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Cystic fibrosis-related diabetes needs novel approach.


SAN DIEGO -- Cystic fibrosis--related diabetes is a unique disease, and it requires a different mindset on the part of the treating physician.

"The risk of cardiovascular death drives a lot of the recommendations for management of our patients with type 1 and type 2 diabetes, but this doesn't apply in cystic fibrosis. Patients with cystic fibrosis-related diabetes do not appear to get macrovascular complications. These patients have other, more important concerns--namely, survival. They die from their CF lung disease. Diabetes is important, but we have to remember that in CF, lung function and nutrition come first. It's our job to work around that," Dr. Antoinette Moran asserted at the annual meeting of the Pediatric Academic Societies.

Diabetes is the most common comorbidity associated with CF. And it spells big trouble. It's associated with pancreatic insufficiency, liver dysfunction, requirement for corticosteroids, and prognostically with under nutrition, worse pulmonary function, and early death, noted Dr. Moran, professor of pediatrics and chief of the division of pediatric endocrinology and diabetes at the University of Minnesota, Minneapolis.

The prevalence of cystic fibrosis--related diabetes (CFRD) is age related. It's rare in children, but the prevalence climbs to about 15% in adolescents, 40% in 20- to 39-year-olds, and 55% after age 40.

"In fact, more than 80% of CF patients with the most severe mutations have diabetes by the time they're 40," according to Dr. Moran, who was lead author of CFRD management guidelines released last year by the International Society for Pediatric and Adolescent Diabetes (Pediatr. Diabetes 2014 Sep;15 Suppl 20:65-76).

CFRD is not an autoimmune disease. Ketones are rare. Glycosylated hemoglobin levels are spuriously low. And the definitive treatment for CFRD is insulin.

"Remember, you're not just treating hyperglycemia, you're treating insulin deficiency. Insulin deficiency is really the hallmark of this disease. It is progressive and eventually severe, but not complete - unlike in type 1 diabetes," she observed. "Treatment of patients in their well state is similar to treating type 1 diabetes in the honeymoon phase.

However, during acute illness patients become extremely insulin resistant. It's a black hole that you can pour insulin into, and sometimes you can't get them to budge. Then a couple of months later they're insulin sensitive again."

Multiple studies have demonstrated that diabetes has a negative impact upon survival in patients with CF. Both hyperglycemia and insulin insufficiency have negative impacts on the CF lung disease.

Insulin is a potent anabolic hormone that's necessary for maintenance of body weight and lean body mass, and insulin insufficiency leads to a catabolic state that accelerates pulmonary decline in CF. Studies show that nutritional status and pulmonary function start to decline in CF patients several years before they're diagnosed with diabetes. Thus, by the time CFRD is diagnosed, patients have already experienced several years of insulin insufficiency, with adverse consequences.

Moreover, when blood glucose levels exceed 144 mg/dL, glucose appears in the airways of CF patients. That's not good. It probably promotes pulmonary infection. Anecdotal evidence suggests hyperglycemia makes sputum thicker and more difficult to clear as well as boosting bacterial growth. And continuous glucose monitoring studies conducted in patients with CFRD indicate they spend roughly half of each day with a blood glucose in excess of 144 mg/dL.

Aggressive screening and early initiation of insulin therapy help reverse chronic weight loss and reduce mortality in patients with CFRD. The various guidelines recommend annual screening for diabetes in CF patients starting by age 10.

"I personally believe it should begin much earlier than that," Dr. Moran said, citing a study led by her colleague Dr. Katie Larson Ode, a pediatric diabetologist at the University of Iowa, Iowa City, that showed that abnormal glucose tolerance was already present in 41% of children with CF at ages 6-9, and that those children had a high rate of early-onset CFRD (Pediatr. Diabetes 2010 Nov; 11:487-92).

The oral glucose tolerance test, performed when the patient is clinically stable, is the screening tool of choice for CFRD.

"It's not that it's such a great test--we all know it has problems--but the other tests perform poorly in CF. And a diagnosis based upon an oral glucose tolerance test correlates with prognosis and future outcomes, so you get meaningful data when you do it," she explained.

Evidence-based guidelines for CFRD put forth jointly by the American Diabetes Association, Cystic Fibrosis Foundation, and Lawson Wilkins Pediatric Endocrinology Society (Diabetes Care 2010;33:2697-2708) emphasize that, unlike in patients without CF, the diagnosis of CFRD can be made while a patient is hospitalized with an acute illness. The criterion is fasting or postprandial hyperglycemia persisting for more than 48 hours after hospitalization.

"Why are we calling this diabetes? These patients have repeated bouts of acute illness. The CF patient you're seeing today in the hospital may very well be back in 5 months, and again 2 months after that. It's a frequent event in these patients, and when their diabetes persists for longer than 48 hours it tends to persist for weeks before their need for insulin goes away until the next time they get sick. But most of these patients spend a substantial amount of time each year hyperglycemic. And most importantly, if you use as your date of diagnosis diabetes that's present at the time of an acute illness, it correlates with microvascular complications and with mortality. So it establishes a meaningful start point for future risk," Dr. Moran said.

She reported financial relationships with Novo Nordisk and Vertex.


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Title Annotation:CLINICAL ROUNDS
Author:Jancin, Bruce
Publication:Pediatric News
Date:Jun 1, 2015
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