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Waugh N, Royle P, Craigie I, et al. Screening for Cystic Fibrosis-Related Diabetes: A Systematic Review. Southampton (UK): NIHR Journals Library; 2012 May. (Health Technology Assessment, No. 16.24.)

1Introduction

Cystic fibrosis

Cystic fibrosis (CF) is a disease that was first described in 1936 by Guido Fanconi.1 It is an autosomal recessive disease that can present at any age, but is more commonly diagnosed in early childhood.2,3 Screening for CF is offered to all babies in Scotland, England, Wales and Northern Ireland. A systematic population antenatal screening is not recommended in the UK but this is currently under review.4

The defective gene causes faulty transport of sodium chloride in the body, leading to thick viscous secretions, mainly affecting the lungs and the digestive system.5 CF affects the lungs, pancreas, liver and intestines, and the process involved eventually leads to multisystem organ failure. According to the Cystic Fibrosis Trust, there are over 8500 people in the UK with CF, the severity of which varies from person to person and changes throughout their life.6 For example, a person with CF may initially have a good quality of life (QoL), where little physiotherapy is required and they are able to play sports, but then recurrent chest infections can lead to deterioration in respiratory function.

There have been major advances in management of, and outcomes from, CF over recent decades. Littlewood has provided a valuable history of the disease, noting that in the course of a professional lifetime, CF has changed from being regarded as almost always fatal in early childhood to a disease in which the aim now is ‘striving to maintain the affected person in the best possible condition to reach adulthood with minimal respiratory and nutritional damage’ (J Littlewood, Cystic Fibrosis Trust, 2010, personal communication; comment was previously in a historical account on the Cystic Fibrosis Trust website).

Epidemiology

The prevalence and distribution of the gene varies among ethnic groups,5 with Caucasians having a higher probability of carrying the abnormal gene.7 Table 1 shows the incidence of CF in various populations.

TABLE 1. Incidence of CF in different populations.

TABLE 1

Incidence of CF in different populations.

The incidence in the Caucasian population is approximately 1 : 2500–4000,5 with a carrier frequency of 1 in 25 live births.7 Ashkenazi Jews and non-Hispanic Caucasians also have a carrier rate of 1 in 25 live births, which is higher than the carrier rate in other ethnic groups;11 Hispanic Americans have a carrier rate of approximately 1 in 46, African Americans have a carrier rate of 1 in 62, and for Asian Americans the carrier rate is 1 in 90.11 There are quite large variations in incidence within Europe, ranging from a high of 1 in 1353 births in Ireland to 1 in 25,000 in Finland.12

Within countries, there are sometimes populations or areas of much higher incidence, such as:13

  • North Brittany – 1 in 377 births
  • The Amish in the USA – 1 in 569 births
  • Saguenay–Lac-Saint-Jean, Quebec – 1 in 902 births.

The incidence rate in the UK is 1 in 2500 live births.8

Genetics

A gene defect occurs on chromosome 7, which affects the production of a protein called cystic fibrosis transmembrane conductance regulator (CFTR). This dysfunctional chloride channel affects the water and electrolyte composition of secretions from various places including the pancreatic ducts and airways. This leads to an accumulation of thick viscous secretions7 and eventually destruction of the affected organs.8

Many genes can cause CF. They are grouped into five classes, as follows:14

  • class I defective protein production; few or no functioning CFTR chloride channels
  • class II defective processing, so that CFTR does not reach the surface membrane where it normally functions
  • class III defective regulation, but it does reach its site of action
  • class IV defective conductance – CFTR is in the right place, but the channel fails to conduct properly
  • class V reduced amounts of functional CTFR protein.

The less functioning CFTR there is, the more severe the phenotype. Classes I–III are associated with more severe disease and higher mortality. Class II is by far the most common type in the UK.

The commonest mutation is delta F508 (ΔF508). There are international variations in the frequency of mutations which can affect the severity of CF and the prevalence of cystic fibrosis-related diabetes (CFRD). For example, in the Netherlands, the second commonest mutation is A445E, which is associated with milder disease.3

There are over 1000 relevant mutations, some of which cause mild disease.

Pathology

The build-up of viscous secretions in the lungs means that patients are prone to repeated infections by organisms such as Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa.5 Owing to the stasis of the secretions, bacterial clearance is reduced and inflammatory lung damage ensues.5 Once severe lung disease is established, lung transplantation is required and if this cannot be carried out, respiratory failure occurs, which eventually leads to death.

The effect on the pancreas causes deficiency of digestive enzymes, leading to malabsorption of undigested foods and undernutrition. Although the primary defect is of exocrine secretion, the islet cells that are initially preserved may become damaged with time, thereby leading to a decrease in insulin and glucagon secretion. Other recognised problems include hepatic cirrhosis and infertility in males.

Management

Management is complex and includes daily bronchial drainage by physiotherapy, nebulised bronchodilators and mucolytics, chronic suppressive antibiotics if infected, anti-inflammatory therapy, nutritional support (such as pancreatic enzymes and vitamin supplements), and frequent monitoring of pulmonary function and microbial carriage.15

Treatment imposes a significant burden on most people with CF. This burden may include getting up at 6.30 am every day so that physiotherapy can be carried out before going to school, ingesting enzymes after consuming any amount of food (e.g. a biscuit), and more physiotherapy in the evenings before going to bed.6 Treatment is generally tailored to the individual but the constant ingestion of medication and the rigid treatment schedule removes the spontaneity and pleasure of life in general.

The burden has been quantified by Sawicki et al.16 in the Project on Adult Care in CF (PAC-CF) carried out in 10 centres in the USA. The median number of daily therapies was seven, and an average of 108 minutes a day was spent on treatment. Common medications were pancreatic enzymes (taken by 85%), β-agonist bronchodilators (65%), anti-reflex agents (50%), DNase (49%) and azithromycin (47%). Ninety-three per cent were on at least one nebulised medication.

Prognosis

In 1938, Andersen17 was the first person to give a comprehensive description of CF. Over 70% of the 49 patients examined in her study died before their first birthday. In the mid-1950s, few children with CF would live to attend elementary school.18 Dodge et al.19 reported that over the period 1947–2003, the average per cent surviving by age were 97% to age 10 years, 90% to age 20 year, 63% to age 30 years and 45% to age 40 years.

However, median survival has been steadily improving. In the UK, median survival was 38.8 years in 2008;20 43.8% of those on the register were aged 20 years or over. In the USA, the median predicted survival in 2007 was 37.4 years.18 One feature associated with this is the improvement in lung function, with the proportion of 18-year-olds with good lung function [forced expiratory volume in 1 second (FEV1) > 70% predicted] increasing from around 32% in 1985 to near 70% in 2008.18 Most people with CF die of lung disease.

The improvement has not applied at all ages. Kulich et al.,21 using US Cystic Fibrosis Foundation Patient Registry data on 31,012 patients with 5234 deaths from 1985 to 1999 (17% of the cohort), reported that mortality had fallen by 61% in the age range 2–5 years, by 70% in the range 6–10 years and by 45% in the range 11–15 years.21 Females had poorer survival. There was little improvement in the over-20s but, as the authors note, this may have been because some who would have died before reaching 20 years were now surviving past it, but not for very long. In the UK, Lewis et al.22 also noted an increase in survival only up to the age of 20 years.

In the UK, Dodge et al.23 reported that CF was no longer an important cause of death in children. With better treatment now available, it is estimated that a child born with CF in 2000 would live to approximately 50 years of age.19

As a result, an increasing proportion of people with CF are adults. In the USA in 1990, about 30% of the patients in the US Cystic Fibrosis Foundation Patient Registry were 18 years or older; in 2008, that figure had reached 46%.18 One consequence of this is that many women with CF are living to have children of their own. A UK survey by Edenborough et al.24 reported 48 live births from 72 pregnancies, with almost half of the births being premature. However, a French study reported 64 live births from 75 pregnancies, with only 18% being premature.25 Gestational diabetes is common, with McMullen et al.26 reporting a baseline diabetes prevalence of 9%, rising to 21% during pregnancy, in a group of women whose age ranged from 15 to 38 years (median 24 years). McMullen et al.26 did note that the high prevalence seen in pregnancy might reflect the more thorough screening during pregnancy.

In the UK, the 2008 Cystic Fibrosis Trust Annual Data Report, using a slightly different age breakdown, showed that 43.8% of people with CF were aged 20 years or over.20 In Canada, similar improvements have been reported, with (rounded) median survival being 24 years in 1982, and 29, 34, 33 and 37 years in 1987, 1992, 1997 and 2002, respectively, reaching 48 years in 2007.27

The severity of CF can be assessed by the Shwachman clinical score (SS), which allocates points for general activity, physical examination, nutritional status and radiographic findings with a score out of 100, with severe disease having a score of < 40.28

Most deaths are due to lung damage.29

Cystic fibrosis-related diabetes

Diabetes mellitus was first described as a complication of CF in 1955.30 The incidence of diabetes is related to the duration of CF, and with the significantly improved survival into adulthood, more patients are living long enough to develop diabetes. Thus, a higher proportion of patients with CF will develop diabetes than would have done in the past.

Epidemiology

The prevalence of CFRD increases with age and occurs in up to 40% of patients with CF by the fourth decade of life.31 The risk factors for developing CFRD are increasing age, genetic factors, pancreatic insufficiency, pulmonary infections, corticosteroid therapy and supplemental nutrition.1 The median age at onset of CFRD is 20 years, and females tend to develop this disease at a younger age than their male counterparts.1

In one study of 448 patients with CF, the median age at onset of CFRD was reported as approximately 20 years (18.7 years for females and 21 years for males).32 The prevalence of CFRD has been variably reported and increases with age owing to the natural progression of impaired glucose metabolism. Lanng et al.33 reported a CFRD prevalence of 1%, 30%, and 75% in those under 10, at 20 and at 30 years of age, respectively.33 In a recent UK-based prospective study, Adler et al.34 reported the incidence of CFRD as 3.4% per year. The definition of diabetes that was used included physician diagnosis, a 2-hour post glucose load blood glucose (BG) concentration of > 11.1 mmol/l or treatment with insulin or oral hypoglycaemic agents (OHAs).

Rosenecker et al.35 reported that CFRD was more common in females, with, for example, prevalence in the age range of 21–25 years being 6% in males and 17% in females.

Although the aetiology of this is unknown, it may be due to the earlier onset of puberty in girls.7 There is also a greater prevalence of CFRD in females.36 Figure 1 shows the prevalence of CFRD and impaired glucose tolerance (IGT) for both sexes in various age groups.37 Here, it can be seen that in the over-30s, > 40% have diabetes and nearly 30% have IGT.

FIGURE 1. Cystic fibrosis-related diabetes prevalence.

FIGURE 1

Cystic fibrosis-related diabetes prevalence. Redrawn from Moran et al. (1998).

The UK Cystic Fibrosis database7 reported that 39% of those > 10 years and who had been tested were diabetic. For the over-30-year-olds it was 59%; 47% of the over-10s had not been tested. In the 15-year-olds, 9% had diabetes and another 8% were classed as glucose intolerant.

The Cystic Fibrosis Foundation (CFF) 2008 annual data report18 showed that in the USA the prevalence of CFRD reached a plateau in the 35- to 44-year age range, with about 32% having CFRD. This may imply that screening for diabetes could stop after the age of 40 years, because those who are going to develop diabetes will have done so by then.

A more recent update from the USA from Moran et al.,38 based on the Minnesota data, reported that CFRD was present in 2% of children (< 10 years), 19% of adolescents (11–17 years) and 40–50% of adults. The younger patients tended to have CFRD without fasting hyperglycaemia (FH), but with age the proportion with FH rose to about half in the 30–39 years age group and about two-thirds in the over-40s (estimated from graph). A higher proportion of women than men in the 30–39 years' age range had CFRD: about 60% versus 40%.

In Australia, Rana39 reported that the incidence of reported CFRD in the under-18-year age group had risen from 0.6 per 106 in 2000 to 6.7 per 106 in 2008, although this may be due to better detection, as 53% were diagnosed by oral glucose tolerance test (OGTT) in 2007–8 compared with 5% in earlier years.

Mackie et al.1 stated that in the UK the prevalence of CFRD has risen from 3–10% in 1969 to 14–30% in the early 1990s, based on differing screening methods.

Droumaguet et al.40 in Paris reported a prevalence of 36% among 243 adults with CF, but their cohort was somewhat unusual in having a mean age at diagnosis of CF of 21.5 years. The mean age at onset of CFRD was 27 years (range 18–60 years).

In Denmark, Lanng et al.33 demonstrated a prevalence of 24% for all ages, rising to 34% in those aged 10 years and above. In the USA, Moran et al. (2009)38 reported an overall prevalence of 33%, with the highest prevalence of just under 50% in the 30- to 39-year age group (from graph, figure 1a).

In Canada, only 21% had developed CFRD by age of 35 years and over and the prevalence had reached a plateau after the age of 25 years.27

Table 2 shows the prevalence of CFRD at different age groups in various different countries.

TABLE 2. Prevalence of CFRD at different ages in different countries.

TABLE 2

Prevalence of CFRD at different ages in different countries.

Genetics

The risk of CFRD varies among the five classes of CF Unfortunately, the risk is highest in the commonest classes, II and III, with 22% of these adults being diabetic, compared with < 2% in classes IV and V.14 In the UK, Adler et al.,42 using UK CF Registry data on a large cohort, found that the incidence of CFRD was 3.5% a year, and was highest in those with CFTR class I and II mutations. About 80% of UK patients have class II mutations.

The ΔF508 mutation appears to increase the risk of CFRD, whereas the N1303K mutation may reduce the risk.43,44 In populations with low prevalence of ΔF508, such as in Brazil, CFRD is less common.45

There appears to be a small subgroup with adult onset and a milder form of CF, with a low prevalence of CFRD. Gilljam et al.46 in Toronto reported 7% of their adult patients to be in this group.46

The risk of CFRD may be increased if there is a family history of type 2 diabetes mellitus (T2DM), possibly because a gene linked to T2DM increases the risk and lowers the age of onset of CFRD.47

Pathology

Endocrine function

In CF, the abnormal function of CFTR leads to the production of viscous secretions and this causes obstructive damage to the pancreas.7 Fibrosis and fatty infiltration of the pancreatic exocrine glands occur and disrupt the islet architecture. Many, but not all, of the islet cells are destroyed and this leads to a progressive loss of endocrine cells,7,15 the main cause of CFRD.48 Whole islets are destroyed, unlike the β-cell-specific obliteration seen in type 1 diabetes mellitus (T1DM),49 leading to the damage of α-cells, β-cells and pancreatic polypeptide-producing cells. This leads to a reduction in glucagon, insulin and pancreatic polypeptide secretions, respectively.7 By the time of diagnosis, there has been a loss of 50% of β-cell mass, similar to that seen in T2DM.50 In addition, amyloid deposits are found within the β-cells. However, it is not clear if the amyloid accumulates during the disease process or even if it contributes to β-cell dysfunction.36

Cystic fibrosis-related diabetes is described more fully in Chapter 2.

The precise mechanism of CFRD is unclear.1 CFRD is characterised by an insulin deficiency7 owing to the loss of insulin-producing β-cells.31 Couce et al.50 state that there is approximately a 50% loss in β-cell mass, which is similar to that seen in patients with T2DM. This occurs after fibrosis and fatty infiltration of the pancreas. This leads to destruction of the pancreatic islet architecture.31

Insulin resistance has also been reported,51 especially at times of infection and inflammation, but the main problem is a progressive fall in β-cell capacity.48,49 This leads to a progressive impairment of insulin production.

Hyperglycaemia may first be seen only at time of metabolic stress, such as lung infections, but is later seen as postprandial hyperglycaemia (PPH) [initially only immediately after meals, so that plasma glucose (PG) may be normal by the time of a 2-hour OGTT test], progressing to IGT then to CFRD without FH, and then to CFRD with FH. Schwarzenberger et al.52 reported that most of their patients (a large cohort of 775) without FH progressed to it over time.

Lung function in diabetes mellitus

As previously mentioned, CF affects the lungs, where the build-up of viscous secretions is not only difficult to expel from the body, but also leaves the person prone to various chest infections. In addition, diabetes also affects the lungs. Although the effects are not widely recognised, owing to any abnormalities being slight and subclinical, in a person with CF these changes could have a greater impact.53 This is discussed in Chapter 2.

Management

Patients with CFRD have the same problems with malabsorption and malnutrition as all other patients with CF do and so their dietary requirements are essentially unchanged.7 In addition, as CFRD is due to insulin deficiency, management with insulin is standard practice. Increasingly, centres treating patients with CF administer insulin early in an attempt to influence body mass index (BMI) and pulmonary function.54 Insulin treatment is used more liberally in Europe, but in the USA it has been mainly used in patients with FH, although guidelines did permit usage in those without FH at the clinician's discretion.1 Treatment options are reviewed in Chapter 3.

As mentioned previously, patients with CF have the daily chore of complying with a relatively rigid schedule, which includes a long list of therapies. If CFRD develops, extra medical therapies and regular health checks are added to the existing burden of self-management. Patients with CFRD need to regularly monitor his or her BG levels, regularly administer insulin and undergo various screening tests for diabetic complications. Furthermore, patients with CFRD need to deal with temporary disturbances of glucose regulation during bouts of illness, when more frequent BG tests need to be carried out55 because control of BG levels is harder.56 As one CFRD patient mentioned, ‘You cannot just go out and do what you want, when you want, you've got to think hard and plan it a bit better. It's inconvenient.’56

Prognosis

The life expectancy of patients with CF is fortunately improving; the median survival age for a child born in 2000 is approximately 50 years.19 However, patients with CFRD have poorer nutritional status and worse lung function than patients with CF, which leads to a higher mortality rate.36 In 1988, a retrospective study of 448 patients with CF living and deceased showed that < 25% of patients with CFRD reached the age of 30 years compared with nearly 60% of patients with CF.32 Age at onset is lower in females than in their male counterparts. Females also have a reduced life expectancy. It is not clear whether or not these two facts are connected. Milla et al.57 found that the median age of survival was 30.7 years for females with CFRD, and for males it was 47.4 years. It must be noted that this difference in age survival may be due to CFRD or it may arise from other factors (e.g. pregnancy can cause a rapid decline in lung function, a trait seen in both CF patients and patients with CFRD). Miller et al.58 reported that patients with CFRD were more likely to have a decline in FEV1 than patients with only CF, and that this affected women especially, suggesting that women were more severely affected by CFRD than men.

Srivastava et al.59 from London also reported that CFRD reduced survival; 25% of patients with CFRD died by the age of 26 years compared with 31 years for those without diabetes. With respect to the patients with CFRD, females had a 50% mortality rate at 29 years, whereas males had the same mortality rate at the age of 37 years. These figures were for the cohort born 1970–91. This may be related to reports that lung function was worse in women than men.60

Kampfert et al.61 in Germany and Austria also noted that the outlook was poorer for women. Among 1334 patients, the prevalence of CFRD at the age of 18 years was 12.5% in women and 4% in men.

However, the most recent mortality data from the USA show no difference between men and women.38 This was different from the previous report from the same centre by Milla et al. in 2005.55 They also found a marked decline in mortality in people with CFRD in both sexes. The authors note that CFRD treatment has become much more vigorous than in the past.

Chamnan et al.62 carried out a retrospective cohort study to determine mortality rates, estimate the risk increase associated with diabetes, and calculate the population attributable fraction (PAF) for mortality associated with diabetes. Their cohort included 8029 people aged 0–65 years, registered on the UK Cystic Fibrosis Registry from 1996 to 2005, of whom 5892 had data for mortality rate follow-up, with 4234 complete data for analysis of risk factors for mortality; 393 subjects died during follow-up. Of the 696 with CFRD, 141 died.

For CF in general, crude annual mortality was 2.2% per annum. Mortality increased with age, but for those with CFRD peaked in the 20- to 29-year age range.62 The risk of death was higher among females than males, with age-adjusted mortality rates of 2.0 [95% confidence interval (CI) 1.8 to 2.4 age-adjusted mortality rate] and 1.6 (95% CI 1.4 to 1.9 age-adjusted mortality rate), respectively. Those with CFRD had much higher age-adjusted mortality rates at 4.2 (95% CI 3.4 to 5.1 age-adjusted mortality rate) per 100 person-years than those with CF alone: 1.5 (95% CI 1.3 to 1.7 age-adjusted mortality rate per 100 person-years). The higher diabetic mortality was seen in all ages.

Chamnan et al.63 estimated that the PAF for diabetes was 14% (95% CI 8% to 19%), i.e. that 14% of all deaths in people with CFRD are due to diabetes. They make the striking point that standardised mortality rates show that the CF population in the UK, with a median age of 13 years, has a mortality rate similar to that of 70- to 74-year-olds in the general population of England and Wales.

Finkelstein et al.32 in 1988 reported that < 25% of patients with CFRD survived (then) to the age of 30 years compared with 60% of those with CF without diabetes.

The excess mortality has been reported to be much worse in females than males. Milla et al.57 reported that median survival was 35.6 years in those with CFRD and 47 years in those with CF without diabetes. However, the median survival in females with CFRD was 30.7 years and in males 47.4 years. Miller et al.58 also reported higher mortality in women with CFRD than in those with CF alone, and that the decline in lung function over time was more marked in females.

Recent work from the UK has shown that there is a link between hyperglycaemia and mortality. Adler et al.,64 using UK Cystic Fibrosis Registry data, found that patients with CFRD who died had higher glycated haemoglobin (HbA1c) levels (7.3%) than those who did not (6.7%). Around 60% of deaths were due to respiratory disease, and those who died had a much lower FEV1 than those who did not (33% vs 54% of predicted).

Survival in patients with CF whose FEV1 has fallen below 30% of expected used to be poor, with half surviving for < 2 years. However, George et al.65 from the Brompton group reported survival of 2-year cohorts: 1990–1 to 2002–3. Median survival improved from 1.2 years in the 1990–1 cohort to 5.3 years in the 2002–3 cohort. The improvement in survival started in the 1994–5 cohort, and reached a plateau after the 1996–7 one, and coincided with the introduction of nebulised human DNase. The proportions with CFRD changed little. In univariate analysis, the presence of CFRD increased mortality by about 80% (our calculations – the figure in the published paper looks wrong).

Complications

Microvascular complications (e.g. retinopathy, neuropathy and nephropathy) occur in patients with CFRD.66,67 Yung et al.,63 albeit in a small study, reported a prevalence of retinopathy among patients with CFRD who had been diagnosed for 5 years or more of 16% (5 out of 31 patients) and among those who had been diagnosed for 10 years or more of 23% (3 out of 13 patients). The prevalence of nephropathy was between 3% and 16% and of peripheral neuropathy between 5% and 21%.68 One problem is that microalbuminuria is common in patients with CF without diabetes and so is not a reliable marker for diabetic nephropathy.69 The microvascular complications appear to occur only in those patients with CFRD with FH.52

Macrovascular complications have been rare.68 It is thought that this is because patients with CFRD do not live with diabetes for long enough for macrovascular complications to occur. Indeed, at least one authority has stated that no patient with CF has so far died of atherosclerotic cardiovascular disease.70 A study from London reported retinopathy, but also that no macrovascular complications were found.31

Georgiopoulou et al.71 may have provided much of the explanation. In their study of metabolic aspects of CF, they noted that total and low-density lipoprotein cholesterol were low (total cholesterol 3.5 mmol/l, low-density lipoprotein 1.27 mmol/l), but that high-density lipoprotein cholesterol was near normal. They also reported low BMI (21 kg/m2), and lowish systolic blood pressure (116 mmHg) and diastolic blood pressure (74 mmHg).

However, as more patients with CFRD progress into the fifth and sixth decades of his or her lives, this may become more common. Rhodes et al.72 from Toronto have reported that adult patients with CF do develop dyslipidaemia, but mainly those with pancreatic sufficiency. Those with CFRD did not have more dyslipidaemias.

In children, CFRD is associated with reduced growth rates, both in the 2 years before and after diagnosis.73

Terminology

In this review, the following categories of glucose status will be used.

  1. Normal glucose tolerance (NGT) requires both fasting plasma glucose (FPG) of < 5.6 mmol/l and 2-hour OGTT level of < 7.8 mmol/l, 2 hours after a 75-g glucose load.
  2. Diabetes is defined as FPG level of > 7.0 mmol/l and/or 2-hour OGTT level of > 11.1 mmol/l, except that the diagnosis must be confirmed – a single glucose level is not enough. Some studies from the USA subdivide diabetes into ‘with FH’ or ‘without FH’. This is partly a question of stage of disease, with diabetes manifesting itself first mainly as PPH.
  3. IGT is based on a 2-hour OGTT level of between 7.8 and 11.1 mmol/l.
  4. Impaired fasting glucose (IFG) means a FPG level of between 6.1 and 6.9 mmol/l, as used by the World Health Organization (WHO).74 The American Diabetes Association (ADA) defines it at a lower threshold of 5.6 mmol/l. The WHO system does not give a name to those with a FPG level of 5.6–6.0 mmol/l, who are above normal but under the IFG threshold.
  5. PPH. There are patients in whom PG after a meal is abnormally high for the first hour or so, but returns to normal by 2 hours. The term ‘lag storage’ has been used in the past. Data from the Royal Hospital for Sick Children in Glasgow show that many patients with CF have high PG levels at 30, 60 and 90 minutes but normal fasting and 2-hour levels. Some of these results are into the range for random BG at which diabetes would be diagnosed.75

The WHO criteria for diabetes are based on the risk of harms such as retinopathy (although the existence of a clear threshold for retinopathy risk has been challenged in recent years, with retinopathy reported in IGT).76 It may be that the threshold for harm in CF, such as bacterial growth, may have a different threshold and that we need a new definition of CFRD. This is discussed further in Chapter 2.

It is usually assumed that people who develop CFRD go through the above stages in sequence, but several studies have shown that there can be regression as well as progression in the early stages. Carpenter et al.77 repeated OGTTs in 94 adolescents and found that 50% (8 out of 16) who had IGT reverted to NGT. The other half progressed to CFRD. Thorsteinsson et al.78 had similar results, with 58% of those with IGT reverting to NGT at the next annual OGTT. Other studies have reported similar results, with very variable glucose tolerance over time79 or reversion from IGT to NGT.33

Decision analysis

Screening for CFRD is necessary because the onset can be insidious, and because it can cause harm before diagnosis. The first question for this review is therefore how best to screen for CFRD – which tests, starting when and how often?

A survey in the USA by Allen et al.80 found a wide range of screening practices and tests, with random PG the most common, followed by HbA1c, and urinary glucose.80 Very few used the OGTT. Most guidelines recommend an annual OGTT but it appears that, owing to the cost, inconvenience and unpleasantness of that test, the guidelines are largely ignored in practice. A similar survey in the UK by Mohan et al.81 also found that there was variation in screening methods. Only 30% used the recommended (by a working group of the UK Cystic Fibrosis Trust) method of the combination of the OGTT and serial glucose monitoring, with another 49% using the OGTT alone. Other tests used (usually in combinations) included HbA1c, FPG, random PG, and glycosuria. However, the survey reported the policies used, but not the proportions of patients screened according to the local policies.

As mentioned, most guidelines regard the OGTT as the ‘gold standard’, but it is often not used in practice. It is therefore necessary to consider:

  • Could other tests such as HbA1c, continuous blood glucose monitoring (CBGM) or home serial capillary BG profiles could be used? Even tests not as sensitive (perhaps such as HbA1c) might still detect more cases in practice owing to better compliance. A test that is 100% sensitive but which has only 50% acceptance will detect 50% of cases; one that has a sensitivity of 80% and an acceptance of 80% will detect 64% of cases.
  • Could a combinations of tests might give better overall results, for example if screening was undertaken in two or more stages? For example, would it be helpful to test HbA1c in the first instance, with patients divided into three groups, as follows?

    HbA1c-negative for diabetes. The cut-off value might be under 5.7%, as recommended by the Expert Working Group on the diagnosis of diabetes,82 but this would need to be reviewed in the context of CFRD. Anaemia is common in adults with CF (43% in a study by Von Drygalski and Biller83) and any reduction in red-cell life would give misleadingly good HbA1c results. Anaemia was much less common in children, so HbA1c might be useful for screening for them, but not for adults.

    HbA1c diagnostic for diabetes (perhaps 6.5%).

    Intermediate HbA1c (say 5.7 to < 6.5%) followed by OGTT.

A sequence with HbA1c or random PG first might allow many patients to avoid OGTT.

In T2DM, HbA1c level is influenced in the early stages more by non-FPG than FPG.84 Whether or not it would be sensitive enough to pick up isolated PPH (without IGT) remains to be examined. The sensitivity would depend on the threshold at which patients were referred for OGTT.

Continuous BG monitoring is carried out by inserting a disposable glucose monitor under the skin, connected to a meter worn externally. A chemical reaction generates a current that is proportional to the level of glucose in the tissues. Strictly speaking it is interstitial tissue glucose that is monitored. A review by the Australia and New Zealand Horizon Scanning Network (ANZHSN) noted that CBGM systems seemed to be better at detecting hyperglycaemia than hypoglycaemia, a problem that would not be relevant to its use in screening for CFRD. All of the trials reported in the ANZHSN review were in people with diabetes; no use in screening was found.85

Home BG involves testing with sticks and meters over the course of a day. This is called blood glucose profiling (BGP).

Again, as with OGTT, these could be used on all patients or only on those shown likely to have CFRD or IGT after a preliminary screen with, for example, HbA1c or a casual PG.

In addition to diabetes, two other conditions may cause harm. The first is IGT, which, as mentioned above, can be associated with microvascular disease.76 IGT is also associated with a reduction in lung function [FEV1 and forced vital capacity (FVC)].86

The second is PPH because it has been suggested that this alone may lead to end products of glycation, which may cause irreversible damage. Gerich87 notes that isolated PPH, with normal FPG and normal HbA1c, is associated with an increase in vascular disease, although he was referring to 2-hour PG. Hanefeld et al.88 reported that glycaemic excursions were associated with carotid intimal thickening in non-diabetic subjects. Hence, it is important to know if isolated PPH can affect lung function. If we should be concerned with IGT, or even just PPH, then that has implications for the choice of screening test. FPG would not be satisfactory.

The second question for this review is therefore whether or not we should be screening for a wider range of hyperglycaemia than diabetes? It would only be worth doing that if treatment of that level of hyperglycaemia was shown to improve outcomes.

© 2012, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of Screening for Cystic Fibrosis-Related Diabetes: A Systematic Review
Screening for Cystic Fibrosis-Related Diabetes: A Systematic Review.
Health Technology Assessment, No. 16.24.
Waugh N, Royle P, Craigie I, et al.
Southampton (UK): NIHR Journals Library; 2012 May.

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