Serum immunoreactive trypsin and pancreatic lipase in cystic fibrosis

Serum immunoreactive trypsin (IRT) and pancreatic lipase have been measured in 59 patients with cystic fibrosis (age 1 month-27 years). Follow-up values were obtained from 49 patients. Their serum enzyme levels were compared to those of 120 healthy children of all age groups. Faecal fat excretion was determined in selected patients (n=23) to elucidate the relationship between serum enzyme levels and pancreatic exocrine function.In cystic fibrosis IRT and lipase showed a very similar agecorrelated pattern: in infancy levels were markedly elevated. During the following years the concentrations of both enzymes decreased rapidly and were found to be far below the normal range after the 10th year of life. Elevated enzyme levels in infancy as well as low levels in all age groups coincided with steatorrhaea. Older patients (11–27 years) without severe pancreatic insufficiency however, had IRT and lipase levels in or above the normal range.In healthy children there was no age dependency of IRT levels, whereas in the first 12 months of life lipase levels were significantly lower than in later childhood.Abbreviations IRT Serum immunoreactive trypsin - CF Cystic fibrosis     

Appendicitis in cystic fibrosis: can morbidity be reduced?

The management of appendicitis in cystic fibrosis (CF) has been controversial, and most series report a mortality of over 30%. Difficulties are distinguishing appendicitis from meconium ileus equivalent (MIE) often cause diagnostic delay and advanced disease by the time surgery is undertaken. We report a series of 9 patients with appendicitis proven on histology in whom there was no mortality and minimal morbidity. Factors likely to reduce morbidity and mortality in appendicitis in children with CF include early diagnosis; preoperative intravenous antibiotics effective against both bowel and chest organisms; early appendicectomy; avoidance of right hemicolectomy, or drainage alone; thorough peritoneal irrigation with warm antibiotic saline solution; and continuous postoperative narcotic analgesia to allow early mobilisation and effective chest physiotherapy. Accurate early diagnosis is facilitated if these children are treated by respiratory paediatricians and paediatric surgeons in a centre familiar with the management of cystic fibrosis. Delay in appendicectomy worsens the underlying respiratory disease. Offprint requests to: S. W. Beasley     

Cyclic AMP in pancreatic and biliary secretion of children with chronic intrahepatic cholestasis and cystic fibrosis

The intracellular transmitter cAMP enters the extracellular space and can be found in the duodenal fluid. The role of this messenger was investigated in response to secretin and CCK in children with secretory insufficiency, i.e. 7 with chronic intrahepatic cholestasis, 7 with cystic fibrosis, and 6 controls.Duodenal juice was collected in 10 min aliquots before and after stimulation with 2 U/kg secretin and subsequently 2 U/kg CCK. cAMP, bicarbonate, Ca⁺⁺, Na⁺, K⁺, bilirubin, protein, amylase, trypsin and lipase were determined. Controls. After the injection of secretin the cAMP concentration increased 2.5-fold, the output 6-fold. Compared to cAMP, the time-concentration curve of bicarbonate and Na⁺, as well as volume output, were slightly delayed after secretin, whereas Ca⁺⁺ and bilirubin concentrations decreased. CCK stimulation resulted in an increase of volume, bicarbonate-Na⁺, Ca⁺⁺-, bilirubin-, protein- and hydrolase concentration. cAMP concentration increased 1.7-fold and the output was doubled. Chronic Intrahepatic Cholestasis. Following secretin the cAMP concentration hardly differed from the control values; the output of cAMP, bicarbonate and Na⁺ was enhanced. Compared to the controls CCK was less effective—the concentration and output of cAMP, bilirubin, K⁺ and Ca⁺⁺ were diminished. Cystic Fibrosis. After both hormones high concentrations of cAMP, Na⁺, K⁺, Ca⁺⁺ and bilirubin were found. Due to the reduced secretion volume the output of these parameters were significantly decreased. The Results Indicate that essentially more cAMP is found in the duodenal juice after secretin stimulation than after CCK. cAMP in response to secretin seems to be mainly of pancreatic origin, that after CCK of hepatic origin. One of the first steps of stimulus-secretion coupling—the activation of the membrane bound adenylate cyclase system by secretin and CCK —seems to be intact in cystic fibrosis. The defect of this disease is probably beyond this mechanism.Abbreviations cAMP cyclic 3,5-adenosine monophosphate - cGMP cyclic 3,5-guanosine monophosphate - CCK Cholecystokinin This study was supported by a grant from the Deutsche Forschungsgemeinschaft     

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.     

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.     

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     

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.     

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.     

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.     

Genetic counselling in cystic fibrosis

In a survey by questionnaire of 572 families with one or more children affected with cystic fibrosis 72% were found to have received genetic counselling. The mode of inheritance was correctly known by only 45% and either not known or incorrectly known by the others. About 75% expressed the wish for more information on the genetics of cystic fibrosis. The data indicate that genetic counselling in cystic fibrosis is not given or is ineffective in a high proportion of families. It is suggested that genetic counselling, backed up by a written resumé should be a regular part of the management of families with this disease. The genetic data are consistent with autosomal recessive inheritance at a single locus.     

Monitoring steatorrhoea in cystic fibrosis

The aim of the study was the evaluation of the relationship between chemical fat analysis and some more rapid tests proposed to estimate steatorrhoea. Stool collections (72 h) were obtained on 32 occasions in 22 patients with cystic fibrosis and in seven healthy children. A very close relationship was found between faecal fat, as measured by standard chemical methods, and faecal energy (r=0.95,P<0.001). We conclude that the determination of faecal energy, easier to measure than faecal fat, can provide reliable information about the extent of steatorrhoea in cystic fibrosis.     

Dopamine-beta-hydroxylase in patients with cystic fibrosis

The enzymatic activity of plasma dopamine-beta-hydroxylase (DBH) was determined in 92 children/adolescents with cystic fibrosis, in 25 parents (heterozygotes) of these patients and in 68 healthy controls. Statistically significant (P<0.01) lower DBH levels were found in cystic fibrosis patients (17.9±1.4 mol/min per 1, SEM) compared to the controls (25.5±2.1 mol/min per 1). In 37 patients plasma norepinephrine and dopamine levels were compared to the enzymatic activity, no significant correlation between these variables being shown (r=-0.134 for norepinephrine; r=0.159 for dopamine). However, due to the large variability of DBH within the groups and due to the lack of relationship of this enzymatic activity to plasma catecholamines, it is concluded that these differences may neither account for the observed elevation of plasma dopamine in cystic fibrosis patients (0.94–6.73 nmol/l vs. 0.01–0.986 nmol/l for controls) nor for their putative autonomic dysfunction.Abbreviations DBH dopamine-beta-hydroxylase - CF cystic fibrosis - NE norepinephrine - DA dopamine - HZ heterozygote - COMT catechol-O-methyltransferase     

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.     

Hearing defects in cystic fibrosis

34 children with cystic fibrosis were investigated for defective hearing. In 11 cases a pathological audiometric finding was observed; 10 of the children had conductive hearing loss, 1 had sensorineural hearing loss. 4 children who were too young for exact subjective audiometry were investigated with the Evoked Response Audiometry method; none of them had an abnormal result.No correlation between the defect and the severity and duration of cystic fibrosis could be demonstrated. The reason for the defect seems to be the hypobaric pressure in the middle ear, possibly caused by pathological secretion of the mucosal glands of the Eustachian tube with resulting obstruction. Ventilation of the tube was therapeutically successfull in 4 out of 5 cases and lead to normalization of the audiogram.A shorter version of this paper was presented at the 3rd Meeting of the European Working Group for Cystic Fibrosis, Erbach, Germany, September 6./7. 1972.     

Efficacy and safety of acarbose in patients with cystic fibrosis and impaired glucose tolerance

Impaired glucose tolerance (IGT) is an increasingly frequent complication of cystic fibrosis (CF). In CF patients, a fast postprandial rise in plasma glucose is typically followed by a delayed but prolonged insulin response. Patients may develop symptoms of both hyper- and hypoglycaemia. The α-glucosidase inhibitor, acarbose, delays the hydrolysis and subsequent absorption of ingested carbohydrates. The aim of this study was to investigate the efficacy of acarbose in CF patients with IGT. During a 2-week inpatient period for treatment of Pseudomonas infection, 12 CF patients with IGT were studied in a double-blinded, randomized crossover trial. Each patient received acarbose (50 mg t.i.d.) for 5 days and placebo for 5 days (days 3–8 and days 10–14, respectively). Glucose, insulin and C-peptide responses to a standardized nutritional load were measured at baseline and at the end of each study period (Days 2, 8 and 14). Treatment with acarbose was associated with significant reductions in the mean value, mean peak values and the area under the curve of plasma glucose, insulin and C-peptide, compared to respective baseline values and placebo. Gastro-intestinal disturbances were recorded in 67% of patients during therapy with acarbose. Conclusion Acarbose has a positive therapeutic effect on glucose tolerance in cystic fibrosis patients, as shown by attenuation of postprandial plasma glucose increase and a significant decrease in insulin secretion response. However, acarbose treatment was associated with adverse gastro-intestinal effects that may prevent patients from accepting long-term therapy. Received: 1 December 1997 / Accepted in revised form: 15 September 1998     

Longitudinal evaluation of glucose tolerance and insulin secretion in non-diabetic children and adolescents with cystic fibrosis: results of a two-year follow-up

Thirty-two patients with cystic fibrosis and repeatedly normal fasting blood glucose underwent oral glucose tests and islet-cell antibody assessments on two occasions approximately two years apart. Fourteen patients underwent two iv glucose tolerance tests also. Although in the group as a whole mean glucose areas in response to the oral test remained substantially unmodified over the two-year period, the prevalence of glucose tolerance abnormalities increased from 37.5 to 50%. Insulin output in response to both oral and iv tolerance tests decreased over time. Worsening of insulin secretion and/or of glucose tolerance was never accompanied by deteriorating clinical status. Islet-cell antibodies were detected in no patients, even in those who developed a diabetic glucose tolerance. These results support, on a longitudinal basis, the view of a progressive impairment of B-cell function in cystic fibrosis, which may precede the onset of metabolic abnormalities and is not triggered by autoimmunity.     

Complement in cystic fibrosis

Complement components C3, C4, and C3A were estimated in 30 patients with cystic fibrosis aged 1 to 21 years (MF=1614) and were compared with results in 40 healthy, age-matched subjects. The influences of the clinical score, sputum microbiology, and the patients' sex were also investigated. In contrast to most previous communications, this paper shows that, compared to the control group, a significant decrease of C3 (P<0.001) and C4 (P<0.02) was observed whereas C3A levels were not altered. There were no increases in complement. Shwachman-scores above or below 70 did not influence the complement levels, nor did exacerbations of the disease change the levels. No influence of the patients' sex could be shown. Pseudomonas aer. in the sputum was clearly associated with complement defects (14/18). Alternative-pathway involvement of complement activation could be demonstrated in 32%. The results make complement activation due to pulmonary infection most likely. The defects observed probably represent secondary changes.Presented at the VIIth Annual Meeting of the European Working Group for Cystic Fibrosis, Dresden, June 20–21, 1977Dedicated to Professor E. Zweymüller on the occasion of his 60th birtday     

A review of cystic fibrosis children born to single mothers

The purpose of this study was to examine the relationship between single parents and the health of their children with cystic fibrosis. Seventy-five children aged between 0.8 and 6.0 y were identified from our patient register; 20 of these children came from single parent families. Socioeconomic profiles were collated for each family. Retrospective medical data including, gene mutation analysis, were recorded from the hospital notes of all 75 patients. Maternal health was assessed by means of the General Health Questionnaire (28-item version). The results show that maternal age of ≤19y and lone parenthood were associated with higher morbidity in CF patients <6y of age. Predicted values of the Shwachman score being lower by 4.1 and 4.3 points, respectively. A declining Shwachman score of 1.1 points/y was associated with increasing patient's age. In addition, analysis showed that the CF children of teenage mothers were 16 times more likely to have admission rates of ≥1/y. Single mothers experienced more stress-related symptoms than those from the married group. We concluded that the young CF children of single or teenage mothers have a significantly worse clinical progress and consequently have a higher demand for hospital services. Clearly this population requires extra clinical vigilance and social support.     

Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations

The cystic fibrosis transmembrane regulator (CFTR) gene in Arab patients with cystic fibrosis (CF) (sweat chloride >60 mmol/l) from 61 unrelated families was screened for mutations in exons 3, 4, 5, 7, 10, 11, 16 and 19 and for mutations W1282X, N1303K and 3849 + 10kbC → T. Eight novel mutations were identified. These are: in exon 4: a) 425del42 (an in-frame 42 bp deletion that removes 14 amino acids and causes Gln₉₈ → His at the point of deletion), b) 475G → T (Glu₁₁₅ → Stop) and c) 548A → T (His₁₃₉ → Leu); in intron 5, 711 + 1G → A (splice site mutation); in exon 10, 1548delG (deletion of a “G” nucleotide causing a frameshift mutation that alters the amino acid sequence at residue 473 and results in translation termination at residue 526); in exon 11, a) 1729T → C (Ph₅₃₃E → Leu) and b) 1811 + 2 (splice site mutation) and finally in exon 19, 3361A → T (Lys₁₁₇₇ → Stop). All mutations were detected by heteroduplex analysis and identified by sequencing. Of more than 850 known CFTR mutations, only 9 were encountered. The comparative frequencies of the most common mutations are: 1548delG> I123V=ΔF508=3120 + 1G → A > H139L. Screening for these five mutations identifies 60% of the CF alleles in Arab populations. The novel mutation 1548delG is the most frequent (17%) among Arabs. Conclusion Novel Arab-specific mutations were identified in the CFTR gene underlying cystic fibrosis. As a result of this study, the CFTR mutation detection rate among Arabs with cystic fibrosis is now comparable to that of other populations. Received: 18 December 1998 / Accepted: 14 May 1999