Vitamin D and bone health in adults with cystic fibrosis

Background  Cystic fibrosis (CF) patients have chronic pancreatic insufficiency leading to malabsorption of fat-soluble vitamins, including vitamin D which can contribute to poor skeletal health and respiratory function.
Objective  This study evaluated the prevalence of vitamin D insufficiency and its impact on bone and respiratory health in adults with CF.
Design and measurements  This was a retrospective study in which data were collected from medical records over a 2-year period. Data included patient demographics, lung function, biochemical data, bone mineral densities, X-rays and ascertainment of use of vitamin supplements. Data were collected from medical records at a single accredited CF Center. Serum 25-hydroxyvitamin D [25(OH)D] levels and bone mineral density studies were also collected.
Patients  A total of 185 adults with CF were identified with a mean age of 29 ± 9 years.
Results  The prevalence of vitamin D insufficiency [25(OH)D < 75 nmol/l] was 76%. Mean serum 25(OH)D concentrations were 58·8 ± 30 nmol/l. Use of specific vitamin D supplementation was protective against vitamin D insufficiency whereas use of multivitamins was not. There was a small, but significant, positive association between serum 25(OH)D and FEV₁ per cent predicted after controlling for age, gender, BMI and race ( R ² = 0·30, P  < 0·001). A high prevalence (27%) of vertebral fractures was detected on lateral chest X-ray.
Conclusions  The prevalence of vitamin D insufficiency and poor skeletal health is high in the US CF population. Vitamin D status appears to be positively associated with lung function. Prospective studies to examine the impact of correction of vitamin D insufficiency on skeletal and lung health in adult CF are warranted.     

Lung disease severity, chronic inflammation, iron deficiency, and erythropoietin response in adults with cystic fibrosis

Chronic lung disorders are usually associated with a hypoxia driven increase in red cell mass. However, patients with cystic fibrosis (CF) often have normal or decreased haemoglobin levels. The present prospective observational study in cystic fibrosis patients was performed to determine which factors were involved in alterations in the hematopoetic response to corresponding arterial oxygen pressure. Sixty adult patients (age 21-51) with stable CF were included. They all had vitamin A, D, E, and K but no vitamin B12 supplementation. Twenty-five patients were on oral Fe(2+) (100 mg/day). Resting arterial blood gases, lung function, complete blood counts, parameters of iron status, CRP, sputum microbiology and serum erythropoietin were measured at recruitment and after 3 and 6 months. Patients had varying degrees of pulmonary functional impairment and 9% were hypoxemic (arterial oxygen pressure <60 mm Hg). Low-grade systemic inflammation (CRP > 0.5 mg/dl) was present in 40% of the patients, who all had bacterial colonization. None of the patient had erythrocytosis and 12 patients had anemia. There was no significant difference in iron status between patients with or without chronic iron supplementation and erythropoietin levels were normal. During the 6 months observation period no significant changes occurred. The patients exhibited an impaired erythropoietic response to hypoxemia with normal or low hematocrit in spite of chronic lung disease which might be caused by chronic inflammation associated with CF. Linear multivariate regression analysis revealed CRP levels but neither iron substitution, nor erythropoietin levels nor lung function parameters as independent determinant of haemoglobin levels. CF may be associated with anemia of variable severity as expression of the chronic inflammation present in these patients. The therapeutic consequences are to treat the underlying inflammation rather than to supplement iron.     

Digestive complications in adults with cystic fibrosis

In France the median life expectancy of patients with cystic fibrosis (CF) is 36 years and one third of patients are adults. Respiratory disorders are the main determinants of survival during adulthood, although gastrointestinal complications can also have a major impact on quality of life and nutritional status. We reviewed gastro-intestinal and pancreatic manifestations of CF in adults. Some complications (diabetes, distal intestinal obstruction syndrome and acute pancreatitis) are more frequent in adulthood than in childhood. Clinical and therapeutic aspects of specific conditions (such as distal intestinal obstruction syndrome) or atypical presentations (including appendicular complications) are presented herein.     

Antibiotic desensitization in adults with cystic fibrosis

OBJECTIVE: Allergic reactions to antibiotics occur in up to 30% of patients with cystic fibrosis (CF). Repeated antibiotic exposure and immune hyper-responsiveness increase the risk of allergic reactions and may limit antibiotic choice. Desensitization may allow the successful administration of an antibiotic despite previous allergy. We aimed to determine the success of antibiotic desensitization in patients with CF in an adult CF unit over a 7-year period. METHODOLOGY: A retrospective medical record review was performed on the 19 patients who had undergone antibiotic desensitization procedures. Data collected included drug allergy and intolerance profiles, nature of allergies, and the outcome of desensitization procedures. Desensitization procedures were performed in a ward setting according to published methods. RESULTS: Nineteen patients (13 females) reported 62 drug allergies with a mean of 3.3 per patient. Of the 71 desensitization procedures undergone by this group, 54 (76%) were successful. Fifteen of the 19 patients were allergic to two or more beta-lactam antibiotics. Over half of the patients were desensitized to more than one antibiotic. Nine different antibiotics were used in 31 different patient/drug combinations. A successful outcome was achieved in 18/31 (58%) combinations, with three requiring treatment for mild allergic reactions. Allergic reactions caused drug cessation in a total of 19 patient/drug combinations (three after initial successful desensitization and full courses of antibiotics). Over 50% of these reactions occurred on day 1. Desensitization failures were more common in patients with well-documented allergic reactions to a specific drug. CONCLUSION: This study demonstrates that multiple antibiotic allergies are common in adults with CF. Cross-reactivity between beta-lactam antibiotics may limit antibiotic choice for the treatment of pulmonary exacerbations. Antibiotic desensitization allows safe and successful treatment in the ward setting of many patients with previous allergies to an antibiotic. In many patients symptoms of allergy still occur and result in cessation of the antibiotics. Use of corticosteroids and antihistamines may improve the success rate of desensitization procedures.     

Bacteraemia and fungaemia in adults with cystic fibrosis

The incidence of bacteraemia and fungaemia was determined in 29 adults with cystic fibrosis (CF) during 50 consecutive admissions to hospital for management of infective exacerbations of pulmonary disease. Blood was drawn for aerobic, anaerobic and fungal cultures from all patients who were febrile on admission or who became febrile during treatment. The population included eight patients who had indwelling venous access systems in situ. The overall incidence of positive blood cultures in febrile patients was 3.5% [95% confidence interval (C.I.), 1-6%]. We recorded one case of Pseudomonas aeruginosa bacteraemia and two cases of Candida albicans fungaemia. The patient with P. aeruginosa bacteraemia died 5 days after isolation of the organism from her blood. The two patients with C. albicans bacteraemia had totally implantable venous access systems (TIVAS) in situ and both recovered following appropriate therapy. These observations suggest that bacteraemia is rare in patients with CF but that there is a significant risk of fungaemia in a susceptible minority. The implications of these findings, as they relate to management of infections and care of indwelling catheters in such patients, are discussed.     

Metabolic abnormalities in adults with cystic fibrosis

Background and objective: Survival of patients with cystic fibrosis (CF) has improved, resulting in increased exposure of patients to cardiovascular risk factors. Diabetes mellitus is common in patients with CF; however, less is known about lipid abnormalities in this population. In this study, the prevalence of lipid abnormalities was investigated in a contemporary population of adults with CF. Methods: Clinical and laboratory data on 221 adult patients with CF were collected retrospectively. Fasting serum glucose levels and lipid profiles were recorded. The age‐specific values for healthy individuals, as reported by the National Health and Nutrition Examination Surveys, were used for comparison. Results: The mean age of the patients was 30 ± 10 years, 55.1% were men and the mean FEV₁% was 68 ± 25%. Sixty‐nine patients (31.2%) had CF‐related diabetes mellitus and 52 (23.5%) were receiving insulin therapy. In addition, 36 patients (16.3%) had impaired glucose tolerance. Triglyceride levels were similar to those of historical control subjects (mean ± SEM, 1.37 ± 0.05 and 1.39 ± 0.02 mmol/L, respectively, P = 0.75). However, in the 30–39 years age group of CF patients, triglyceride levels were increased relative to those of their control counterparts (1.79 ± 0.14 vs 1.38 ± 0.04 mmol/L, P = 0.006). Total cholesterol levels were lower in the CF patients compared with control subjects, across all age groups. Conclusions: Abnormalities of glucose metabolism are highly prevalent in CF patients, and are accompanied by hypertriglyceridaemia in the 30–39 years age group. Prospective studies are required to confirm lipid abnormalities and investigate possible cardiovascular complications in patients with CF.     

Failure of high-dose ergocalciferol to correct vitamin D deficiency in adults with cystic fibrosis

RATIONALE: Treatment guidelines for vitamin D monitoring and supplementation in cystic fibrosis (CF) have recently been developed and published by a consensus committee, but have not been prospectively tested. OBJECTIVES: To use these guidelines to determine the percentage of adults with CF requiring vitamin D repletion therapy and to evaluate the effectiveness of the currently recommended high-dose oral ergocalciferol repletion protocol. METHODS: Prospective study of clinical outcomes after therapy with the recommended vitamin D repletion algorithm. RESULTS: Of 134 adults with CF, 109 (81.3%) were found to have 25-hydroxyvitamin D (25-OHD) levels below the recommended 30 ng/ml. Sixty-six of these adults completed the recommended course of 400,000 IU of oral ergocalciferol over 2 months, and only five (8%) responded with correction of their serum 25-OHD to the goal of 30 ng/ml or greater (mean change, +0.3 ng/ml; from 18.8 to 19.1 ng/ml). In the 33 adults with CF who also completed the recommended second course of 800,000 IU of ergocalciferol over 2 months, none demonstrated correction of their deficiency (mean change, -1.2 ng/ml). CONCLUSION: The results of this study demonstrate that a majority of adults with CF have serum 25-OHD levels below 30 ng/ml, and the currently recommended ergocalciferol repletion regimen often does not fully correct vitamin D deficiency and may need to be revised to include even higher dosing of ergocalciferol. Further work is needed to establish the ideal 25-OHD level for maximizing calcium absorption and bone health in CF.     

Vitamin E deficiency and its clinical significance in adults with primary biliary cirrhosis and other forms of chronic liver disease

The vitamin E status of 146 adults with chronic liver disease was assessed by estimating both their serum vitamin E concentration and the ratio of serum vitamin E to serum cholesterol concentration. Low levels of vitamin E occurred most frequently in patients with primary biliary cirrhosis and other forms of chronic cholestatic liver disease. When a serum vitamin E concentration of 12.3 mumol/l (mean-2 SD of a control population) was taken as the lower limit of normal, 44% of patients with primary biliary cirrhosis and 32% with other chronic cholestatic liver disease had a reduced concentration, indicating a biochemical deficiency of vitamin E. If a vitamin E/total cholesterol ratio of 2.35 mumol/mmol was taken as the lower limit of normal, then 64% and 43% of patients with primary biliary cirrhosis and other chronic cholestatic liver disease, respectively, had a biochemical deficiency of vitamin E. Of the patients with chronic cholestasis and a serum bilirubin concentration greater than 100 mumol/l, 91% had a reduced vitamin E/cholesterol ratio. Twelve patients with primary biliary cirrhosis and severe vitamin E deficiency (serum vitamin E less than 5.0 mumol/l and a vitamin E/cholesterol ratio less than 1.0 mumol/mmol) underwent extensive neurological investigation. Five had a mild mixed sensorimotor peripheral neuropathy, which was not, however, typical of the neurological syndrome associated with vitamin E deficiency. In patients with severe biochemical deficiency of vitamin E (less than 5 mumol/l and less than 1 mumol/mmol total cholesterol), administration of large oral doses of vitamin E only increased serum concentrations to within the normal range in one patient; in the others even weekly parenteral administration over a 3-month period did not correct deficiency. In patients with less severe biochemical deficiency, the serum vitamin E concentration and vitamin E/total cholesterol ratio were restored to normal by oral or intramuscular supplements of the vitamin.     

Predictors of mortality in adults with cystic fibrosis

Assessment of prognostic indicators in patients with cystic fibrosis (CF) is important. The study's aim was to assess the relative contribution of gender, genetics and microbiology on survival in adults with CF. Adult patients were studied from 1995 to 2005 and data collected included FEV(1) (%predicted), body mass index (BMI), genetics, and microbiology. Data was available on 183 patients in 1995. Forty-five patients died in the subsequent 10 years. Patients who died during the study had lower mean (SD) FEV(1) %predicted in 1995 when compared to those remaining alive, 41.5 (15.2)% versus 69.8 (23.2)% predicted, respectively, P<0.001 and they had lower mean (SD) BMI in 1995, 19.2 (3.3) kg/m(2) in comparison to those remaining alive, 20.7 (3.4) kg/m(2), P=0.008. The proportion of patients infected with Pseudomonas aeruginosa and Burkholderia cepacia complex was higher in the group who died during the study compared to those remaining alive, odds ratio 20.9 P<0.0001 and 7.1 P<0.0001, respectively. The presence of the Delta F508 homozygous mutation did not alter survival, P=0.3. Patients infected with either P.aeruginosa or B.cepacia complex had reduced survival compared to those without infection, P=0.01 and P<0.0001, respectively. FEV(1)% (P<0.0001), infection with P.aeruginosa (P=0.005) or B.cepacia complex (P=0.03) were the only significant predictors of mortality. This study demonstrates adults who died were more likely to have worse lung function and be infected with either P.aeruginosa or B.cepacia complex. FEV(1)% and infection with P.aeruginosa or B.cepacia complex were the most significant predictors of survival in adults with CF.     

Psychological functioning of adults with cystic fibrosis

STUDY OBJECTIVES: The purpose of this study is to assess the psychological profiles of adult patients with cystic fibrosis (CF) and to investigate predictors of patients' psychological status. PATIENTS AND METHODS: Thirty-four adults with CF completed a battery of psychological testing including the Minnesota Multiphasic Personality Inventory-2, Beck Depression Inventory, and State-Trait Anxiety inventory. These were compared to health status data, including pulmonary function testing and nutritional status measures. RESULTS: As a group, adults with CF did not demonstrate significant levels of depression, anxiety, or other psychopathology. Results were not affected by age, sex, or severity of disease. Male gender predicted higher scores for depression and anxiety, and better lung functioning predicted less anxiety. Having a higher level of psychosocial support emerged as a strong predictor of better psychological functioning. CONCLUSIONS: Overall, adults with CF report relatively healthy psychological functioning. Better lung function and a strong social support system predicted better psychological functioning, which may have implications for clinical intervention.     

Variable severity of pulmonary disease in adults with identical cystic fibrosis mutations.

Adults with CF followed in a university center were assessed for the presence of the most common CF gene mutation, delta-F508. Excluding one member of a sibling pair, 29 of 55 subjects had two copies of delta-F508 (homozygotes), 23 had one copy of delta-F508 with the other CF mutation not identified (complex heterozygotes) and three were lacking delta-F508. A wide range of clinical severity was seen among individuals carrying two copies of the delta-F508 gene, who are genetically identical at the CF gene locus. The number of individuals diagnosed with CF as adults was significantly lower in the homozygote group (1 of 29) as compared with the heterozygote group (7 of 24). No differences were detected between groups in pulmonary function, non-pulmonary complications or overall clinical severity. These results suggest that environmental or background genetic factors contribute significantly to the variability in pulmonary and other complications seen among individuals with CF.     

Vitamin D metabolism and osteomalacia in cystic fibrosis

A 25-yr-old black man with cystic fibrosis and cirrhosis developed symptoms of osteomalacia and hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and low circulating 25-hydroxyvitamin D (25-OHD). Serum 1,25-dihydroxyvitamin D (1,25-[OH]2D) was within the normal range. Iliac crest bone biopsy confirmed the diagnosis of osteomalacia. Oral administration of 50,000 IU of vitamin D2 failed to relieve symptoms or raise serum 25-OHD levels to normal. Intramuscular vitamin D2, 10,000 IU every 8-12 week, improved symptoms, raised serum 25-OHD to normal, and increased circulating 1,25-[OH]2D to values five times normal. Over the next 10 mo circulating 1,25-[OH]2D remained elevated despite normalization of serum calcium, phosphorus, and parathyroid hormone. Repeat bone biopsy 1 yr after parenteral vitamin D showed healing of the osteomalacia. Malabsorption of vitamin D appears secondary to profound steatorrhea due to pancreatic insufficiency and secondary biliary cirrhosis. Although extensive hepatocellular disease was present, hepatic conversion of vitamin D to 25-OHD was intact. Both high and low circulating 1,25-[OH]2D levels during active osteomalacia have been reported; initially, the level was in the normal range and higher values in this patient occurred with repletion of 25-OHD substrate. This study shows that symptomatic osteomalacia may be a major manifestation of cystic fibrosis in those patients surviving into adulthood. Measurements of serum 25-OHD in cystic fibrosis patients may identify those who should receive supplemental vitamin D.     

Changes in pulmonary mechanics with increasing disease severity in children and young adults with cystic fibrosis

Obstructive apnea during sleep is associated with a substantial transient blood pressure elevation. The mechanism of this pressor response is unclear. In this study we measured muscle sympathetic nerve activity (MSNA), mean arterial pressure (Psa), and mean limb blood velocity as an index of blood flow (MBV, Doppler) and calculated changes in limb vascular resistance during and after apneas during both wakefulness and sleep in patients with the obstructive sleep apnea syndrome. Immediately postapnea during sleep Psa increased significantly compared with the earlier stages of apnea and this was preceded by a rise of MSNA (n = 5). In contrast to blood pressure, MBV remained unchanged. Because resistance = blood pressure/blood flow, limb vascular resistance increased by 29 +/- 8% from late apnea to postapnea (n = 7, p < 0.002). Voluntary breathhold maneuvers during room air exposure evoked similar responses (n = 10). Supplemental oxygen administered via nonrebreather face mask attenuated the MSNA and vasoconstrictor responses to obstructive (n = 2) and voluntary apneas (n = 10). Our data suggest that obstructive apneas in patients with the obstructive apnea syndrome are accompanied by transient limb vasoconstriction. This vasoconstrictor response appears to be, at least in part, mediated by the sympathetic nervous system and may be linked to hypoxia.     

Sleep quality and daytime function in adults with cystic fibrosis and severe lung disease.

It was hypothesized that adult cystic fibrosis (CF) patients with severe lung disease have impaired daytime function related to nocturnal hypoxaemia and sleep disruption. Nineteen CF patients (forced expiratory volume in one second 28+/-7% predicted) and 10 healthy subjects completed sleep diaries, overnight polysomnography (PSG), and assessment of daytime sleepiness and neurocognitive function. CF patients tended to report more awakenings (0.7+/-0.5 versus 0.3+/-0.2 x h(-1), p=0.08), and PSG revealed reduced sleep efficiency (71+/-25 versus 93+/-4%, p=0.004) and a higher frequency of awakenings (4.2+/-2.7 versus 2.4+/-1.4 x h(-1), p=0.06). Mean arterial oxygen saturation during sleep was lower in CF patients (84.4+/-6.8 versus 94.3+/-1.5%, p<0.0001) and was associated with reduced sleep efficiency (regression coefficient (r)=0.57, p=0.014). CF patients had short sleep latency on the multiple sleep latency test (6.7+/-3 min). The CF group reported lower levels of activation and happiness and greater levels of fatigue (p<0.01), which correlated with indices of sleep loss, such as sleep efficiency (r=0.47, p=10.05). Objective neurocognitive performance was also impaired in CF patients, reflected by lower throughput for simple addition/subtraction, serial reaction and colour-word conflict. The authors concluded that adult cystic fibrosis patients with severe lung disease have impaired neurocognitive function and daytime sleepiness, which is partly related to chronic sleep loss and nocturnal hypoxaemia.     

Expiratory airflow patterns in children and adults with cystic fibrosis

STUDY OBJECTIVE: To determine whether tidal expiratory airflow patterns change with increasing airways obstruction in patients with cystic fibrosis. DESIGN: An observational study. SETTING: Lung function laboratory. PATIENTS: Sixty-four children and young adults with cystic fibrosis. MEASUREMENTS: After measuring FEV(1) and airways resistance using body plethysmography, each subject was seated and asked to mouth breathe through a pneumotachograph for 2 min. The collected data were analyzed, and three expiratory airflow pattern-sensitive indexes were computed. The first index was derived from the ratio of the time to reach peak expiratory flow to the total expiratory time (tPTEF/tE). The second index, Trs, was an estimate of the time constant of the passive portion of expiration. The third index, f1.gif" BORDER="0">, describes the slope of the whole post-peak expiratory flow pattern after scaling. RESULTS: Compared with FEV(1), the index tPTEF/tE was a poor indicator of airways obstruction (r(2) = 0.15, p = 0.002). Trs showed a strong relationship with the severity of airways obstruction (r(2) = 0.46, p < 0.001). Using f1.gif" BORDER="0">, the postexpiratory profile could be categorized into three shapes, and provided a good indicator of airways obstruction when linear and concave-shaped profiles occurred (r(2) = 0.42, p < 0.001). Convex-shaped flow profiles had to be treated separately and were indicative of normal lung function. CONCLUSIONS: In a cross-sectional study of patients with cystic fibrosis, increase in airways resistance above normal is reflected by quantifiable changes in the expiratory airflow pattern.     

Vitamin K status in cystic fibrosis patients with liver cirrhosis

The available data on the influence of liver cirrhosis on vitamin K status in CF patients is scarce. Therefore, the aims of the present study were to assess the prevalence of vitamin K deficiency in cirrhotic CF subjects and to determine whether it correlates with liver cirrhosis.The study group comprised of 27 CF patients with and 63 without liver cirrhosis. Vitamin K status was assessed using prothrombin induced by vitamin K absence (PIVKA-II) and the percentage of undercarboxylated osteocalcin (u-OC).PIVKA-II concentrations were higher in cirrhotic than in non-cirrhotic CF patients (median [1st–3rd quartile]: 3.2 ng/ml [1.0–10.0] vs. 1.3 ng/ml [0.2–2.6], p = 0.0029). However, the differences in u-OC percentages between the studied groups did not reach the level of significance (49.4% [7.0–73.8] vs. 8.0% [2.6–59.1], p = 0.0501). Based on multiple linear regression analysis the dose of vitamin K and F508del mutation were potentially defined as determinants of vitamin K deficiency. Liver cirrhosis was not documented to be an independent risk factor.In CF patients with liver cirrhosis vitamin K deficiency is not only more frequent, but also more severe. However, not liver cirrhosis, but the presence of a F508del CFTR mutation constitutes an independent risk factor for vitamin K deficiency.