Pediatrics

Cystic Fibrosis–Related Diabetes

OVERVIEW: What every practitioner needs to know

Are you sure your patient has cystic fibrosis–related diabetes? What are the typical findings for this disease?

Diabetes is the most common comorbidity in people with cystic fibrosis (CF). Cystic fibrosis–related diabetes (CFRD) is found in about 15% of adolescents with cystic fibrosis, 40% of individuals in their 20s and 30s, and more than half of those older than 50 years of age. It shares features of both type 1 and type 2 diabetes, but is a distinct clinical entity.

Patients have modest insulin resistance, which waxes and wanes depending on the acute state of infection and inflammation. The primary defect, however, is insulin insufficiency, caused by fibrosis of the pancreas combined with probable genetic defects in beta cell function. Diabetes is associated with a worse prognosis in patients with CF. This is felt to be related to both the catabolic effects of insulin insufficiency and the proinflammatory effects of hyperglycemia.

With extreme hyperglycemia, polyuria and polydipsia may be present. Usually, there are no obvious symptoms, so routine screening is critical to make the diagnosis of CFRD. Screening will also identify high-risk patients with impaired glucose tolerance.

What other disease/condition shares some of these symptoms?

Type 1 and type 2 diabetes may present with polyuria and polydipsia. Unlike patients with type 1 diabetes, patients with CFRD seldom experience diabetic ketoacidosis (DKA). Patients with CF and DKA should be screened for concomitant type 1 diabetes with diabetes autoantibodies.

Unlike patients with type 2 diabetes, patients with CFRD are seldom obese. Cholesterol levels are low (although triglyceride levels may be elevated), and they do not have a risk of atherosclerotic cardiovascular disease.

What caused this disease to develop at this time?

The primary defect leading to CFRD is insulin insufficiency caused by fibrotic destruction of the islets. During baseline periods of stable health, patients with CF compensate for insulin insufficiency by being insulin sensitive. During acute illness and/or steroid treatment, they become very insulin resistant and can no longer compensate. Acute illness does not so much cause diabetes as unmask the underlying insulin insufficiency. It is not uncommon for hyperglycemia to wax and wane in CF in response to changes in inflammation and infectious status.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

All hospitalized patients with CF should have capillary blood glucose levels measured before and 2 hours postprandially for the first 48 hours of hospitalization. These are the recommendations of the 2009 CFRD Consensus Conference. After 48 hours, glucose monitoring can be discontinued if criteria for the diagnosis of CFRD are not met.

CFRD is diagnosed if fasting glucose levels greater than or equal to 126 mg/dL or postprandial levels greater than or equal to 200 mg/dL persist beyond 48 hours.

This 48 hour "waiting" period was based on the clinical observations that blood glucose levels immediately normalize in some patients when treatment for infection begins, but in those in whom hyperglycemia persists beyond 48 hours, it tends to last for weeks.

Would imaging studies be helpful? If so, which ones?

There are no useful imaging studies. The pancreas is grossly abnormal by computed tomography or magnetic resonance imaging in all patients with CF, but the images do not distinguish patients with and those without diabetes.

Confirming the diagnosis

The diagnosis of diabetes in CF is associated with increased risk of death from pulmonary disease. This is true even for patients who are otherwise completely asymptomatic. Fortunately, recent studies show that aggressive screening and insulin treatment improve prognosis in this population. CFRD is diagnosed by standard ADA criteria for all forms of diabetes.

If you are able to confirm that the patient has cystic fibrosis–related diabetes, what treatment should be initiated?

Insulin is the only recommended treatment for CFRD. Many different treatment regimens are possible, but most patients are placed on basal bolus insulin therapy, similar to that provided for patients with type 1 diabetes. Once the acute illness resolves, insulin needs decrease substantially and some patients only have illness during periods of infection.

Insulin Therapy for CFRD

Patients are generally treated with standard basal bolus insulin therapy by multiple subcutaneous injections or by insulin pump according to the following principles. They should be taught to adjust their insulin dose for special circumstances such as exercise, travel, and acute illness. Those already on insulin therapy usually require 2-4 times as much insulin during illness or steroid therapy. The dose must subsequently be reduced to baseline when the patient recovers.

Basal Insulin

Many patients with CF require a 50:50 basal:bolus insulin ratio. Some require lower amounts of basal insulin, likely because of residual endogenous insulin secretion.

Subcutaneous basal insulin is often given in the morning or at midday rather than bedtime to reduce the risk of nocturnal hypoglycemia.

Fasting glucose levels help determine if the basal insulin dose is appropriate.

CFRD without fasting hyperglycemia does not require basal insulin therapy to normalize fasting glucose levels. Whether basal insulin is beneficial for anabolic purposes is a research question.

Meal Coverage

Usual doses of rapid-acting insulin for meal coverage range from 0.5 units to about 2.0 units/15 g of carbohydrate, with the lower doses being more common when patients are in their stable baseline state of health.

If meal coverage doses greater than approximately 2.0 units/15 g of carbohydrate are needed, the basal insulin dose is probably not high enough.

If the meal coverage dose is appropriate (the insulin is matched to the carbohydrate intake), glucose levels preprandially and 2-3 hours postprandially should be about the same.

Correction Dose (“Sensitivity Factor”)

A typical starting correction dose is 1 unit of rapid-acting insulin to lower the glucose by about 50 mg/dL (2.8 mmol/L).

During a period when the patient is not eating or exercising, the correction dose can be tested and readjusted as necessary by determining how much it lowers the glucose level over a 2-3–hour period.

Overnight Continuous Drip Gastrostomy Feedings

These are “long” meals that require about 8-10 hours of insulin coverage.

A single injection of regular and NPH insulin before the feeding (with or without rapid-acting insulin as correction for the prefeeding glucose level) covers the feeding. The regular insulin covers the first half and the NPH covers the last half.

The usual starting dose is 0.5-1.0 units/15 g carbohydrate in the total feeding, divided as half regular and half NPH insulin.

Glucose levels 3-4 hours into the feeding are used to adjust the regular insulin dose and at the end of the feeding to adjust the NPH insulin.

An appendix on insulin therapy for cystic fibrosis-related diabetes is provided in Table I. (Adapted from Moran A, Brunzell C, Cohen RC, et al; CFRD Guidelines Committee. Clinical care guidelines for cystic fibrosis–related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 2010;33:2697-708.)

Table I.

Insulin Therapy for CFRD

What are the adverse effects associated with each treatment option?

The only adverse effect of insulin is hypoglycemia. Patients on insulin therapy should monitor blood glucose levels at least four times a day. Extra monitoring is required during situations that place the patient at higher risk for hypoglycemia such as increased activity. Also, patients require more insulin when they are sick than when they are well because of increased insulin resistance. A patient who is recovering from an acute illness will likely need progressive reduction in the insulin dose in the month after the illness to avoid hypoglycemia.

All patients and their families should be taught to recognize and treat hypoglycemia. Usually oral treatment with 15-30 g of carbohydrate is sufficient. However, family members should be provided with glucagon and taught how to use it for patients on basal insulin therapy.

What are the possible outcomes of cystic fibrosis–related diabetes?

The additional diagnosis of diabetes has a negative impact on survival in people with CF. However, recent studies have shown that aggressive treatment with insulin is able to reverse this phenomenon and improve nutritional status and survival from the lung disease of CF.

Patients with CFRD are also at risk for diabetes microvascular complications (retinopathy, nephropathy), but the risk appears to be lower than in other forms of diabetes.

What causes this disease and how frequent is it?

Twenty percent of adolescents and 40%-50% of adults with CF have diabetes. The primary cause is fibrotic destruction of pancreatic islets. Genes related to the development of type 2 diabetes may be more common in patients with CF and diabetes.

How do these pathogens/genes/exposures cause the disease?

Like all secretions in CF, pancreatic exocrine secretions are thick and sticky. This plugs the pancreatic ductules, leading to scarring, fibrosis, and adiposis. Genetic defects, related to the defects that cause type 2 diabetes, may further impair beta cell function in these patients with reduced islet mass.

What complications might you expect from the disease or treatment of the disease?

Over time, diabetes causes a decline in both nutritional status and pulmonary status in CF. This is believed to be primarily due to the catabolic effects of insulin insufficiency. In addition, hyperglycemia per se may help promote a proinflammatory, proinfectious environment. Microvascular complications occur in patients with long-standing CFRD, although they tend to be less frequent and less severe than in other forms of diabetes..

Are additional laboratory studies available; even some that are not widely available?

Additional studies are not useful. Of note, hemoglobin A1c levels are spuriously low in patients with CF. if they are high, they indicate the patient has been hyperglycemic, but low levels do not exclude a diagnosis of diabetes.

How can cystic fibrosis–related diabetes be prevented?

There is no known way to prevent the development of diabetes in CF.

What is the evidence?

The evidence is summarized in a recent consensus conference document sponsored by the ADA, the Cystic Fibrosis Foundation, and the Pediatric Endocrine Society (PUBMED:21115772) as well as in an accompanying technical review (PUBMED:21115770).

Patients with CF frequently first have hyperglycemia during stressors such as acute illness. Blood glucose levels may normalize when the stress is not present. In the past, this was called "intermittent CRFD." In the general population, hyperglycemia that develops during acute illness may be called "stress hyperglycemia" and the patient might not be given a diagnosis of diabetes. In CF, however, the 2009 CFRD Consensus Committee recommended that the patient be given a diagnosis of diabetes under these circumstances because of the following:

The presence of hyperglycemia during illness reveals those CF patients who have the greatest degree of insulin insufficiency.

Bouts of acute illness are frequent and patients tend to remain hyperglycemic for weeks at a time during these episodes.

Longitudinal outcome data have shown that CF morbidity and mortality are associated with CFRD first diagnosed in the setting of acute illness.

Aggressive treatment of hyperglycemia has been associated with improvements in prognosis.

Ongoing controversies regarding etiology, diagnosis, treatment

There is little controversy regarding patients with CF and diabetes. The greatest question at present is whether patients with CF and milder degrees of abnormal glucose tolerance should also receive insulin replacement therapy.

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