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 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.

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.

Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations.

OBJECTIVE: To compare differences in epithelial chloride conductance according to class of mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: We evaluated the relationship between the functional classes of CFTR mutations and chloride conductance using the first diagnostic sweat chloride concentration in a large cystic fibrosis (CF) population. RESULTS: There was no difference in sweat chloride value value between classes of CFTR mutations that produce no protein (class I), fail to reach the apical membrane because of defective processing (class II), or produce protein that fails to respond to cyclic adenosine monophosphate (class III). Those mutations that produce a cyclic adenosine monophosphate-responsive channel with reduced conductance (class IV) were associated with a significantly lower, intermediate sweat chloride value. However, patients with the mutations that cause reduced synthesis or partially defective processing of normal CFTR (class V) had sweat chloride concentrations similar to those in classes I to III. CONCLUSION: Studies of differences in chloride conductance between functional classes of CFTR mutations provide insight into phenotypic expression of the disease.

Longitudinal evaluation of serum trypsinogen measurement in pancreatic-insufficient and pancreatic-sufficient patients with cystic fibrosis.

We studied serial measurements of serum cationic trypsinogen in patients with cystic fibrosis to assess the predictability of changes in individuals and the value of longitudinal measurement in defining pancreatic status. Three hundred twenty-nine patients with cystic fibrosis, aged 3 days to 40 years, had serum levels of trypsinogen measured on 2 to 12 occasions for periods ranging from 1 week to 7 years. Patients were classified into three groups on the basis of 72-hour fecal fat studies performed at the time of diagnosis. Two hundred thirty-three patients had pancreatic insufficiency (PI), 78 had pancreatic sufficiency (PS), and 18 had PS at diagnosis but acquired PI during follow-up (PS-->PI). Infants with PI had greatly elevated serum trypsinogen levels that fell sharply in the first years of life, so that by age 7 years more than 95% had subnormal values; individual patient values followed a predictable course similar to previously reported cross-sectional age-related values. In patients with PS, serum trypsinogen levels generally remained within or above the normal range and, after age 10 years, were well above the upper limit for PI patients. Within-patient variance was significantly greater (p < 0.0001) in patients with PS than in those with PI who were older than 7 years of age. Changes in patients within PS-->PI generally followed the pattern seen in patients with PI, but values in older patients tended to be in the higher range. We concluded that serial measurement of serum trypsinogen is a valuable tool for monitoring the pancreatic status of patients with cystic fibrosis and PS.

Pathophysiology of the pancreatic defect in Johanson-Blizzard syndrome: a disorder of acinar development.

We compared pancreatic acinar and ductal secretion in two patients with Johanson-Blizzard syndrome, age-matched control subjects, and patients with other primary pancreatic diseases. Patients with Johanson-Blizzard syndrome had preservation of ductular output of fluid and electrolytes, as in patients with Shwachman syndrome but differing from those with cystic fibrosis, who have a primary ductular defect. They also had decreased acinar secretion of trypsin, colipase and total lipase, and low serum immunoreactive trypsinogen levels, consistent with a primary acinar cell defect.

Bentiromide test using liquid-chromatographic measurement of p-aminobenzoic acid and its metabolites for diagnosing pancreatic insufficiency in childhood.

We assessed the diagnostic capability of the bentiromide test using a high-pressure liquid-chromatography method to analyze p-aminobenzoic acid and its metabolites in plasma as an indirect measure of exocrine pancreatic function. Mean total amine concentration in pancreatic-insufficient subjects was significantly lower than in control subjects. There were 3 of 15 false-negative results and no false-positive results. We conclude that this chromatographic method is an effective means of analyzing p-aminobenzoic acid and its metabolites after ingestion of bentiromide.

Correlation of intestinal lactulose permeability with exocrine pancreatic dysfunction.

Increased intestinal permeability to lactulose has been reported in patients with cystic fibrosis (CF). To determine whether this finding is unique to CF or whether it is related to accompanying exocrine pancreatic dysfunction, we evaluated 31 patients with CF and 10 with Shwachman syndrome who had variable degrees of pancreatic dysfunction, together with 17 healthy control subjects. There was no significant difference in the mean urinary lactulose excretion, expressed as the percentage of dose recovered, between CF and non-CF patients with pancreatic insufficiency (2.1% +/- 1.2% and 1.9% +/- 0.8, respectively) or between CF and non-CF patients with pancreatic sufficiency (0.6% +/- 0.5% and 0.6% +/- 0.3%, respectively). However, there was a significant difference in mean lactulose excretion between the pancreatic-insufficient and the pancreatic-sufficient patients (both CF and non-CF groups; p less than 0.001 and p less than 0.013, respectively). We further analyzed the results from 26 of the 41 patients (16 patients with CF and 10 non-CF patients) with pancreatic dysfunction who had previously undergone quantitative pancreatic function testing. A nonlinear, inverse relationship was found between urinary lactulose excretion and exocrine pancreatic function determined by duodenal trypsin output. These data confirm a direct relationship between intestinal lactulose permeability and the degree of exocrine pancreatic dysfunction, unrelated to the cause of the pancreatic disease.

The cystic fibrosis gene and resting energy expenditure.

To determine whether the increase in resting energy expenditure in cystic fibrosis is associated with the primary genetic defect (delta F508) or with declining pulmonary function, or both, we tested resting every energy expenditure prospectively in 32 male subjects (aged 7 to 39 years) who were normally nourished and had good pulmonary function. They were categorized into three genotype groups on the basis of the presence or absence of delta F508 and pancreatic function. Mean resting energy expenditure was 104% of the predicted value and was not associated with genotype. When 29 subjects with normal nutritional status but variable lung function were added to the group, there was a strong correlation between declining pulmonary function and increased resting energy expenditure. We conclude that increased resting energy expenditure in normally nourished boys and men with cystic fibrosis appears to be more closely associated with declining pulmonary function than with genotype.

Effects of cisapride in patients with cystic fibrosis and distal intestinal obstruction syndrome.

In a double-blind, placebo-controlled, crossover trial, we investigated the effects of the prokinetic drug cisapride in patients with cystic fibrosis and chronic recurrent distal intestinal obstruction syndrome (DIOS). After a baseline period, 17 patients (12.9 to 34.9 years; 12 boys) received, in random order, cisapride (7.5 to 10 mg) and placebo three times daily by mouth, each for 6 months. Gastrointestinal symptoms (flatulence, abdominal pain, fullness, abdominal distension, nausea, anorexia, heartburn, diarrhea, vomiting and regurgitation) were scored three times monthly and physical examinations assessed. At baseline and at each 6-month period, assessment included food intake for 7 days, 3-day stool collection, pulmonary function tests, and abdominal radiographs. During cisapride therapy compared with placebo, there were significant reductions in flatulence (p less than 0.005), fullness, and nausea (p less than 0.05). Patients with the worst symptom scores benefited most from cisapride. With cisapride, 12 patients felt better and three worse (p less than 0.05); physicians judged 11 patients improved and two worse (p less than 0.05). No side effects were noted. There were no significant differences between cisapride and placebo periods in nutritional status, x-ray scores, pulmonary function, food intake (fat, protein, calories), stool size and consistency, and fecal losses of fat, bile acids, chymotrypsin, and calories. For acute episodes of DIOS, intestinal lavage was needed 6 times in 4 patients during treatment with cisapride, and 11 times in 6 patients receiving placebo. In comparison with unselected patients with cystic fibrosis and pancreatic insufficiency who were receiving enzyme supplements and who had no distal intestinal obstruction, fecal fat losses (percentage of intake) were almost twice as high in the study group with DIOS (31.2 +/- 20.6% vs 16.2 +/- 17.6%; p less than 0.01). We conclude that in the dosage used, long-term treatment with cisapride appears to improve chronic abdominal symptoms in patients with cystic fibrosis and DIOS, but fails to abolish the need for intestinal lavage. Cisapride treatment had no effect on digestion and nutritional status of cystic fibrosis patients with pancreatic insufficiency.

Acute pancreatitis in childhood.

Sixty-one patients (1 to 18 1/2 years of age) with acute pancreatitis were evaluated. In over one third of cases, acute pancreatitis was one feature of a multisystem disease (Reye syndrome, sepsis, shock, hemolytic-uremic syndrome, viral infections). Other common causes included blunt trauma (15%), acquired or congenital structural defects (10%), metabolic diseases (10%), and drug toxicity (3%). In 25% of cases, no cause was identified. All conscious patients complained of abdominal pain, but the location, severity, and duration of pain were extremely variable. Vomiting was a common symptom. Ultrasonography was helpful in establishing the diagnosis and for assessment of complications such as pseudocyst formation. Endoscopic retrograde cholangiopancreatography was used to identify structural or anatomic lesions in patients with recurrent acute pancreatitis. Serum cationic trypsin(ogen) was superior to amylase in the early diagnosis of acute pancreatitis, and was more consistently elevated during the first 5 days in the hospital. Patients were managed conservatively with complete bowel rest, gastric decompression, intravenous fluid therapy, and pain relief. Pancreatic pseudocysts occurred in 10% of patients. There were 13 fatalities, all in patients with a severe multisystem disorder. Recurrences of acute pancreatitis were noted only in certain diagnostic groups: idiopathic pancreatitis, structural anomalies of the pancreaticobiliary tree, metabolic disorders, and (in a single patient) familial pancreatitis.

Effects of long-term nutritional rehabilitation on body composition and clinical status in malnourished children and adolescents with cystic fibrosis.

Fourteen patients aged 4.9 to 21.5 years with cystic fibrosis and moderate to severe lung disease, malnutrition, or growth failure were given nocturnal supplemental feeding by gastrostomy tube. Mean follow-up was for 1.1 years (range 0.8 to 2.78 years). Patients were studied to observe the effect of nutritional support on body composition, growth, pulmonary function, and quality of life. A contemporary group of patients with CF was retrospectively pair matched to the study group. The supplemental feeding resulted in positive changes in body composition and in growth velocity. Weight, as a percentage of standard in the control group, declined by 3% over 1 year, whereas it increased by 2% in the treatment group (P less than 0.05). Pulmonary function, assessed as a percent of predicted FVC and FEV1, did not change significantly in the treatment group over 1.1 years, whereas FVC declined by 12% (P less than 0.01) and FEV1 declined by 13% (P less than 0.01) in the control group. There was a marked increase in patient ability to participate in activities of daily living, even in those patients in whom pulmonary function deteriorated during the study.

Elevated serum immunoreactive pancreatic cationic trypsinogen in acute malnutrition: evidence of pancreatic damage.

We used a sensitive probe of pancreatic dysfunction, serum immunoreactive cationic trypsinogen, to study 50 infants and children with varying degrees of malnutrition. Patients were classified into subgroups according to the severity of malnutrition. Mean serum trypsinogen concentration was significantly elevated in 25 patients with "severe" malnutrition (77.4 +/- 42.0 ng/ml, P less than 0.001) and in 23 with "moderate" malnutrition (55.2 +/- 16.1 ng/ml, P less than 0.02) compared with the mean value (32.5 +/- 10.4 ng/ml) for well-nourished controls. The level of circulating trypsinogen tended to rise with increasing severity of malnutrition. There was no relationship between serum trypsinogen and other variables such as age, specific diagnosis, or mode of feeling. Elevated serum trypsinogen levels could not be attributed to renal disease or cystic fibrosis. In patients who showed an improvement in nutritional status, serum trypsinogen tended to revert toward normal. Elevated serum trypsinogen values in acutely malnourished infants and children may result from pancreatic acinar cell damage or regurgitation of enzymes from obstructed pancreatic ducts.