A unique type of diabetes which develops. only in patients with cystic fibrosis. significantly contributes to diabetes complications. …
Cystic Fibrosis Related Diabetes CFRD
Dana S Hardin, MD Professor of Pediatrics The Ohio State University
What is CFRD?
A unique type of diabetes which develops only in patients with cystic fibrosis It has features of both type 1 juvenile onset and type 2 adult onset diabetes It is important that people with CF realize
that their diabetes requires special treatment which may be different than treatment received by friends and relatives who have diabetes, but who do not have CF
How common is CFRD?
Diabetes is more common in patients with CF than in any other age-matched group 40 have impaired glucose tolerance 15 have frank diabetes
These numbers are under-reported In Europe, 50 have CFRD
If new guidelines for fasting glucose are used, then many more have DM than previously reported If new guidelines for fasting glucose are used, then many more have DM than previously reported for the US
Recent studies on Incidence of CFRD
Cincinnati Childrens Hospital
Study of 73 children and adolescents
154 years, followed by serial OGTT no previous CFRD diagnosis
38 with abnormal glucose tolerance
ESCF Database
DM defined as use of insulin or oral agent Analysis of 8,247
patients older than 13 years Prevalence of CFRD 143
Features of CFRD
Begins after puberty or during young adulthood Patients do not develop ketoacidosis It cannot be controlled by diet Generally does not occur in patients who have pancreatic exocrine sufficiency
Does CFRD cause any problems?
60 of CF patients without diabetes survive to age 30 Less than 25 of CF patients with diabetes survive to age 30 21 of CFRD have diabetes-related eye disease retinopathy 3 have diabetes-related kidney disease
Clinical consequences of CFRD
Thick dehydrated mucous which is difficult to clear Difficulty maintaining or gaining weight Increased infection Increased fatigue Decreased pulmonary function
Co-Morbidities of CFRD
CFRD FEV1 Height for age Weight for age BMI 554 24 289 27 283 27 205 33 Normal CF 675 26 353 29 327 28 205 34 p value 0001 0001 0001 0001
CFRD Decreases Survival More in Females than Males
Review of clinic outcomes in 1,081 CF patients
University of Minnesota 123 CFRD 58 males
Male Survival
With CFRD 474 w/o diabetes 495
Female Survival
With CFRD 407 w/o diabetes 307
Classification of Glucose Tolerance in CF
Normal glucose tolerance
Impaired glucose tolerance CF related diabetes CFRD
With fasting hyperglycemia Without fasting hyperglycemia Transient CFRD
Why 3 Classifications for CFRD?
No other disease state uses unique classifications and only the US has them This was based on the belief that patients with fasting hyperglycemia were generally symptomatic, but people without fasting hyperglycemia did not have symptoms 1998 Consensus participants did not feel there was enough research to mandate treatment for patients who have CFRD w/o fasting hyperglycemia
We Should not Have Separate Classifications for CFRD
Europeans treat patients who do not have FH the same as those with FH Evidence suggests post-prandial hyperglycemia significantly contributes to diabetes complications It is important to know that the criteria for CFRD were based on outdated values for fasting blood glucose Separate classifications may be useful for research, but not for patient care
Etiology of CFRD
First Phase Insulin Response Children Peak Insulin Response Adults
CFRD
Insulin Secretion
Insulin Deficiency
Insulin Resistance
Abnormal Substrate Metabolism
Metabolic Disorders Which Cause CFRD Affect Therapy
Insulin
deficiency leads to protein catabolism Insulin resistance affects insulin needs, postprandial hyperglycemia and protein catabolism
Post-prandial hyperglycemia must be addressed Protein needs may be high
Abnormal fat metabolism may cause excessive calorie needs and may necessitate use of other fuels, such as amino acids, for fuel at times of fast
Goals for Management of CFRD
Maintain optimal nutritional status Control hyperglycemia to reduce acute and chronic diabetes complications Avoid severe hypoglycemia Promote optimal psychological, social and emotional adaptation to living with diabetes Be as flexible as possible within the guidelines of the patients lifestyle
CFF Consensus Conference Guidelines for Medical Management of CFRD 1998
Insulin is the only treatment
Based on studies documenting efficacy of insulin No studies documenting efficacy of oral agents Concern for potential side effects of oral agents
Insulin Use in CFRD
When formulating insulin administration schedule, the patients lifestyle must be considered Multiple insulin injections per day may be required Post-meal blood sugar elevation is generally a much bigger problem than fasting blood sugar
elevation Ways to correct:
Pre-meal dose of rapid-acting insulin based on carbohydrate intake Low dose of background long-acting insulin Pre-meal PrandinTM
Insulin Treatment, cont
Some patients have hyperglycemia only during enteral feeding
Any patient with blood sugars greater than 180 mg/dl during the middle of their enteral feeding should be treated with insulin Consider duration of the feeding when choosing the insulin regimen Use of NPH and Regular is best choice
Improved FEV1 with Insulin
Arch Dis Child 87, 2000
26 Forced expiratory volume liters 24 22 2 18 16 14 12 1 08 12/12 prior 6/12 prior 3/12 prior Insulin 3/12 post Case 1 Case 2 Case 3 Case 4
Improved FVC with Insulin
Arch Dis Child 87, 2000
45 Forced vital capacity liters 4 35 3 25 2 15 1 05 0 12/12 prior 6/12 prior 3/12 prior Insulin 3/12 post Case 1 Case 2 Case 3 Case 4
Insulin and Steroids
Corticosteroids are prescribed fairly often to help reduce lung inflammation Systemic steroids greatly exacerbate underlying insulin resistance Insulin needs may double or triple during systemic steroid use The effect of inhaled steroids on blood sugar control in CF is unclear
Oral Agents as Treatment for CFRD
One study demonstrated that glipizide resulted in improvement in glucose control
No long-term improvement Evaluated in pts with and without fasting hyperglycemia
Another study demonstrated improvement in glycemic control with Rapaglinide
Only tested in patients without fasting hyperglycemia Short-term study did not address sustained effect
Recent study by Onady with Metformin and thiodolazinediones indicate further studies are needed
HbA1c Change with Metformin
16 14 HbA1c 12 10 8 6 4 2 0 
HbA1cs Change per Year HbA1ce
M5 M1/4 M3/5 M6 M4 M2
Weight Change with Metformin
90 80 HbA1c 70 60 50 40 30 Wts Change per Year Wte
M4 M2 M5 M3/5 M1/4 M6
FEV1 Change with Metformin
120 100 HbA1c 80 60 40 20 0 FEV1s Change per Year FEV1e
M1/4 M2 M4 M5 M6 M3/5
HbA1c Change with Thiazolidinedione
16 14 HbA1c 12 10 8 6 4 2 0 HbA1cs Change per Year HbA1ce
T1 T6 T3/6 T4/7 T5S4 T2
Weight Change with Thiazolidinedione
100 90 HbA1c 80 70 60 50 40 30 Wts Change per Year Wte
T1 T4/7 T6 T2 T5S4 T3/6
FEV1 Change with Thiazolidinedione
120 100 HbA1c 80 60 40 20 0 FEV1s Change per Year FEV1e
T4/7 T6 T1 T3/6 T2 T5S4
Dietary Management of CFRD
People with CF need 120 150 of the RDA for
calories when clinically well These needs increase when they are ill Management of CFRD should not include limiting food intake This includes carbohydrates
Routine Dietary Therapy of CFRD
Combines dietary management of both CF and diabetes Fats are recommended to use liberally 3540 of calories Vital to follow three meals and three snacks routine to maximize calorie intake No restriction on total carbohydrate intake Allow flexibility
CFRD vs Traditional Diabetes Meal Planning
CFRD
High calorie, fat protein Unlimited entrée snack sizes Variance of meal size with disease state and pulmonary function
Traditional Diabetes
Typically lower in fat, especially type II Set amount of CHO grams per meal snack Scheduled meals with scheduled insulin dosing
Carbohydrates and CFRD
Percent affect on blood sugar level
120 100 80 60 40 20 0 Carb Protein Fat
Do not use a Constant Carbohydrate Diet in CFRD
It is difficult to maintain necessary caloric intake with a constant carbohydrate meal plan A calorie, is a calorie, is a calorie, even if it comes from carbohydrate CF patients vary their desire for food based on how they are feeling and thus do not respond well to
constancy
Strategies for Effective Nutrition Therapy
Allow patient to eat freely throughout the day, with early education on carbohydrate counting Until the patient is able to quantitate carbohydrates, give a set dose of insulin to match their average meal at each time of day Then teach them to adjust for less intake Protein and fat have a minimal effect on postprandial blood glucose, therefore are an optimal option to increase calories
Protein and CFRD
Protein requirements currently are set as similar for age-matched normal intake People with CFRD have protein catabolism both from underling insulin deficiency and from resistance to insulins anti-catabolic effect Thus protein needs may be greater Protein supplementation alone does not reverse catabolism Studies suggest that certain amino acids become essential at times of illness
Fat intake in CF
Despite replacement with pancreatic enzymes, patients still have fat loss Fat is an excellent calorie source Current recommendation is 35 40 of caloric intake, keeping in mind the higher caloric needs
Fat needs for CFRD
No evidence for macrovascular complications thus CFF Consensus Conference did not limit fat intake
Recent publication suggests increase triglyceride levels in CF patients, thus this recommendation may need to be changed Fat slows the absorption of glucose Some good fat sources may contain some carbohydrate
Essential Fatty Acids
Essential fatty acids are polyunsaturated fats which are precursors to docosohexanoic acid DHA DHA down-regulates amino acid incorporation in phospholipid membranes Few clinical symptoms with this deficiency Essential fatty acid deficiency should be considered in patients with failure to thrive
Vitamins
Patients have increased needs for fat soluble vitamins Vitamin D 10 - 40 are deficient Vitamin A 15 - 40 are deficient Vitamin K needs increase with antibiotic therapy Vitamin E 5 - 10 are deficient -Carotene low levels in many patients
Vitamins
The best supplement for these vitamins are one - two ADEKs per day Vitamin levels should be checked annually Additional supplementation of fat soluble vitamins if levels are low Needs may increase during acute illness and antibiotics can decrease absorption
Other Nutritional Needs
CF patients require additional salt in their diet
2 to 4 meq/kg/day
Calcium supplementation is often required
Iron and Zinc often need supplementation Adequate hydration must be obtained to avoid dehydration
Require minimum of 64 oz per day Hyperglycemia results in greater needs
Enzyme therapy with all meals and snacks in pancreatic insufficient patients
Needs often increase in undiagnosed CFRD
Caloric Supplements
These are advised for many patients to aid in weight gain Supplements should be taken as needed, however, CHO grams must be counted and treated Sugar free or Diabetic supplements are an option for CFRD
Pumps in CFRD?
Many patients require more than three injections/day for optimal glucose control The pump is well suited to meet the needs for flexibility with food intake We have conducted a clinical trial in 8 patients and have demonstrated improved glycemic control and weight gain
How CFRD Affects Transplant
Having poorly controlled CFRD lowers priority for transplant Having well controlled CFRD does not affect placement on transplant list Poorly controlled CFRD negatively affects outcome of transplant Anyone contemplating a transplant should have consultation and management by a doctor wellskilled in managing CFRD
CFRD and Transplant Rejection
courtesy of Dr
Astor
25 2
Relative Risk
15 p 038 1
p 0006
153
05 0
1
118
No diabetes
Diabetes pre-transplant
Diabetes posttransplant
Hospitalization for Rejection Increase with CFRD
25 2
Relative Risk
p 00001 p 00072
15 1
156 18
05 0
1
No diabetes
Diabetes pre-transplant
Diabetes posttransplant
POST-LUNG TRANSPLANT MORBIDITY FOR ADULTS
Cumulative Prevalence in Survivors within 5 Years Post-Transplant Follow-ups: April 1994 - June 2003
Outcome Hypertension Renal Dysfunction Abnormal Creatinine 25 mg/dl Creatinine 25 mg/dl Chronic Dialysis Renal Transplant Hyperlipidemia Diabetes Bronchiolitis Obliterans Within 5 Years 864 384 213 129 34 07 454 294 344 Total number with known response N 1,196 N 1,275
N 1,315 N 1,172 N 921
Summary
The pathophysiologic changes unique to CF and CFRD necessitate CF specific medical and nutritional management Caregivers for CFRD should receive additional education about CF and CFRD CF patients contemplating transplant need excellent diabetes management
