Conference report
Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: A consensus conference report

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Introduction

Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disease of Caucasians in the USA, affecting 1/3000 live births [1]. Gene defects on the long arm of chromosome 7 lead to defective production of a protein called the cystic fibrosis transmembrane regulator (CFTR). CFTR is a cAMP-dependent chloride channel which influences the water and electrolyte composition of secretions from sweat glands, airways, pancreatic ducts, hepatobiliary ducts and intestinal glands. The common pathological finding in these organs is accumulation of thick, viscous secretions associated with progressive obstruction, scarring and destruction; 84% of CF patients die from respiratory disease [2]. Improvements in pulmonary and nutritional care over the last few decades have led to dramatic improvements in the mortality rate, and now many patients with CF live into their third, fourth or fifth decades. The median life expectancy for CF patients at present is 31.3 years [2]. As CF patients live longer, glucose intolerance and cystic fibrosis related diabetes (CFRD) are common complications.

Diabetes requiring insulin is the leading co-morbidity in approximately 21,000 CF patients reported to the National CF Patient Registry, a national database of CF patients maintained for more than 30 years [2]. Approximately 5–6% of CF patients in North America and Europe are reported to have diabetes [2], [3]. Because of the insidious nature of diabetes in CF and the lack of routine diagnostic screening, these figures may grossly underestimate the true prevalence of the full spectrum of CFRD. In Denmark, where annual oral glucose tolerance testing (OGTT) is performed, 50% of the CF population older than 30 years of age is reported to have diabetes [4]. Based on OGTT screening, one large United States CF Center found a CFRD prevalence of 9%, 26%, 35% and 43% in patients age 5–9, 10–19, 20–30 and >30 years, respectively [5] (Fig. 1).

CFRD shares features of both type 1 and type 2 diabetes, but is a distinct clinical entity. The primary cause is insulin deficiency, but glucose metabolism is strongly influenced by factors unique to CF, including undernutrition, chronic and acute infection, elevated energy expenditure, glucagon deficiency, malabsorption, abnormal intestinal transit time and liver dysfunction. These factors are not static, and glucose tolerance may fluctuate over time in CF.

Understanding the nature of CFRD is critical for patients with CF, because the additional diagnosis of diabetes is associated with greater nutritional failure, worse pulmonary disease and earlier death [6], [7], [8]. Retrospective studies have shown that pulmonary decline and weight loss begin 2–4 years before diagnosis of CFRD [6], [7], [8], and mortality is dramatically higher in CF patients with diabetes than in the general CF population. In one study of 448 patients, nearly 60% of the non-diabetes CF population was alive at age 30 years, while only 25% of patients with diabetes reached this age [6]. Recent analysis of the National CF Patient Registry data shows that the mortality rate was 6-fold greater in patients with CFRD (S. FitzSimmons, unpublished analyses, National CF Patient Registry).

The etiology of clinical deterioration in CFRD is unknown. This association may simply reflect a propensity for diabetes in the sickest of patients. The finding that insulin therapy appears to reverse negative changes in weight and lung function [7], however, suggest a cause and effect relationship between insulin deficiency and clinical decline. Muscle mass is often reduced in CF [9], [10], and many of these patients are in a state of chronic protein catabolism [11]. Insulin deficiency may promote negative protein balance, contributing to CF morbidity and mortality [11]. Furthermore, hyperglycemia may directly damage the lung since chronic abnormalities in pulmonary function have been reported in both type 1 and type 2 diabetes [12], [13].

In 1990 the Cystic Fibrosis Foundation convened the first consensus conference on diabetes in CF. At that time there were few data available to guide the conference participants. Since then, our understanding of CFRD has increased greatly. Because considerable confusion still exists over the diagnostic criteria for diabetes in CF, however, it is difficult to interpret or to generalize findings from much of the CFRD literature.

In February 1998, the CF Foundation gathered a group of individuals with expertise in CF, diabetes, and nutrition to review the scientific literature on CFRD and to accomplish the following tasks:

  • •

    Establish clear and appropriate terms to define the various states of glucose tolerance in CF as we know them today and agree on a unified nomenclature for the disease.

  • •

    Provide guidelines for screening procedures to diagnose diabetes in CF.

  • •

    Develop a protocol for the inpatient and outpatient management of CF patients with diabetes.

  • •

    Set priorities for CFRD research funding.

Whenever possible, the recommendations set forth in this document are based upon well-documented research findings. In areas where no data are yet available, suggestions represent expert opinion and consensus, and are stated as such. This document is meant to reflect our understanding of CFRD at this point in time, and will need to be updated and changed as new data become available.

Section snippets

Description and pathophysiology of CFRD

CFRD has an average age of onset of 18–21 years [3], [4], [6]. There is a slight female predominance [3], [6] and the disease may be more common in patients homozygous for the most frequent CF gene mutation, ΔF508 [3]. Patients do not have the immunological serum markers or HLA-DR profiles typical of type 1 diabetes [14], [15], [16]. A minority of CF patients do not have pancreatic exocrine insufficiency; these patients have much milder malnutrition and pulmonary disease than other patients

Diagnostic criteria for CFRD

The terms type 1 and type 2 diabetes are not appropriate to describe the patient with CFRD. The new classification scheme of the American Diabetes Association (ADA) places CFRD in the category of ‘Other specific types [of diabetes]…diseases of the exocrine pancreas’ [42]. The consensus committee recognized four glucose tolerance categories in CF, based on the results of the 1.75 g/kg (maximum 75 g) OGTT (Table 1):

  • •

    Normal glucose tolerance (NGT).

  • •

    Impaired glucose tolerance (IGT).

  • •

    CFRD without

Fasting blood glucose levels

The ADA recommends FPG as the screening test of choice for diabetes, with a value >126 mg/dl (7.0 mM) considered diagnostic [42]. Casual glucose levels are generally measured annually in CF patients as part of routine management [44]. If this level is <126 mg/dl (7.0 mM), it is unlikely that fasting hyperglycemia is present and there is no need for further work-up unless symptoms of CFRD are present (Table 3). FPG levels should be measured on all patients with casual glucose levels ≥126 mg/dl

Outpatient office management

Patients with CFRD should be seen quarterly by a medical team experienced in their management. Suggested team members include, but are not limited to, physicians, diabetes nurse educators, dietitians with experience in both diabetes and CF, and mental health professionals. The goals of treatment are:

  • 1.

    Maintain optimal nutritional status, including normal growth and development in children and adolescents, and achievement/maintenance of normal weight in adults.

  • 2.

    Control hyperglycemia to reduce acute

Nutritional management of CFRD

Nutritional therapy is an integral component of the management of both cystic fibrosis and diabetes. Malnutrition in CF is associated with stunted growth, pubertal delay, deterioration of lung function and early death. Dietary therapy in diabetes is necessary to achieve glycemic control. The challenge to CF caregivers is to combine the nutritional principles of these two diseases in such a way as to normalize growth and weight and maintain near normal blood glucose levels. Management of

Management of CFRD without fasting hyperglycemia

Because patients with CFRD without fasting hyperglycemia are at high risk for development of fasting hyperglycemia, they should be followed closely so that progression to fasting hyperglycemia, if it occurs, is detected and treated promptly. Glucose levels should be measured more frequently during acute illness. Management goals and practices for CFRD without fasting hyperglycemia, including medical nutrition therapy, exercise recommendations and screening for chronic complications, are no

Management of the CF patient with impaired glucose tolerance

Impaired glucose tolerance is found in 18–47% of CF patients who undergo oral glucose tolerance testing [5], [47]. The nutritional and metabolic consequences of this condition in CF are unknown. At present, there are no specific guidelines for management of the CF patient with impaired glucose tolerance. Because these patients are at risk for progression to diabetes [47], they should be followed carefully for development of potential clinical symptoms.

Inpatient management of CFRD

For CF patients with established diabetes on insulin therapy, it is not unusual for insulin needs to substantially increase during acute illness. Care providers must be ready to aggressively increase the insulin dose. Conversely, as the illness subsides, rapid reduction of the insulin dose to baseline levels is often necessary (usually within 2–8 weeks of the acute illness). Sometimes a dramatic increase in insulin requirements is the first sign that an illness the patient perceives as minor is

Pregnancy

Increasing numbers of women with CF are becoming pregnant each year. Early fears that pregnancy would shorten survival appear to be unfounded for most of these patients [58]. National CF Registry data demonstrate, however, that women with CF who have diabetes during pregnancy experience unusually rapid deterioration of pulmonary function in the years following pregnancy compared to non-pregnant CF controls matched for age, weight and baseline pulmonary function [58]. There are no data about

Adherence issues in adolescents and adults with CFRD

There is growing recognition that lack of adherence to treatment regimens in patients with chronic illness is an important clinical problem that can lead to unnecessary hospitalizations, increased risk for illness-related complications and increased health care costs [59], [60]. The treatment of CF presents particularly difficult challenges for patients and their families because it involves a time-consuming, complex daily medical regimen. Although there is little empirical evidence addressing

Future research directions

One of the goals of this consensus conference was to identify and prioritize areas of future research effort. Studies involving patients with CFRD without fasting hyperglycemia were seen to be the most critical. Specific issues in this group included exploring their risk for malnutrition and protein catabolism secondary to insulin deficiency, identifying whether they are at risk for microvascular disease, evaluating their prognosis compared to CF patients without diabetes or patients with CFRD

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