Objectives
In a previous lesson (Lesson 11, Volume 8 [1992]), cystic fibrosis (CF) genetics, pathogenesis, nutrition, and treatment strategies were presented. The purpose of this lesson is to update the information previously presented and to expand the discussion of important elements of adult CF care. The educational objectives include the ability to:

1. Understand the genetics, pathogenesis, and epidemiology of CF.
2. Understand nutritional failure and its impact on survival.
3. Understand cystic fibrosis-related diabetes (CFRD), pathogenesis, and screening.
4. Understand CFRD goals for treatment.
5. Understand special challenges to adolescents and adults with CF.

Key words:
airway clearance; CFRD; DF508 mutation; insulin sensitivity; malnutrition; tobramycin solution for inhalation

Abbreviations
BMI = body mass index; CF = cystic fibrosis; CFF = Cystic Fibrosis Foundation; CFRD = cystic fibrosis-related diabetes; CFTR = cystic fibrosis transmembrane conductance regulator; FDA = Food and Drug Administration

Genetics of CF

The genetic defect giving rise to CF affects the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7, which was first discovered in 1989.¹ Since that time, hundreds of mutations have been described. DF508 is the most common mutation of the CFTR gene and results in a deletion of a phenylalanine residue at the 508th position of the protein. The resulting CFTR has partially preserved function but inappropriate intracellular trafficking. The DF508 CFTR gene is transcribed and translated within the cell but is never shuttled to the membrane surface.² DF508 is the most common genetic defect in patients with CF, with about 70% of patients heterozygous and 50% of patients homozygous for this mutation.² Extensive research has focused on finding compounds that might facilitate the shuttling of the DF508 CFTR to the membrane surface, in hopes that this would result in enough functioning CFTR at the cell surface to reverse the clinical manifestations of the disease. A recent publication by Egan and colleagues³ reported promising results using curcumin, a component of the spice turmeric, to accomplish this goal.The investigators gave this compound to DF508 mice and found a normalization of their nasal potential difference, an indication of successful shuttling of CFTR to the respiratory epithelium. Human trials are currently being planned with this compound.

Pathogenesis and Treatment of CF Airway Disease

The absence of the CFTR on epithelial cells is an important contributor to clinical symptoms, although its loss on B and T lymphocytes (also expressing surface CFTR) suggests that a primary immune defect may also exist in this disease.⁴ The vast majority of the morbidity, and nearly all of the mortality, from CF results from progressive obstructive lung disease and, ultimately, respiratory failure. CF airway disease is characterized by airway inflammation (which can exist even in the absence of airway infection),⁵ thick airway mucus, and bacterial colonization/infection—all of which lead to progressive airway destruction and bronchiectasis.

The mainstay of treatment for CF airway disease is focused on treating the central features of its pathogenesis. Systemic antibiotics are used to treat bacterial infection at times of exacerbation, and inhaled antibiotics, like tobramycin solution for inhalation (TOBI; Chiron Corportion; Emeryville, CA) and, to a lesser extent, colistin sulfate, are used to decrease bacterial colonization. When used in an alternating month schedule, tobramycin solution for inhalation has been shown to improve lung function and decrease the need for hospitalization without increasing antimicrobial resistance.⁶ Airway clearance is another major component of the treatment of CF lung disease. Dornase alfa (Pulmonzyme; Genentech; San Francisco, CA) works by digesting inflammatory cell DNA from the CF airway and, therefore, promotes thinning of secretions and facilitates airway clearance.⁷ There are also many different mechanical modalities used for airway clearance. Pneumatic vest, flutter valve (Axcan Scandipharm; Birmingham, AL), acapella value (DHD Healthcare; Wampsville, NY), and special breathing techniques all can be used as adjuncts to manual chest physiotherapy. No one modality has been shown definitively to be better than another. However, studies have shown that satisfaction with a given technique improves the compliance, regardless of whether or not it is a time-consuming treatment regimen.⁸

Uncontrolled airway inflammation, either primary or in response to infection, is a key feature of CF airway disease. Although antibiotics, dornase alfa, and airway clearance techniques act to manage the consequences of airway inflammation once it has started, they have no known antiinflammatory activity. To date, two therapies exist that directly address inflammation and have been shown to be effective in treating CF lung disease. High-dose ibuprofen has been studied in a large, randomized, controlled trial and found to effectively slow the rate of lung function decline in children.⁹ Despite this result, the drug is not in extensive use today, with <5% of patients with CF currently using this therapy.¹⁰ Concern over side effects is the most commonly sited explanation for the infrequent use, despite a favorable side effect profile in the initial studies.^9,11 More recently, chronic macrolide therapy has been studied; it is believed to work through a variety of mechanisms, including a direct antiinflammatory effect, and was first used for the treatment of diffuse panbronchiolitis, a disease that shares many features with CF. Diffuse panbronchiolitis is a lung disease rarely found in the United States. It is more frequently encountered in Japan and is characterized by diffuse airway inflammation and Pseudomonas aeruginosa colonization. The beneficial effect of macrolide therapy in this disease prompted similar studies in the population of patients with CF. A recent multicenter, randomized, controlled trial showed a 6% improvement in lung function over 18 months, decreased hospitalization, and improved quality of life in patients treated with alternating days of azithromycin¹² and justified the addition of this medication to the chronic treatment regimen for CF airway disease. Close monitoring of liver function tests and sputum culture for atypical mycobacterium is recommended for patients using this therapy. Patients colonized with Burkholderia cepacia were not included in this trial, making azithromycin therapy of unclear benefit in this subgroup of patients with CF.

Epidemiology and the CF Center

As the understanding of CF airway disease improves, so do available treatments and, ultimately, survival. The median survival for a patient with pancreatic insufficient CF is 32 years and 52 years for those with pancreatic sufficient disease.¹⁰ It is estimated that 1:30 people in the United States is a carrier of a mutation in CFTR (1:28 Caucasians), which corresponds to approximately 3,000 live births per year affected in the United States. Genotype analysis is available, both prior to conception (parental screening) and after (fetal screening), but is not uniformly performed. In 2001, the American College of Obstetricians and Gynecologists began recommending that information on parental screening for CF (25 most common mutations) be offered to all couples, regardless of risk.¹³ They also recommend that a follow-up discussion regarding screening be held with couples who are considered high risk (Caucasians of European and Ashkenazi Jewish descent).

As survival improves, so does the number of patients with CF who reach adulthood. The current number of patients with CF over the age of 18 years in the United States is 13,000 (40% of total), and projections are that, by the year 2008, the number of adults with CF will exceed 50% of the CF population. Traditionally, patients with CF were cared for in a single CF center, sponsored by the Cystic Fibrosis Foundation (CFF), by a single team of CF physicians, primarily of a pediatric background. As the CF patient population has aged, adult programs have surfaced, run by physicians trained in adult medicine. CFF-sponsored CF centers follow approximately 25,000 patients with CF nationwide, in both adult and pediatric programs. The CF care team consists of a physician, nurse, therapist, and social worker and follows a multidisciplinary approach to patient care. All members of the team work to address the complex issues, both medical and social, that arise for patients with CF.

Nutrition

In a society that is becoming increasingly obese, patients with CF are constantly struggling to maintain an adequate body weight. CF can affect the gastrointestinal mucosa, pancreatic ducts, and liver and give rise to significant protein and fat malabsorption and to partial or complete bowel obstructions, if not appropriately treated.

Most of the nutritional problems in patients with CF arise in patients with pancreatic insufficient disease. The 2002 CFF registry indicated that 92% of patients were taking pancreatic enzymes, suggesting that the vast majority of patients fall into the “pancreatic insufficient” category. Unlike lung disease severity in CF, which shows no correlation with genotype, certain CF genotypes are associated with pancreatic sufficient disease. Interestingly, pancreatic sufficient patients frequently have milder lung disease, and this appears to lead to their improved survival (52 vs 32 years).¹⁴ The gold standard for determining if a patient’s pancreas is affected by CF is by performing a 5-day fecal fat measurement. This test can be problematic to perform, and a onetime fecal elastase-1 measure often is used in its place.¹⁵ A fecal elastase-1 of <100 mg/g of stool suggests a high likelihood of pancreatic insufficiency when performed by the appropriate assay.

The mainstay of treatment for pancreatic insufficient CF is pancreatic enzyme supplementation, which can improve fat absorption from 50% to nearly 90% if prescribed and taken properly. Recommended pancreatic enzymes are enteric-coated to allow absorption at a pH >5.5. Typically, absorption is in the first portion of the duodenum, and pancreatic enzyme absorption efficiency can be enhanced by concurrent administration of H₂-antagonists or proton pump inhibitors that increase gastric and proximal duodenum pH.¹⁶ The maximum recommended dose of pancreatic enzyme is 10,000 U/kg/d. Doses in excess of this have been associated with fibrosing colon disorders and bowel obstruction.¹⁷ Most patients can be treated successfully with a dose of 2000 to 2500 U/kg/d. Pancreatic enzymes are not regulated by the Food and Drug Administration (FDA) and, as a result, many reports exist of unacceptable formulations being dispensed.¹⁸ Recently, the FDA has announced a plan to begin regulation of these medications in hopes of improving the quality and consistency of the drugs available.

Vitamin A, D, E, and K are fat soluble and need to be supplemented in patients with CF and pancreatic insufficiency. Combination vitamins, of vitamins A, D, E, and K, are recommended for such patients, and annual vitamin levels should be checked to ensure adequate supplementation.

One of the gravest long-term consequences of malabsorption in the patient with CF is malnutrition. Nutritional failure, defined in the adult as a body mass index (BMI, measured in kilogram per square meter) <85th percentile, or >5% loss from usual weight for >2 months, carries an increased risk of death.¹⁹ Multiple studies, dating back to the 1970s, describe a strong association between weight loss and decline in FEV₁ in the patient with CF.¹⁹ Failure of a patient to maintain ≥70% of their ideal body weight carries a 50% 2-year mortality risk.²⁰ These statistics underscore the critical importance of nutrition in this patient population.

A nutritionist sees all patients with CF annually as part of their CF center visits and more frequently if the patient is at risk for, or in, nutritional failure. Additionally, aggressive nutritional support is recommended to underweight patients in the form of calorie-dense nutritional supplements, either orally or via a gastrostomy tube, if caloric needs cannot be otherwise met. Multiple studies have shown an improvement in FEV₁ and survival with increases in weight.²¹ Despite this, however, nutritional issues continue to be an area in which most centers struggle, with 39% of patients with CF <30 years reported as at risk for, or in, nutritional failure.¹²

CF-Related Diabetes

Screening
Weight gain in a patient with CF is a challenging task, and unrecognized CFRD is often an important contributor to failure. CFRD is primarily a disease of adolescence and adulthood, with the registry reporting <1% of patients <10 years of age having the disease and >15% of patients >35 years of age. Data from Moran and colleagues²² suggest that the true prevalence is higher still when screening by oral glucose tolerance tests. Blood hemoglobin A1C is not adequate for screening, because it is often normal despite CFRD, due to increased RBC turnover.²³ Current recommendations for screening are summarized in Figure 1. An annual random blood glucose test is recommended in all adults with CF, with follow-up fasting blood glucose tests if the result is >126 mg/dL. Two random blood glucose test value >200 mg/dL, or one random blood glucose test value >200 mg/dL and a fasting blood glucose test value >126 mg/dL are diagnostic of CFRD. The above screening approach identifies patients with CFRD and fasting hyperglycemia but will not identify patients with CFRD without fasting hyperglycemia, which requires a screening oral glucose tolerance test. CFRD without fasting hyperglycemia is defined as a normal fasting glucose value (<126 mg/dL) and a 2-h glucose value after challenge (1.75 g/kg, up to 75 g of glucose) of >200 mg/dL. In one study, patients with CFRD without fasting hyperglycemia made up 27% of adults >30 years old.²² The clinical significance of CFRD without fasting hyperglycemia at the present time remains unclear, and a study to determine if this subgroup of patients should be treated aggressively is currently ongoing.

Figure 1. Screening Algorithm for CF-Related Diabetes*

*BG = blood glucose; CFRD = CF-related diabetes; FBG = fasting blood glucose.

Pathogenesis
The pathogenesis of CFRD is complex and results from an impaired balance of insulin production and tissue insulin sensitivity. CFRD is seen almost exclusively in patients with CF who are pancreatic insufficient. At baseline, patients with CF have increased tissue sensitivity and impaired insulin production.²⁴ The impaired production results from impaired endocrine pancreatic function and frequently worsens over time, as the pancreas becomes more damaged with age. Initially, patients with CF are able to maintain appropriate serum glucose levels with less insulin, because their tissues have increased insulin sensitivity. But, as their insulin production falls, they ultimately develop an insulin-deficient state and diabetes. Hyperglycemia may also be seen transiently at times of stress when tissues are less sensitive to insulin. As a result, patients at risk for developing CFRD often have significant hyperglycemia with pulmonary exacerbations or with corticosteroid treatment.

The concomitant diagnosis of CFRD has important implications for CF survival. Multiple studies have demonstrated an increase in morbidity and mortality,²⁵ and several have shown a decline in FEV₁ and BMI of 2 to 4 years preceding the CFRD diagnosis,²⁶ highlighting the potential importance of early recognition of the disease. It remains unclear at present whether CFRD causes excess morbidity and mortality or if it represents a marker of more advanced disease. However, studies documenting improved lung function and BMI following initiation of insulin therapy²⁷ support a cause-and-effect role and suggest CFRD may be an independent marker of poor outcomes.

Microvascular complications occur in patients with CFRD but at a much lower rate than associated with other types of diabetes.²⁸ Macrovascular complications, such as coronary artery disease and stroke, are extremely rare.²⁹ These differences may reflect the limited life expectancy of patients with CFRD or may reflect fundamental differences in disease pathogenesis.

Treatment
The current recommendation is to treat patients with CFRD and fasting hyperglycemia aggressively and with a multidisciplinary approach, including input from a nutritionist, endocrinologist, and CF physician. The goals of CFRD management are different than the goals of treatment of either type 1 or type 2 diabetes; they include the maintenance of optimal nutritional status without limitation of dietary intake and control of hyperglycemia while preventing episodes of hypoglycemia. Additionally, it is important to remain supportive and flexible in the management of the disease, as many patients find it difficult to adopt another complicated treatment regimen.²⁹ The benefits of treating impaired glucose tolerance or CFRD without fasting hyperglycemia are unclear, and it is not currently recommended outside of clinical trials or in the setting of unexplained weight loss.²⁹

The mainstay of treatment of CFRD with fasting hyperglycemia is insulin. Oral hypoglycemics are not recommended outside of clinical trials. Hyperglycemia in patients with CFRD is primarily postprandial, as there is typically some degree of maintained basal insulin secretion. Ketosis is uncommon. Therefore, a typical regimen usually includes a very short-acting insulin, like lispro insulin or equivalent, prior to each meal, with the dose adjusted for the amount of carbohydrates consumed. Occasionally, small amounts of long-acting insulin are required, but patients should be monitored closely for evidence of hypoglycemia, particularly in the early morning hours. Patients should also be monitored daily with home glucose kits and screened annually with eye exams for microvascular complications and urinalysis for microalbuminuria. If these complications are found, they should be treated as with type 1 and type 2 diabetes.

Growing Older With CF

As survival in patients with CF increases, so do the physical, social, and emotional challenges facing these patients. Adolescents with CF experience all of the typical stressors of their age, while coping with a chronic medical condition. Risk-taking behavior, common in the adolescent age group, can result in poor medical compliance during this period. Studies to determine the efficacy of alternating months of inhaled tobramycin solution demonstrated that adolescents had the greatest improvement in FEV₁, suggesting that this age group has the most to gain and, potentially, the most to lose by noncompliance during this period.³⁰ Developing into an independent, well-adjusted individual is often difficult in the setting of chronic illness, and the CF care team strives to guide patients and their families in this journey. Early planning for the future is critical to this process. This planning includes the following: placing appropriately high expectations on the potential for accomplishment; encouraging maximal attainable education; and having adolescents consider careers that will provide flexibility and important benefits, like health insurance, while, at the same time, acknowledging an increased uncertainty of the future.

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