Cystic Fibrosis-Related Diabetes _CFRD_

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					Cystic Fibrosis-Related Diabetes
            (CFRD)

        Robert Slover, M.D.
             Keystone
               2006
 Why do we care if CF patients
       have diabetes?
They are already burdened with complex
 medical cares.

Arguably, they may not live long enough
 to develop diabetes microvascular
 complications
   CF Foundation Patients Registry:

More than 22,000 US Patients

The mortality rate is 6-fold greater in
 patients with CFRD

They are more likely to be underweight
 and to have severe pulmonary disease
 than CF patients without diabetes
Survival of Patients with Cystic Fibrosis
  Prevalence of CFRD (2003)
16.9 % of CF patients >13 in the US have
 CFRD requiring insulin therapy
  Population of 21,742 at 117 US care centers


2003 CF Foundation Patient Registry
 Annual Report
     Cystic Fibrosis Related Diabetes
           (CFRD) in the US

Most common co morbid complication
  4.4% (1992) to 12% (2002)
  (173% increase)
Prevalence increases with age
  14% of CF patient > 13 years old
  25% of CF patients 35-44 years old
Estimates have been as high as 43% of
 CF patients > 30 years
   CFRD: Not Type 1 or Type 2
 Most like type 2 diabetes, but requires
 insulin treatment like type 1 diabetes rather than diet
    and oral therapy like type 2

1. Caloric intake needs to be maintained to meet
   metabolic demands of CF
2. Oral medications used in type 2 diabetes cannot
   be used in CF
   •   Major side effect may be liver damage
   •   Sulfoylureas interfere with the chloride transporter
3. Insulin is required for CFRD
Comparison of CFRD to Types 1 and 2 Diabetes

                      Type 1   Type 2   CFRD
Most common age of
onset                 <20      >40      18-21
Usual Body Habitus
                      Normal   Obese    Thin
Insulin secretion
                      Absent
Insulin sensitivity

Autoimmune etiology
                      Yes      No       No
Ketoacidosis
                      Yes      Rare     Rare
Microvascular
complications         Yes      Yes      Yes
Macrovascular
complications         Yes      Yes      No?
        Factors Unique to CF
Under nutrition
Chronic inflammation with intermittent acute
 infection
Glucagon deficiency
Altered gut nutrient absorption and transit time
Liver disease
Increased energy expenditure
Thin, low lipid levels, normal blood pressure
  Cystic Fibrosis Related Diabetes:
         Insulin Deficiency
Autoimmune induced insulin deficiency is the cause
 of type 1 diabetes

Insulin deficiency in CFRD is due to scarring and
 destruction of the pancreatic islets and their beta
 cells
  CFRD is not associated with the autoimmune
    process and the autoantibodies seen in type 1
    diabetes
  Scarring (fibrosis) occurs due to thickened
    exocrine secretions?
            Insulin Secretion in CF


Insulin
                                                       CONT
Or                                                     CF-PS
C-Peptide                                              CF-no DM
                                                       CFRD




            CONT    CF-PS         CF-no DM      CFRD

                   (PS=pancreatic sufficient)
                          Insulin Sensitivity in CF
                   8000
                                    *
Rd AUC mg/kg/min




                   6000
                                           *
                   4000


                   2000


                     0
                            CONT    CF    CFRD
           CFRD: Caveats
DKA rare
  Poor fatty acid metabolism
Pancreatic insufficiency associated
 associated with CFRD
A1c may underestimate abnormal glucose
 metabolism
  Increased red cell turnover so A1c is
   ‘diluted’
           Survival in CFRD,
   University of Minnesota 1988-2003
Retrospective study of 1081 CF patients followed
 at the University of Minnesota over the last 25
 years.

Classified based on presence of diabetes with
 fasting hyperglycemia.

123 patients with CFRD with FH identified (58
 male, 65 female)

Mean age at diagnosis 23 +/- 9 years.
       Median Survival in CFRD
   University of Minnesota 1988-2003
  Total Cohort                     47.0 Years
  Women with Diabetes              30.7 Years
  Women without Diabetes           47.0 Years
  Men with Diabetes                47.4 Years
  Men without Diabetes             49.5 Years

* Female gender and FEV1 at time of diagnosis associated
with death by Cox proportional hazards regression
 Outcome of those with CFRD
   diagnosed in childhood
Mean Current age           19.2 yrs (12-29)
Mean Age of diagnosis      14.2 yrs (8-19)
Current A1c                 8.6 % (5.3-12)
These data suggest that diabetes control
is difficult to maintain in young adulthood
when diabetes duration exceeds 3-5 years.
This may be related to our current, more
aggressive approach to CFRD management
       Adolescent Outcome
Those with Current age <20
Mean Age                      15.2
Mean Age of diagnosis        14.0
Mean A1c                     7.2/ 6.7*%


                             *Minus A1c=12%
           Lanng data, Denmark
Weight loss and decline in pulmonary function
 began 4-6 years before the onset of diabetes.

After two years of insulin therapy, weight returned
 to levels seen six years earlier and the decline in
 pulmonary function stabilized

Suggests a cause and effect relationship between
 clinical decline and the pre-diabetic state.
           CFRD:Denver
The Children’s Hospital CF Center
  Over 500 children and young adults
    6% with CFRD (15% reported in literature,
     40% with ‘prediabetes’)
  Newborn Colorado screening program

National Jewish Hospital CF Program
  200 adults with CF
  50% with CFRD
 Outcomes in CFRD in Denver

Median age of diagnosis:   15.0 (11-40)
Mean Current age           26.1 (12-54)
Mean Duration                5.6
Mean A1c                    7.0 %
                CFRD
       Pediatrics Clinic - BDC

Total patients = 26; (12 male, 14 female)
Mean age at last visit = 16.3
Seen in past year = 16; (6 male, 10 female)
Last mean A1C (all patients) = 5.9%
Latest A1C mean (seen in past year) = 6.0%
A1C range at last visit = 4.8% - 9.3%
  How might early diabetes cause
      CF clinical decline?
Insulin Deficiency
  Insulin is an anabolic hormone which promotes
   conservation of body protein, fat and
   carbohydrate stores.

  Malnutrition and protein catabolism are
   clearly associated with death in CF.
     Metabolic Consequences
    of Insulin Deficiency in CF
Malnourished or very sick CF patients are
 severely protein catabolic.

Healthy, well-nourished CF patients have subtle
 defects in protein and fat breakdown that may
 compromise nutrition.

Increased protein and fat breakdown can be
 prevented if high enough insulin levels are
 achieved.
             Hypothesis
Insulin deficiency leads to protein
 catabolism in CF, even in the face of
 relatively normal blood glucose levels,
 and thus negatively affects morbidity and
 mortality.
Figure 2— Adverse impact of CFRD on female predicted FEV1 percentage when stratified by chronic P.
aeruginosa (PA) infection. A: Chronic P. aeruginosa–free females and males. B: Chronic P. aeruginosa–present
females and males. Box plots in the left and middle panels show median FEV1 in female and male subjects with
CFRD ( ) compared with control subjects with NGT ( ). 95% CIs are also indicated (•). Left panels show all
patients, middle panels show F508/ F508 patients, and right panels show FEV1 for age-, sex-, and center-
matched CFRD and NGT patients. Median FEV1 is indicated by black bar. The number of patients in each group
is shown on the abscissa. Sims E, Green M, Mehta A, Diabetes Care 28:1581-87, 2005.
             Survival Curves for Subjects with CF




Figure 1— Survival curves for male subjects with CF but without diabetes (green, median survival 49.5
years), male subjects with CF and diabetes (blue, median 47.4 years), female subjects with CF but
without diabetes (black, median 47.0 years), and female subjects with CF and diabetes (red, median
survival 30.7 years). Milla CE, Billings J and Moran A. Diabetes Care 28:2141-2144, 2005
 Gender difference in survival
         with CFRD
Males without CFRD – 49.5 years
Males with CFRD – 47.4 years

Females without CFRD – 47.0 years
Females with CFRD – 30.7 years

  *Milla, C. et al. Diabetes Care 28:2141, 2005
   CFRD is Associated with decreased
  pulmonary function in females but not
                 males

Female patients with CFRD but without
 chronic P. aeruginosa infections had
 20% worse percent predicted FEV1

Male patients with CFRD did not have a
 similar reduction in FEV1.
    Genotype is predictive of
       Pancreatic status
Delta F508 homozygous genotype is
 associated with pancreatic insufficiency
 in nearly all patients.

This genotype is also at higher risk for
 CFRD
   Pulmonary Function in CFRD
1. Prevalence of CFRD is higher in patients with
 more severe pulmonary disease.

2. CFRD population has worse pulmonary funtion
   FEV1 55.4% versus 67.5% age adjusted (P<0.001)


3. More pulmonary exacerbations treated with
 parental antibiotics.

4. Higher prevalence of pseudomonas, Burkhdderia
 cepacia, Candida, and Aspergillus.
  Nutritional Status of patients
           with CFRD
1. Lower mean height-for-age percentile
2. Lower mean weight-for-age percentile
3. Lower BMI
     Epidemiology of CFRD

Marshal et al. Journal of Pediatrics
 146:681, May 2005

Data gathered from 8247 patients in the
 Epidemiologic Study of Cystic Fibrosis
Gender and Age Distribution of
           CFRD
Males: 54.4 % of CF population
  12% with CFRD
Females: 45.6% of CF population
  17.1% with CFRD
Mean age of CFRD group 25.9 (8.9)
 years
Mean age of non-CFRD group 22.5 (8.5)
 years
Summary of the epidemiologic date
    in patients with CFRD
1. CFRD is associated with increased age,
 female gender, pancreatic insufficiency, and
 delta F508 genotype.

2. There is a striking correlation between
 CFRD and worsened clinical status, with
 poorer pulmonary function, increased acute
 pulmonary illnesses, increased prevalence of
 important sputum pathogens, poorer nutritional
 stats, and a higher prevalence of liver disease.
    Complications of CFRD
      (poorly controlled)
Infections due to decreased WBC
 phagocytosis
Increased viscosity of mucous secretions
 with hyperglycemia and dehydration
Increased protein catabolism with CF and
 with DM
Increased fatigue with poorly controlled
 DM
      Medical interventions and comorbid
        medical conditions in CFRD
Therapy        CFRD Group   Non-CFRD       Age-Adjusted p
               (n=7067)     group (n=1180) value

Pulmozyme      57.6%        49.8%          <.001
(dornase)
Airway         90.7%        84.3%          <.001
Clearance
Mast Cell      20.3%        17.5%          <.001
Stabilizer
BD (oral)      21.5%        13.7%          <.001
BD (Inhaled)   91.5%        84.3%          <.001
NSAID          10.6%        9.6%           .206
                           (table cont.)

Therapy           CFRD Group   Non-CFRD         Age-Adjusted p
                  (n=7067)     group (n=1180)   value
Oral supplement   40.5%        32.7%            <.001
Enteral           11.7%        7.7%             <.001
Supplements
Parental          2.4%         0.9%             <.001
supplements
Steroids(oral)    27.6%        17.9%            <.001
Steroids          48.9%        39.6%            <.001
(Inhaled)
Contraceptives    12.7%        7.0%             <.001
Oxygen            24.2%        9.7%             <.001
Diuretic          5.5%         1.0%             <.001
     Long term side effects of
             CFRD
Decreased life expectancy from pulmonary
 complications
  without diabetes, 60% live to 30 years
  25% with diabetes survive to age 30
Also subject to the microvasular
 complications of diabetes hyperglycemia
  Retinopathy, nephropathy, gastroparesis
     Current Goals of Therapy
Determine if near-normalization of blood
 glucose will prevent the deterioration of
 lung function associated with onset of
 CFRD
Maintain nutrition and weight with
 attention to appetite, and post-prandial
 glucose as well as fasting glucose
Avoidance of diabetes and CFRD
 complications
      Glucose Tolerance in CF

280
240
200                            CFRD with FH
160                            CFRD without FH
                               IGT
120
                               NGT
80
40
 0
      0   30   60   90   120
  Evaluation for Diabetes in CF
Annual random glucose beginning at age 10
 If the random glucose is > 125
     Obtain oral glucose tolerance test
At all admissions for illness, check random
 glucose
Diabetes
  Fasting glucose > 125
  2 hour glucose > 200
    CFRD – who should have an
            OGTT?
Patients unable to gain or maintain appropriate
 weight, despite optimal nutrition.
Patients with a poor growth rate
Patients with delayed puberty
Patients with declining pulmonary function
 studies
Patients whose fasting glucose level exceeds
 125
All women planning pregnancy or pregnant.
Oral Glucose Tolerance Categories
        in Cystic Fibrosis
  Category                            FBG                2-h PG
                                     mg/dl (mM)         mg/dl (mM)

Normal Glucose Tolerance (NGT)          <126 (7.0)          <140 (7.8)


Impaired Glucose Tolerance             <126 (7.0)       140-199 (7.8-11.1)


CFRD Without Fasting Hyperglycemia    <126 (7.0)           ≥200 (11.1)


CFRD With Fasting Hyperglycemia        ≥126 (7.0)      OGTT not necessary



The OGTT is performed by giving a 1.75 gr/kg body weight (max 75 gr)
oral glucose load to fasting patients. FBG and 2-h PG are measured.
Criteria for the Diagnosis of CFRD

 2-h PG ≥ 200 mg/dl (11.0 mM) during a 75 gram OGTT.

 FBG ≥ 126 mg/dl (7.0 mM) on two or more occasions.

 FBG ≥ 126 mg/dl (7.0 mM) plus casual glucose level >
  200mg/dl (11.1 mM).

 Casual glucose levels ≥ 200 mg/dl (11.1 mM) on two or
  more occasions with symptoms.
Glucose Tolerance Prevalence
  3%
   |
          ---6%     11%
                              15%       16%
                   15%
                              20%
 34%                                    27%
                                               CFRD-FH
                   38%                         CFRD-no FH
                              38%       27%    IGT
                                               NGT
 57%

                   36%                  30%
                              23%


 5 to 9           10 to 19   20 to 29   30 +
   Practical Aspects of diabetes
      management in CFRD
 Patients should be cared for by multidisciplinary teams
 A dedicated nurse specialist and interested physician
  are preferred to review in general DM clinic
 Aim for optimal nutritional status with weight
  maintenance
 Diet is largely unrestricted, with insulin adjusted
  accordingly
 Insulin regimens should be tailored to suit patient’s
  eating pattern and lifestyle
      Practical Aspects of diabetes
     management in CFRD (cont.)
 Basal/bolus regimens are acceptable, though some
  individuals require only meal-time injections
 Intermittent insulin therapy may be necessary during
  steroid administration, enteral feeding and infection
 Insulin infusion may be required with enteral feeding
  regimens
 Subjects with CFRD should receive annual screening
  for microvascular complications
       Team Care of CFRD
Diabetic glucose tolerance test
 Referred to diabetes team
    Physician
    Dietitian
    Diabetes nurse - liaison with the
               diabetes team
    Medical social worker
  Ways in Which CFRD Medical Nutrition
  Therapy Differs from that of Type 1 and
             Type 2 Diabetes
 High energy intake is necessary for survival – caloric restriction is
  never an appropriate means of glycemic control.

 High fat intake is recommended (40% of total calories) to provide
  increased calories and because macrovascular disease does not
  appear to be a concern.

 Protein reduction may not be appropriate in diabetic nephropathy
  because of the potential for malnutrition.

 Frequent intercurrent illness necessitates constant adjustment of
  the meal plan.
Principles of Dietary treatment in
   CFRD compared with DM
Nutrient       NON-CFRD                   CFRD
Energy         100% of RDA or less if     120-150% RDA
               overweight
Fat            30% of Energy (with        30-40% of energy (no
               restriction of sat. fats   restriction on type of fats.)
Carbohydrate Promotion of complex         Promotion of complex
               carbohydrates spread       carbohydrate
               evenly throughout the
               day (low glycaemic
               index foods).


            RDA, Recommended daily allowance
 Principles of Dietary treatment in CFRD
        compared with DM (cont.)
Refined CHO      Restriction to   Allowed liberally
                 < 25 g/day       throughout the day(although
                                  avoid sugary drinks between
                                  meals)

Fiber            Soluble and      Not encouraged as may
                 insoluble        increase satiety and so
                 encouraged       decrease energy intake

Salt             Low intake       Increased intake



   CHO, carbohydrate
             Conclusion
Aggressive glucose management in patients
 with CFRD results in dramatically
 improved quality of life and life span,
 especially in females.

YOU can make a difference!

               Thank You!

				
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