnosis of cystic fibrosis (CF). Molecular analysis revealed heterozygosity for the common mutation delta F₅₀₈. He died unexpectedly of a sudden cardiac arrest 2 days later. Autopsy revealed scattered myocardial necrosis and fibrosis. Some 50 documented cases of myocardial fibrosis in infants with CF have been reported. Suggested causes such as malnourishment and hypovitaminosis remain speculative as systematic studies have yet to be done.     

Calcification of the pancreas in cystic fibrosis

Using the gastric insufflation method, 5 cases of pancreatic calcification have been detected in a series of 60 patients with cystic fibrosis. All patients were over 5 years of age. Four of them showed a diabetic curve at glucose tolerance test and 2 have recently developed frank diabetes mellitus. The value of gastric distension by gas in the radiological detection of pancreatic calcification and the relatively high frequency of such calcification in cystic fibrosis are emphasized. The pathogenesis of the calcific change and its clinical significance are briefly discussed.     

Chest radiographs in cystic fibrosis. A follow-up study with application of a quantitative scoring system

A modified Chrispin-Norman score was used to investigate at what age typical X-ray signs of cystic fibrosis (CF) appear and for the follow-up of patients with CF. Scores of patients with chronic obstructive lung disease (COLD) and with innocent heart murmurs were used for comparison. The findings were: 1. Hyperinflation and line shadows are early but not specific symptoms of CF. 2. Mottled and ring shadows can be considered as specific for CF. In most patients they only appear after the age of 3. They are never present in COLD. 3. The mean annual increase between the ages of 3–8 is 2 points. No difference existed between boys and girls in total scores and annual increase up to the age of puberty. 4. CF patients with portal hypertension have the same scores as CF patients without portal hypertension.     

Granulomatous appendiceal disease in cystic fibrosis

Abdominal pain due to acute appendicitis in patients with cystic fibrosis is uncommon. A review of 572 patients with cystic fibrosis from the cystic fibrosis clinic of the Children's Hospital of Pittsburgh from 1959 to 1983 disclosed only 4 in whom the diagnosis of acute appendicitis lead to appendectomy. In 3 of these the diagnosis was confirmed at operation. In 1 child, laparotomy for a persistent asymptomatic abdominal mass disclosed a huge cecal fecaloma originating in the appendiceal lumen. Histological examination of the appendix established the diagnosis of cystic fibrosis. Large, symptomatic appendiceal granulomas were noted in 6 other children; these simulated abdominal tumors in 2. In 3 others there was smoldering infection and abscess with sepsis and in 1 a colocystic fistula. Such chronic granulomas, acute appendicitis, meconium ileus, and nonsurgical abdominal pain in cystic fibrosis can best be differentiated by careful clinical examination before and after treatment for meconium ileus equivalent. The granulomas involve not only the appendix but also the cecum and ascending colon. Contrast X-ray studies are of little value in diagnosis. The appendix in cystic fibrosis undergoes changes that are diagnostic even in the newborn; the granulomas described here appear to represent a progression of these changes.Offprint requests to: W. K. Sieber     

Appendico-cutaneous fistula in cystic fibrosis

Appendico-cutaneous fistulae are rare. We describe a 12-year-old girl with cystic fibrosis (CF) and a chronically draining sinus in the right iliac fossa, found to be a primary appendico-cutaneous fistula. Misdiagnosis of right iliac fossa pain in patients with CF and the preponderance of complicated disease frequently lead to manifestations of appendicitis rarely seen in usual clinical practice.     

HL-A antigens in cystic fibrosis

HL-A frequencies of 28 patients with cystic fibrosis and of 240 unrelated controls were compared. No statistically significant difference of HL-A frequencies could be observed for both groups. A slightly increased HL-A 2 frequency is considered a chance phenomenon. In accordance with a previously demonstrated lacking association of the ABH blood group substances no correlation with certain HL-A antigens was demonstrable.     

Diagnosis of cystic fibrosis : Indian perspective

Cystic fibrosis (CF) is one of the common life limiting inherited diseases in Caucasian population. Recent reports suggest that the diagnosis of cystic fibrosis in Indian children is missed or delayed due to low index of suspicion. The diagnosis of cystic fibrosis is suspected by the typical clinical features and should be confirmed by doing sweat chloride estimation. If sweat test is not available, ancillary tests including blood electrolyte and acid base balance, airway microbiology, tests to identify pancreatic insufficiency and semen analysis for obstructive azoospermia in post pubertal boys should be carried out. Positive results of these tests make the suspicion very strong. A strongly suspected case should be treated as cystic fibrosis, but for giving a diagnosis of CF, sweat test should be done from the nearest centre where it is available. In the presence of typical clinical features with borderline sweat chloride values sweat test should be repeated 2-3 times and the child should be investigated for alternative diagnosis. In the absence of alternative diagnosis with consistently high or borderline sweat chloride values an attempt should be made to get tests for mutations.     

Abdominal manifestations of cystic fibrosis in children

Pulmonary complications remain the main cause of mortality in cystic fibrosis, but the presenting symptoms in children are often related to gastrointestinal or pancreaticobiliary disease. Furthermore, abdominal manifestations are now seen throughout childhood, from infancy to adolescence. The child might present in the neonatal period with meconium ileus or its attendant complications. The older child might present with distal intestinal obstruction syndrome or colonic stricture secondary to high doses of pancreatic enzyme replacement. Less-common gastrointestinal manifestations include intussusception, duodenitis and fecal impaction of the appendix. Most children also show evidence of exocrine pancreatic deficiency. Radiologically, the combination of fat deposition and pancreatic fibrosis leads to varying CT and MR appearances. A higher than normal incidence of pancreatic cysts and calcification is also seen. Decreased transport of water and chloride also increases the viscosity of bile, with subsequent obstruction of the biliary ductules. If extensive, this can progress to obstructive cirrhosis, portal hypertension and esophageal varices. Diffuse fatty infiltration, hypersplenism and gallstones are also commonly seen in these patients. We present a pictorial review of the radiological appearance of these abdominal manifestations. The conditions are dealt with individually, together with typical appearances in various imaging modalities.     

Pubertal growth and development in cystic fibrosis: a retrospective review

AIM: Normal growth patterns are seen throughout the first decade in children with cystic fibrosis (CF). Growth in the second decade is, however, less satisfactory and may reflect pubertal delay. This study was performed to assess the extent of pubertal delay, to examine factors that influence the timing and magnitude of the pubertal growth spurt, and to establish whether the final height for most CF patients differed significantly from the normal population. METHODS: Thirty subjects (16 male) attending a single centre were studied. Peak height velocity (PHV), final height and ages when achieved were compared with population norms. Outcome data were correlated with disease severity using Shwachman and Chrispin-Norman scores and forced expiratory volume in 1 s. RESULTS: PHV was significantly later in both genders in this CF population compared with Tanner and Whitehouse standards: boys 14.6 y (95% confidence interval (95% CI) 12.4-16.8, p < 0.01) and girls 12.6 y (95% CI 10.5-14.7, p < 0.01). Mean PHV was also lower in both genders (boys 7.7 cm y(-1) and girls 6.4 cm y(-1), both p<0.001). However, final heights did not differ significantly from Freeman standards (height standard deviation scores: males--1.2, females--0.1); 52% of final heights equalled or exceeded the mid-parental centile. CONCLUSION: CF patients showed suboptimal PHVs with a later pubertal growth spurt influenced by disease severity, but eventually achieved a normal final height.     

Factors affecting diabetes mellitus onset in cystic fibrosis: evidence from a 10-year follow-up study

This study reports the results of genotype characterization and of a 10-y prospective evaluation of clinical status, glucose tolerance and insulin secretion in 28 originally normoglycaemic patients with cystic fibrosis (CF). The aim of the study was to assess whether any genetic, clinical or metabolic parameters could identify in advance those patients at risk of developing diabetes mellitus over time. During the follow-up 42.8% of patients became diabetic. Neither gender, age nor clinical parameters were significantly different at entry in the patients who eventually developed diabetes compared with those who did not. Insulin secretion during oral glucose tolerance tests (OGTT) deteriorated over time in both groups, whereas a progressive deterioration of glucose tolerance was only evident in the patients who developed diabetes and increased baseline glucose areas were the only predictive parameter of diabetes onset. Genotype analysis revealed significant differences between patients with and without diabetes: ΔF508 homozygosis was more frequent in the first group and N1303K mutation in the second group. In conclusion, in CF: (i) increased glucose areas during OGTT and deterioration of glucose tolerance over time can predict the evolution towards diabetes; and (ii) ΔF508 homozygosis may predispose to the risk of diabetes, whilst N1303K mutation seems to play a protective role.     

Encephalopathy in cystic fibrosis

Cystic fibrosis liver disease (CFLD) affects a large proportion of cystic fibrosis (CF) patients; however encephalopathy is a rare complication. While classical hepatic encephalopathy can be a feature of end-stage liver disease, “hyperammonemic encephalopathy” can be precipitated in previously stable CFLD by various triggers including systemic corticosteroids. We describe one such case and review the relevant literature.