Overview
Definition:
Cystic Fibrosis-Related Diabetes (CFRD) is a distinct form of diabetes mellitus occurring in individuals with cystic fibrosis (CF)
It arises from progressive pancreatic exocrine and endocrine dysfunction, leading to insulin deficiency and, to a lesser extent, insulin resistance, mimicking both type 1 and type 2 diabetes.
Epidemiology:
CFRD affects approximately 20-50% of adults with CF and about 10-20% of prepubertal children, with prevalence increasing significantly with age and CF severity
The cumulative incidence is high, with most CF patients developing CFRD by their 30s.
Clinical Significance:
CFRD significantly worsens CF outcomes, accelerating pulmonary decline, increasing respiratory infections, reducing nutritional status, and negatively impacting bone health and quality of life
Early detection and appropriate management are crucial for improving patient prognosis and reducing morbidity and mortality.
Clinical Presentation
Symptoms:
Often subtle or absent initially
May include increased thirst (polydipsia)
Frequent urination (polyuria)
Unexplained weight loss
Fatigue
Blurred vision
Increased frequency of pulmonary exacerbations
Decreased pulmonary function
Recurrent skin infections.
Signs:
Hyperglycemia on random or fasting blood glucose tests
Glycosuria
May have signs of dehydration
Evidence of CF complications (e.g., lung crackles, clubbing, poor weight gain).
Diagnostic Criteria:
Diagnosis typically follows consensus guidelines (e.g., Cystic Fibrosis Foundation consensus)
Criteria include: 1
Oral glucose tolerance test (OGTT) with 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) OR fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L) OR HbA1c ≥ 6.5% (48 mmol/mol)
2
For children, CFRD is often diagnosed with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) on an OGTT, in addition to clinical features of CF
Persistent hyperglycemia or abnormal glucose metabolism on at least two occasions is required for diagnosis.
Diagnostic Approach
History Taking:
Focus on symptoms of hyperglycemia: polydipsia, polyuria, weight loss, fatigue
Inquire about changes in pulmonary status, cough, sputum production, and frequency of respiratory infections
Assess nutritional intake and weight trends
Screen for GI symptoms and malabsorption
Family history of diabetes is relevant but not primary for CFRD.
Physical Examination:
Thorough respiratory examination for signs of lung disease
Assess nutritional status (weight, height, BMI)
Examine skin for signs of infection
Fundoscopic examination for diabetic retinopathy (less common in early CFRD).
Investigations:
Annual screening for all patients > 1 year old with CF
Recommended tests: Oral Glucose Tolerance Test (OGTT) using 1.75 g/kg body weight (max 75g glucose) with plasma glucose measurements at fasting and 2 hours
Fasting plasma glucose and HbA1c levels are also used
For patients with known CFRD, regular monitoring of glucose levels, HbA1c (every 3-6 months), and assessment for complications is crucial.
Differential Diagnosis:
Other types of diabetes (Type 1, Type 2, MODY) – less likely in a confirmed CF patient
Stress hyperglycemia due to acute illness or infection
Impaired glucose tolerance (IGT) secondary to other conditions.
Management
Initial Management:
Education of patient and family regarding CFRD, its implications, and management plan
Initiate lifestyle modifications: optimize CF care (airway clearance, nutrition), ensure adequate caloric intake, promote physical activity within limits of pulmonary status.
Medical Management:
Insulin therapy is the cornerstone of CFRD management, even with residual beta-cell function, to normalize glucose levels and improve CF outcomes
Initial therapy often involves basal-bolus insulin regimen
Basal insulin (e.g., glargine, detemir) once or twice daily
Bolus insulin (e.g., aspart, lispro) before meals
Dosing is individualized based on glucose monitoring, age, weight, and nutritional status
Typical starting dose for basal insulin: 0.1-0.2 units/kg/day
Mealtime insulin: ~50% of total daily dose
Goal HbA1c: <7.0% (<53 mmol/mol) for most children and adults, or individualized based on age and comorbidities
Consider insulin pump therapy for improved glycemic control and flexibility.
Surgical Management:
Not applicable for CFRD itself
However, CF patients may undergo lung transplantation, which requires careful perioperative glycemic management and insulin therapy adjustments.
Supportive Care:
Regular monitoring of blood glucose levels (self-monitoring of blood glucose - SMBG, continuous glucose monitoring - CGM)
Nutritional assessment and support, ensuring adequate intake to prevent weight loss and support growth
Management of pulmonary exacerbations and infections
Screening for and managing other CF complications (e.g., bone disease, liver disease)
Psychological support for patient and family.
Complications
Early Complications:
Diabetic ketoacidosis (DKA) – less common than in Type 1 diabetes due to some residual insulin secretion but can occur during severe illness or stress
Hypoglycemia due to overtreatment with insulin or inadequate food intake.
Late Complications:
Accelerated pulmonary decline
Worsening lung infections
Malnutrition and failure to thrive
Osteoporosis and fractures
Diabetic nephropathy, retinopathy, neuropathy – risk is lower than in Type 2 diabetes but increases with duration and poor glycemic control
Increased risk of other CF complications.
Prevention Strategies:
Timely and consistent screening for CFRD
Strict adherence to insulin regimen
Maintaining optimal CF care
Close monitoring of glucose levels and HbA1c
Adequate nutritional intake
Patient and family education to prevent hypoglycemia and hyperglycemia.
Prognosis
Factors Affecting Prognosis:
Severity of underlying CF lung disease
Glycemic control (HbA1c levels)
Nutritional status
Adherence to treatment
Early diagnosis and initiation of insulin therapy
Presence of other CF-related complications.
Outcomes:
With appropriate insulin therapy and optimal CF management, outcomes can be significantly improved
Insulin therapy is associated with improved pulmonary function, better weight gain, and reduced mortality in CF patients with CFRD
However, CFRD remains a significant factor contributing to morbidity and mortality.
Follow Up:
Lifelong follow-up is required
Regular visits to CF center and endocrinologist
Annual screening for complications of diabetes (retinopathy, nephropathy, neuropathy)
Bone density scans
Ongoing assessment of pulmonary function, nutritional status, and psychosocial well-being.
Key Points
Exam Focus:
CFRD is a form of diabetes due to progressive pancreatic beta-cell dysfunction in CF
Annual screening starting at age 1 year is mandatory
Insulin therapy is the treatment of choice for all CFRD patients to improve outcomes, not just glycemic control
Differentiate from IGT and IFG in CF patients
Recognize that CFRD increases the risk of pulmonary exacerbations and accelerates lung decline.
Clinical Pearls:
Consider CFRD in any CF patient with unexplained weight loss, fatigue, or increased pulmonary infections
Always start insulin in confirmed CFRD, do not delay even if oral agents are tempting
Individualize insulin doses based on age, weight, and CF phenotype
Educate families on sick day rules and hypoglycemia management
Regular communication between CF team and endocrinologist is vital.
Common Mistakes:
Delaying or omitting annual CFRD screening
Not initiating insulin therapy promptly in diagnosed CFRD
Underestimating the importance of insulin for improving CF outcomes beyond glycemic control
Inadequate education of patients/families on self-management and monitoring
Treating CFRD solely as Type 1 or Type 2 diabetes without considering its unique pathophysiology and impact on CF.