Cystic Fibrosis Genetic disorder Exocrine pancreas dysfunction Autosomal recessive inheritance Several identified genes Presentation Newborn screening Failure to thrive in infancy Chronic pulmonary disease in older individuals
Cystic Fibrosis Treatment Nutritional support High caloric diet- carbohydrate and protein Exocrine pancreatic enzymes Pulmonary toilet Monitor and aggressively treat pulmonary infection Course Failure to thrive/ poor growth Progressive pulmonary disease Diabetes Early death due to pulmonary disease Genetic testing has demonstrated significant variability in presentation and course
History of CF 1980s Children and Teens died of respiratory failure Diabetes was a pre-morbid event 1990s Aggressive nutritional support Extended lifespan Increased incidence of diabetes <25% of patients with CFRD reach age of 30 years vs 60% of those without 2000s Increased life span, Average life expectancy 37.4 yrs Impact of diabetes?
Incidence of CFRD CFRD increases with age 2% children 19% adolescents 40-50% adults Normal OGTT (standard definition) 60% children 30% of adults 20-40 years 20% of adults > 40 years
CFRD – Etiology Originally hypothesized to be due to fibrosis and destruction of islet cells in pancreas Autopsy data demonstrated that CF patients with AND without diabetes had the same islet cell mass Family history of type 2 diabetes increases the risk of CFRD Genetic predisposition towards type 2 diabetes?
Impact of Diabetes in CF Insulin deficiency Catabolic state- malnutrition Until recently focus has been here Hyperglycemia Airway glucose concentrations increased Immune function Long term complications Microvascular disease in CFRD is less common and less severe in CF Not described in CF patients without fasting hyperglycemia
Impact of Diabetes on CF patients CF patients die of pulmonary disease rather than atherosclerotic cardiac disease Insulin deficiency Poor nutrition is linked to decline in pulmonary function Insulin is anabolic involved in conservation of lean body mass and weight Patients with IGT (on OGTT) have more rapid decline in pulmonary function than NGT CFRD without fasting hyperglycemia is bad prognostic indicator
Definition of CFRD Same as the ADA definition Oral glucose tolerance test Glucose load is low compared to normal intake Random glucose over 200mg/dl and symptoms Overnight tube feedings may make it hard to see symptoms Is this the best or right definition for CF?
CFRD- how to define it? “Normal glucose tolerance” on OGTT Increased 30, 60, and 90 minute glucoses Increase area under the curve glucose CGMS Mean glucose levels higher in CF (106 vs 92 mg/dl) 33% of CF patients had a glucose >200 mg/dl (vs 5% of control patients) / day
Risk of Diabetes in CF Family history of type 2 diabetes increases risk to CF patients OR- 3.1 (p = 0.009) Sibling-twin data from a study on type 2 diabetes demonstrated genetic component Concordance rate for monozygotic twins higher than dizygotic twins or sib pairs (p=0.002) Genetic variant associated with Type 2 commonly found in CFRD Presence associated with earlier age of diagnosis of diabetes TCF7L2 = transcriprtion factor 7-like 2
Etiology of CFRD Originally thought to be due to purely mechanical issues Destruction of pancreas, loss of ß cell mass Autopsy data demonstrated essentially equivalent mass in non-diabetic CF and diabetic CF patients Autopsy data demonstrated amyloid deposits similar to that seen in type 2 DM patients but not in type 1 nor in pancreatitis patients
Hyperglycemia in CF OGTT demonstrates glucose “area under the curve” is higher in non-diabetic CF patients than controls matched for for age and BMI Higher 30, 60 and 90 minute glucose levels CGMS demonstrates CF patients with normal OGTT have “diabetic” glucose values in normal life Average glucose higher (106 vs 92 mg/dl) 33% of CF patients had one or more glucose over 200 mg/dl vs 5% of controls Hgb A1C and OGTT may underestimate glucose abnormalities in CF patients
Hyperglycemia in CF Blood glucose over 144 mg/dl associated with increased airway glucose levels CGMS demonstrates levels higher than this 50% of the time in CFRD, 6% of the time in CF with normal GT, and 1% of the time in controls Staph aureus and Pseudomonas growth was accelerated when cultured in a similar glucose environment Potential impact: increased bacterial growth, increased glycation products, increased inflammatory process, decrased immune function
CFRD Increases with age 2% of children, 50% of adults At younger ages, more individuals have normal fasting glucose (CFRD FH-) Mortality is decreasing (1992-7 vs 2003-8) Pre-screening, mortality was 20% within 5 years of diagnosis, now 3% Lung function continues to be worse in CFRD patients
When to Treat CFRD Macrovascular complications really aren’t seen in CF Microvascular complications are seen in CFRD FH+ What about CFRD FH- Multicenter trial of CFRD FH-, IGT Oral replaglinide, pre-meal insulin aspart, oral placebo End point BMI Pre-treatment BMI decreased in all groups, reversed in insulin group only No difference in pulmonary function over 1 year but study time frame is likely too short to see difference
Diagnosis and Treatment Oral glucose tolerance test End point Area under the curve? CFRD FH+ Basal-bolus insulin similar to type 1 DM Consider Insulin pump CFRD FH- Watch BMI trajectory Consider pre-meal bolus insulin
Summary CFRD is a significant contributor to burden of disease in CF Increased illness, earlier death CFRD may look more like type 2 diabetes than type 1 and may have identifiable risk factors Appropriate diagnosis and timing of intervention is a work in progress Therapy is classic basal-bolus insulin