The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

 

1922 Banting FG, Best CH. Internal secretion of the pancreas. J Lab Clin Med 1922; VII: 251-266.

 

Fig. 1: Sir Frederick Banting. From Wikipedia.

The work reported in this classic paper eventually led to a Nobel Prize in 1923 for Banting and Macleod, in whose Toronto laboratory the work was done. Frederick Banting (1891-1941) (figure 1) was a Canadian orthopaedic surgeon who became an assistant in physiology in Ontario where he worked in Richard McLeod’s laboratory with Charles Best, a medical student. It was here, after many ups and downs and arguments and with the help of Bertram Collip, a highly trained biochemist, to extract the insulin, that they eventually produced and tried the insulin on a diabetic patient in 1922.

The paper begins –“The hypothesis underlying this series of experiments was first formulated by one of us in November 1920 (Banting was then assistant in Physiology at Western University, London, Ontario) while reading an article dealing with the relation of the isles of Langerhans to diabetes (Barron M: The relation of the islets of Langerhans to diabetes with special reference to cases of pancreatic lithiasis. Surg Gynec Obstetr 1920; xxxi :437-448). From the passage in the article which gives a resume of degenerative changes in the acini of the pancreas following ligation of the ducts, the idea presented itself that since the acinous but not the island tissue degenerates after this operation, advantage might be taken of this fact to prepare an active extract of the islet tissue. The subsidiary hypothesis was that trypsinogen or its derivatives was antagonistic to the internal secretion of the gland. The failures of other investigators in this much worked field were thus accounted for”.

The authors concluded from their experiments that –“intravenous injections of extract from dog’s pancreas, removed from 7 to 10 weeks after ligation of the ducts, invariably exercises a reducing influence upon the percentage sugar of the blood and the amount of sugar excreted in the urine”

 

This medical classic is a “good read” and one of the most significant medical papers of the 20th century as also is Moses Barron's paper that gave Banting the idea (above). It is included here not only for its historical interest but also for its relevance to CF as the majority of those affected will eventually develop CF related diabetes in adult life. Although the Islets of Langerhans in CF are functioning adequately through childhood in most patients, despite their severe exocrine pancreatic insufficiency, they are eventually destroyed resulting in the majority of adults with CF developing diabetes mellitus.

Efforts to prevent the slow destruction of the pancreas and prevent or delay the onset of CF related diabetes will surely become an area of research as more people survive to develop this complication which has an adverse effect both on their prognosis and quality of life.

 

1955 Shwachman H, Leubner H. Mucoviscidosis. Advan Pediat 1955; 7:249-323.[PubMed]
The paper contains the first detailed report of symptomatic diabetes mellitus and CF in a white boy aged 5 years from Kaloa, Hawaii – considered to be the superimposition of one serious disease on another.

The authors note that “mucoviscidosis is so well established today that we seldom see individual case reports except in areas where interest in the disease is awakening (for example South Africa, Canada and Germany). Rather we look forward to monographs such as Bodian’s (1952 above) and May’s (May CD. Cystic fibrosis of the pancreas in infants and children. Springfield Ill: Charles C Thomas. Publisher, 1954 above) where accumulated experience is recorded”.
They note that in Bodian’s book Cedric Carter, the geneticist, combined the data from Andersen and Hodges, Lowe, May and Reed with his own to confirm the expected probability of 1 in 4 children being affected. The importance of di Sant’Agnese’s recent (1953) description of the sweat electrolyte abnormality is mentioned particularly its importance in the recognition of the 5 - 10% of people with CF without clinical pancreatic insufficiency – but the tryptic activity of duodenal juice was still of great importance in diagnosis. Shwachman describes their experience of inducing sweating in 300 children by placing the child in a plastic suit bag for 30-90 minutes with pieces of covered gauze on the back. Values of over 80 meq/l were considered diagnostic of cystic fibrosis.
The beneficial effect of controlling infection with antibiotics in contrast to the relatively unsuccessful attempts with various inhalations including trypsin and oral iodides was stressed – “early recognition of the disease and prompt antibiotic therapy may be so encouraging that parents as well as doctor begin to question the original diagnosis”!
Finally, Shwachman notes that the average age of death from 1940-48 was 12.8 months and from 1949-53 was 45.2 months – the broad spectrum antibiotics came into use in 1949 and were considered likely to be one of the reasons for the improvement.

This 74 page paper, with 142 references, is a very detailed review of the current knowledge of CF up to that time by Harry Shwachman, written with the assistance of Hugo Leubner of the WHO and Pincus Catzel, then a research fellow; it makes very interesting reading.

 

1961 Huhnstock K, Schwarz G. On mucoviscidosis in adults and diabetes mellitus. Klinische Wochenschrift 1961; 39:854-7. [PubMed]
These authors screened 250 adults with diabetes mellitus using Shwachman plates (Shwachman et al, 1956. above) and those who were positive had sweat tests performed by the bag method. Nine of the 250 diabetic adults had positive sweat tests but no other signs of cystic fibrosis.

These findings are difficult to explain as diabetes mellitus is usually a late feature in the progression of cystic fibrosis. Also the ages of the patients (between 49 and 66 years) were quite against the individuals having cystic fibrosis. It is difficult to accept these findings particularly as there were no other signs of cystic fibrosis in these middle aged patients. Also a number of authors had found some apparently healthy adults with sweat tests with values of sodium and chloride over 60 meq/l.

This paper was followed by a number of publications on the relationship between established diabetics and cystic fibrosis.

The first description of diabetes mellitus in cystic fibrosis is usually attributed to Shwachman & Leubner, 1955 (reviewed above).

 

1962 Rosan RC, Shwachman H, Kulczycki LI. Diabetes mellitus and cystic fibrosis of the pancreas. Laboratory and clinical observations. Am J Dis Child 1962; 104:625-34. [PubMed]
One of the early descriptions of diabetes mellitus in cystic fibrosis; the first was in 1955 by Shwachman & Leubner (above). In the present paper 10 patients with diabetes mellitus were identified in a CF population of about 1300 patients seen since 1947 - one adult, three teenagers and the rest children. Reviewing the 10 patients – eight required insulin therapy, they noted that diabetes complicates management but does not necessarily shorten survival; it may begin at any age; four of the 10 patients were mentally retarded – an unusual occurrence in CF which was not discussed in the paper; the complication was indistinguishable from juvenile diabetes except ketosis was very rare; all were pancreatic insufficient.

The authors predicted that subclinical diabetes must exist in a large proportion of people with CF. This prophetic observation was absolutely correct but was a new concept at the time when there were very few adults with cystic fibrosis. There were so few patients with diabetes mellitus and CF that this paper reporting 10 patients was published.

 

1969 Milner AD. Blood glucose and serum insulin levels in children with cystic fibrosis. Arch Dis Child 1969; 44:351-355. [PubMed]
One of the early studies on glucose metabolism from Great Ormond Street, London by Tony Milner at a time when few patients survived to an age when they developed diabetes. However, it had been predicted that this might occur as patients became older. Glucose and insulin levels were measured after oral glucose and intravenous glucose, glucagon and tolbutamide in 61 children with CF. The results suggested that the increased incidence of impaired glucose tolerance was due to a defect in the release of an glucagon-like substance from the alimentary system in addition to defective islet cell function. (also Rosan et al, 1962 above; Huhnstock K & Schwarz G, 1961 above)

 

1992 Lanng S, Thorsteisson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on the clinical status in patients with cystic fibrosis. Eur J Paediatr 1992; 151:684-687. [PubMed]
The first of a series of papers about CF related diabetes (CFRD) from Copenhagen and other centres. The new and important message from this paper being that diabetes mellitus adversely affects progress for some time before it becomes clinically obvious. When diabetes develops in CF patients, an insidious decline in overall clinical status is observed for some years prior to its clinical diagnosis. Whether clinical deterioration in CF leads to DM, or pre-diabetes results in declining CF clinical status is unclear. Accumulating evidence suggests that the latter may be the case since insulin therapy seems to improve lung function in cystic fibrosis.

This important Danish study encouraged the introduction of the policy of searching for glucose intolerance when patients of 12 years and older were seen for their Annual Review - a policy agreed by most, but not all, CF physicians.

 

2000 Moran A. Cystic fibrosis-related diabetes: an approach to diagnosis and management. [PubMed]
The Cystic Fibrosis Foundation held a consensus conference in 1998 to define the current standards for the diagnosis and care of CF related diabetes (Moran A, Hardin D, Rodman D et al. Diagnosis, screening, and management of CFRD: a consensus conference report. J Diabetes Res Clin Pract 1999: 45: 61-73). This article reviews those recommendations, and presents the practical approach to the management of CFRD used at the University of Minnesota.
The CF Foundation recommendations were recently reviewed again (Moran A. Updates on CFRD guidelines. Pediatr Pulmonol 2009; Suppl 32:208-209. S19.4). There was a further CFF Consensus Conference on CFRD in Sept. 2009.

 

Fig. 2: Antoinette Moran

 

Dr Antoinette Moran (figure 2) was awarded the CF Foundation's Distinguished Clinical Achievement Award in 2007 for her work in this area.

 

 

 

2004  The UK CF Trust consensus document Management of Cystic Fibrosis Related Diabetes Mellitus by the CF Trust's Diabetes Working Group was published in 2004 and is available on the website (www.cftrust.org.uk).

 

 

 

 

 

2004 Starkman H, Das S. Cystic fibrosis presenting as new onset diabetes mellitus in adolescent twins. Pediatr Diabet 2004; 5:99-101. [PubMed] Identical adolescent twin girls presented with symptoms consistent with type 1 diabetes. Medical work up for evaluation of gastrointestinal symptoms led to a diagnosis of cystic fibrosis (CF) in both. These cases suggest that diabetes can be a presenting symptom of CF in the absence of pulmonary symptomatology.

This is the first report of such a presentation of CF. In 1961 Huhnstock K, Schwarz G reporting on mucoviscidosis in adults and diabetes mellitus [PubMed] (above) screened 250 adults with diabetes mellitus using Shwachman plates and those who were positive had sweat tests performed by the bag method. Nine of the 250 diabetic adults had positive sweat tests but no other signs of cystic fibrosis. It seems most unlikely that they had CF.

 

2006 Andersen HU, Lanng S, Pressler T, Laugesen CS, Mathiesen ER. Cystic fibrosis-related diabetes: the presence of microvascular diabetes complications. Diabetes Care 2006; 29:2660-3.[PubMed]
Thirty-eight patients aged 30 years (range 18-55yrs) with CF-related diabetes for 20 years (0-31yrs) were screened for diabetes complications at the Copenhagen CF Centre. Because of chronic pulmonary infections, the majority of patients were regularly treated with aminoglycoside and cyclosporine was given to those who had lung transplants. Since the pharmacological treatment of lung transplant patients could influence metabolic regulation and renal function, the results were given separately for nontransplanted (n = 29) and transplanted (n = 9) CF patients.
Nine of these diabetic patients (27%) had retinopathy, two of whom had proliferative retinopathy requiring laser treatment. Lung transplantation did not affect the prevalence of retinopathy. In 29 non-transplanted patients, nine had hypertension, three microalbuminuria, and one elevated creatinine; none had macroalbuminuria. In transplanted patients (9), eight had hypertension, two had microalbuminuria, and none had macroalbuminuria; seven of the nine had elevated plasma creatinine, and severely reduced glomerular filtration rate was significantly more frequent.

So a high frequency of diabetic retinopathy was found in patients with insulin-treated CF-related diabetes, stressing the need for a regular screening program as in type 1 diabetes. Severely impaired kidney function was common in lung transplant patients, probably secondary to cyclosporine treatment but many would also have had life long regular courses of intravenous aminoglycosides. As age increases so do complications. Eventually the majority of older people with CF will develop diabetes and it is clear that eventually many will develop diabetic complications particularly retinopathy. The added complications associated with immunosuppressant drugs in those who have had lung transplants and the effects of repeated courses of aminoglycosides contribute to the high frequency of renal complications.

 

2007 Schwarzenberg SJ, Thomas W, Olsen TW, Grover T, Walk D, Milla C, Moran A. Microvascular complications in cystic fibrosis-related diabetes. Diabetes Care 2007; 30:1056-1061. [PubMed]
The incidence of cystic fibrosis-related diabetes (CFRD) and the prevalence of diabetic microvascular complications were determined at the University of Minnesota. During 1990-2005, 775 patients aged 6 years and older were followed. CFRD was diagnosed in 285 subjects (52% female), 64% of whom had fasting hyperglycaemia. No subject with CFRD without fasting hyperglycaemia had retinopathy or abnormal urine albumin/creatinine ratio. In CFRD subjects with fasting hyperglycaemia and diabetes for 10 years or longer, 14% had microalbuminuria and 16% had retinopathy. Autonomic neuropathy and gastrointestinal symptoms each were seen in 52% and somatic abnormalities in 22% of patients with or without fasting hyperglycaemia.
The authors concluded that diabetic microvascular complications occur in CFRD, although the prevalence of retinopathy and nephropathy appears to be less than that found in other forms of diabetes. They advised that annual complication screening should occur after known diabetes duration of 5 years in patients with CFRD with fasting hyperglycaemia.

It is likely that CFRD will prove to be an increasingly important complication as the age of the adult CF population increases as will its complications as described here (Also Andersen HU et al, 2006 above).

 

2007 Battezzati A, Battezzati PM, Costantini D, Seia M, Zazzeron L, Russo MC, Dacco V, Bertoli S, Crosignani A, Colombo C. Spontaneous hypoglycaemia in patients with cystic fibrosis. Euro J Endocrinol 2007; 156:369-376. [PubMed]
A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Fasting plasma glucose of < 60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycaemia (PG < 50 mg/dl (2.8 mmo/l)) in 15%. The oral glucose tolerance test-based diabetes frequency was similar in the lowest quartile (Q1) and Q2-3 for fasting plasma glucose (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among fasting plasma glucose (FPG) quartiles. Those with class I CFTR mutations had higher insulin concentrations than class II, especially in Q1 for FPG. Lower FPG was associated with more frequent hospitalization rates and lower Shwachman scores.

Fasting asymptomatic hypoglycaemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low fasting plasma glucose does not exclude impaired glucose tolerance and diabetes in CF and does reflect worse clinical status.

 

2008 van den Berg JM, Morton AM, Kok SW, Pijl H, Conway SP, Heijerman HG. Microvascular complications in patients with cystic fibrosis-related diabetes (CFRD). J Cyst Fibros 2008; 7:515-519. [PubMed]
79 patients with CFRD were matched with 79 patients with DM1 according to sex, age and duration of insulin therapy. Retinopathy, peripheral neuropathy, nephropathy and microalbuminuria were the microvascular complications assessed. Risk factors studied were: smoking, BMI, HbA1c, cholesterol, cholesterol/HDL ratio, diastolic and systolic blood pressure. Both groups had the same number of microvascular complications (29%). CFRD patients showed more microalbuminuria (21% versus 4.1%; p=0.003), while retinopathy was more common in patients with DM1 (24% versus 10%; p=0.044). The prevalences of peripheral neuropathy and nephropathy were similar. Patients with CFRD had lower BMI (p<0.0001), total cholesterol (p<0.0001) and HbA1c (p=0.056) levels, and a lower prevalence of smokers (p<0.0001). Cholesterol/HDL ratio and diastolic and systolic blood pressure were similar in both groups.


The microvascular complications shown by patients with CFRD are similar to those seen in patients with DM1 but with a lower prevalence of retinopathy and a higher prevalence of microalbuminuria. The latter may reflect the influence of other cystic fibrosis-related factors on renal function.

 

2009 Moran A, Dunitz J, Nathan B, Saeed A, Holme B, Thomas W. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care 2009; 32:1626-1631. [PubMed]
Cystic fibrosis (CF)-related diabetes (CFRD) diagnosis and management have considerably changed since diabetes was first shown to be associated with a poor prognosis in subjects with CF. Current trends in CFRD prevalence, incidence, and mortality were determined from a comprehensive clinical database.

Data were reviewed from 872 CF patients followed at the University of Minnesota during three consecutive intervals: 1992-1997, 1998-2002, and 2003-2008. CFRD is currently present in 2% of children, 19% of adolescents, and 40-50% of adults. Incidence and prevalence are higher in female subjects aged 30-39 years; otherwise, there are no sex differences. In younger individuals, CFRD without fasting hyperglycemia predominates, but fasting hyperglycemia prevalence rises with age. CFRD mortality has significantly decreased over time. From 1992-1997 to 2003-2008, mortality rate in female subjects dropped by >50% from 6.9 to 3.2 deaths per 100 patient-years and in male subjects from 6.5 to 3.8 deaths per 100 patient-years. There is no longer a sex difference in mortality. Diabetes was previously diagnosed as a perimorbid event in nearly 20% of patients, but of 61 patients diagnosed with diabetes during 2003-2008, only 2 died. Lung function but not nutritional status is still worse in CF patients with diabetes compared with those without diabetes. Nutritional status and pulmonary status are similar between patients without fasting hyperglycemia and those with fasting hyperglycemia.
Previously noted sex differences in mortality have disappeared, and the gap in mortality between CF patients with and without diabetes has considerably narrowed.

The auhtors believe that early diagnosis and aggressive treatment have played a major role in improving survival in these patients.

A useful review of changes in the features of CFRD by Antoinette Moran an expert on CFRD from Minnesota.

 

2009 Moran A, Pekow P, Grover P, Zorn M, Slovis B, Pilewski J, Tullis E, Liou TG, Allen H. Cystic Fibrosis Related Diabetes Therapy Study Group. Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial. Diabetes Care 2009; 32:1783-1788. [PubMed]
Cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia (CFRD FH-) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment.

The Cystic Fibrosis Related Diabetes Therapy (CFRDT) Trial sought to determine whether diabetes therapy improves BMI in these patients. A three-arm multicenter randomized trial compared 1 year of therapy with premeal insulin as part, repaglinide, or oral placebo in subjects with cystic fibrosis who had abnormal glucose tolerance. One hundred adult patients were enrolled. Eighty-one completed the study, including 61 with CFRD FH- and 20 with severely impaired glucose tolerance (IGT).

During the year before therapy, BMI declined in all groups. Among the group with CFRD FH-, insulin-treated patients lost 0.30 +/- 0.21 BMI units the year before therapy. After 1 year of insulin therapy, this pattern reversed, and they gained 0.39 +/- 21 BMI units (P = 0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (P = 0.45). Repaglinide-treated patients had an initial significant BMI gain (0.53 +/- 0.19 BMI units, P = 0.01), but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared with the year before (P = 0.33). Among patients with IGT, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group.

The authors concluded that insulin therapy safely reversed chronic weight loss in patients with CFRD FH-.

A conclusive result showing that insulin improves the nutritional state of people with CF who have impaired glucose tolerance without fasting hyperglycaemia.

 

Two more recent reviews on CF related diabetes mellitus, not included in main text, are as follows -

 

*2010 Stecenko AA, Moran A. Update on cystic fibrosis-related diabetes. Curr Opin Pulm Med 2010; 16:611-615. [PubMed]
A detailed review of recent publications on cystic fibrosis-related diabetes (CFRD) with a particular focus on the interplay between cystic fibrosis (CF) lung disease and diabetes.

 

*2010 Laguna TA, Nathan BM, Moran A. Managing diabetes in cystic fibrosis. Diabetes Obes Metab 2010; 12:858-64. [PubMed]
Cystic fibrosis related diabetes (CFRD) is the most common co-morbidity in persons with cystic fibrosis (CF). As the life expectancy of persons with CF continues to increase, the need to proactively diagnose and aggressively treat CFRD and its potential complications has become more apparent. CFRD negatively impacts lung function, growth and mortality, making its diagnosis and management crucial in a population already at high risk for early mortality. Compared to type 1 and type 2 diabetes, CFRD is a unique entity, requiring a thorough understanding of its unique pathophysiology to facilitate the creation and utilization of an effective medical treatment plan. The physiology of CFRD is complex, likely consisting of a combination of insulin deficiency, insulin resistance and a genetic predisposition towards the development of diabetes. However, the hallmark of CFRD is insulin deficiency, necessitating the use of exogenous insulin as the mainstay of therapy. Insulin administration, in combination with a multidisciplinary team of health professionals with expertise in the care of patients with CF and CFRD, is the cornerstone of the care for these patients. The goals of treatment of the CFRD population are to reverse protein catabolism, maintain a healthy weight, and reduce acute and chronic diabetes complications. Creating a partnership between the treatment team and the patient is the ideal way to accomplish these goals and is essential for successful diabetes care.

 

2010 Rogan MP, Reznikov LR, Pezzulo AA, Gansemer ND, Samuel M, Prather RS, Zabner J, Fredericks DC, McCray PB Jr, Welsh MJ, Stoltz DA. Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth. Proc Nat Acad Sci 2010; 107:20571-5. [PubMed]
People with cystic fibrosis (CF) exhibit growth defects. That observation has been attributed, in part, to decreased insulin-like growth factor 1 (IGF1) levels, and the reduction has been attributed to malnutrition and pulmonary inflammation. However, patients with CF already have a reduced weight at birth, a manifestation not likely to be secondary to poor intrauterine nutrition or inflammation. Also CF pigs were smaller than their non-CF littermates and had lower IGF1 levels. To better understand the basis of IGF1 reduction, the authors studied newborn CF pigs and found low IGF1 levels within 12 hours of birth. Moreover, humerus length and bone mineral content were decreased, consistent with less IGF1 activity in utero. These findings led them to test newborn humans with CF, and they found that they also had reduced IGF1 levels. Discovering lower IGF1 levels in newborn pigs and humans indicates that the decrease is not solely a consequence of malnutrition or pulmonary inflammation and that loss of cystic fibrosis transmembrane conductance regulator function has a more direct effect. Consistent with this hypothesis, they discovered reduced growth hormone release in organotypic pituitary slice cultures of newborn CF pigs. These findings may explain the long-standing observation that CF newborns are smaller than non-CF babies and why some patients with good clinical status fail to reach their growth potential. The results also suggest that measuring IGF1 levels might be of value as a biomarker to predict disease severity or the response to therapeutics. Finally, they raise the possibility that IGF1 supplementation beginning in infancy might be beneficial in CF.

These very interesting findings do suggest a possible explanation the suboptimal growth of some CF infants despite optimal treatment and a good clinical condition. Also they provide a very plausible explanation for the well documented reduced birth weight of CF infants as a group.

Various studies have shown that growth hormone has some value in improving growth of CF children (see TOPICS - ENDOCRINOLOGY) but as yet IGF-1 supplementation has not been reported although the relationship of growth and IGF-1 has been described in CF (Switzer M, Rice J, Rice M, Hardin DS. Insulin-like growth factor-I levels predict weight, height and protein catabolism in children and adolescents with cystic fibrosis. J Pediatr Endocrinol 2009; 22:417-424.[PubMed]).

 

2011 Haupt ME, Kim EE, Prestridge AL. Successful prolonged use of recombinant human insulin-like growth factor-1 in a child with cystic fibrosis. Pediatr Pulmonol 2011; 46:1137-41. [PubMed]
These authors report the successful prolonged use of recombinant human insulin-like growth factor-1 in an adolescent boy with CF, who demonstrated significant clinical benefits from the therapy.

Growth failure is a common and complicated process in children with cystic fibrosis. Growth hormone, which is becoming a more commonly used agent in such patients, has demonstrated beneficial effects aside from increased growth velocity. Recently, insulin-like growth factor-1 has gained significant attention in the understanding of growth failure in children with CF. This present report is the first of its use in a child with CF.

 

 

2011 Rana M, Munns CF, Selvadurai HC, Simonds S, Cooper PJ, Woodhead HJ, Hameed S, Verge CF, Lafferty AR, Crock PA, Craig ME. Increased detection of cystic-fibrosis-related diabetes in Australia.  Arch Dis Child 2011; 96:823-826.[PubMed]
To estimate the incidence of cystic-fibrosis-related diabetes (CFRD) in youth from New South Wales (NSW) and the Australian Capital Territory (ACT), Australia and to examine demographic/clinical features at diagnosis.

Incident cases of CFRD in young people aged <= 18 years diagnosed during 2000 to 2008 were identified from four paediatric cystic fibrosis (CF) clinics and the NSW/ACT Australasian Paediatric Endocrine Group Diabetes Register.

CFRD was diagnosed in 41 cases (59% girls). The estimated mean annual incidence of CFRD among patients with CF was 9.4 per 1000 person years (95% CI 6.8 to 12.8). Incidence increased from 2.0 per 1000 person years in 2000 to 22.1 per 1000 in 2008 (incidence RR 1.3, 95% CI 1.1 to 1.4). Haemoglobin A1c (HbA1c) was abnormal in the majority at diagnosis: median HbA1c was 6.9% (6.2-8.1%). More cases were diagnosed using an oral glucose tolerance test in 2007-2008 compared with previous years (61% vs 6%, p<0.001).

 

CFRD is increasingly recognised and now affects approximately one in five young people with CF. The rising incidence is likely to be due to increased detection, resulting from greater awareness and changes in screening practices. Widespread uptake of consensus guidelines for screening will ensure accurate case detection, but will also impact on patient care and resource allocation.

As CF has become a condition of older people so the complications have become an increasing problem none less than diabetes mellitus. Although there is adequate insulin produced by the damaged pancreas for most children, as destruction of the pancreas continues diabetes develops in the majority. It is unfortunate that the destruction of the pancreas cannot be halted to preserve the islet cells for further destruction. Perhaps the systemic effect of the mutation specific drugs such as Kalydeco will have a favourable effect on halting the destruction of the pancreas and preserving the islet cells - already some evidnec that this may occur (Bellin et al. 2013. below)

 

 

2012 Waugh N, Royle P, Craigie I, Ho V, Pandit L, Ewings P, Adler A, Helms P, Sheldon C. Screening for cystic fibrosis related diabetes : a systematic review. Health Technology Assessment (Winchester, England) 2012; 16(24):iii-iv, 1-179.  [PubMed]

The initial aim was to review the methods for screening for CFRD, which can be symptomless but still be causing harm. As the aim of screening and early detection is to allow earlier treatment, a second aim was to assess the effectiveness of treatments. However, during the review it became clear that there were problems with how CFRD is defined, uncertainty about when hyperglycaemia should be treated. Details of relevant studies were obtained from the usual bibliometric databases. Diabetes is usually defined based on the level of blood glucose (BG) at which the risk of retinopathy occurs. For CFRD, it would be better to define it on the level at which the risk of lung disease (pulmonopathy) rises. There seems little place for treatments other than insulin, but the best insulin regimen remains to be confirmed. The best screening test may be by continuous glucose monitoring systems but further evidence is required. Screening may need to detect BG levels of > 8 mmol/l because that may be the level above which pulmonopathy starts in people with CF.

The evidence base for treatment is disappointing with few large randomised controlled trials. The key question is when treatment should start, perhaps at the post-prandial hyperglycaemia stage. Research is needed. Until that is done, we cannot be sure what we are screening for, and, therefore, which screening strategy should be used.

The definition of CFRD should probably be based on pulmonopathy risk, rather than using the classical definition of diabetes. That implies that we should be screening for a wider range of hyperglycaemia than in other forms of diabetes, perhaps to detect BG excursions of > 8 mmol/l. Insulin treatment may need to start at lower levels than formerly accepted.

This HTA document contains a vast amount of up to date information and over 250 previous references regarding CF related diabetes.

 

 

2013 Bellin MD. Laguna T. Leschyshyn J. Regelmann W. Dunitz J. Billings J. Moran A. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes 2013; 14:417-421. [PubMed]

An open-label pilot study in CF patients with the G551D mutation given new prescriptions for ivacaftor. At baseline and 4wk after daily ivacaftor therapy, intravenous glucose tolerance tests (IVGTT) and oral glucose tolerance tests (OGTT) were performed.

Five patients aged 6-52 were studied. After 1month on ivacaftor, the insulin response to oral glucose improved by 66-178% in all subjects except one with long-standing diabetes. OGTT glucose levels were not lower in the two individuals with diabetes or the two with normal glucose tolerance (NGT), but the glucose tolerance category in the subject with impaired glucose tolerance (IGT) improved to NGT after treatment. In response to intravenous glucose, the only patient whose acute insulin secretion did not improve had newly diagnosed, untreated CFRD. The others improved by 51-346%. Acute insulin secretion was partially restored in two subjects with no measurable acute insulin response at baseline, including the one with IGT and the one with long-standing diabetes.

The authors concluded the results suggest there is a direct role of CFTR in human insulin secretion. Larger, long-term longitudinal studies are necessary to determine whether early initiation of CFTR correction, particularly in young children with CF who have not yet lost considerable beta-cell mass, will delay or prevent development of diabetes.

 

These are really exciting results. The prevention of CF realted diabetes would represented a major advance in improving the health and quality of life of many people with CF.

 

 

2013 Kelly A. Moran A. Update on cystic fibrosis-related diabetes. J Cyst Fibros 2013; 12:318-31. [PubMed]

This paper will review the 2010 U.S. and other international guidelines for screening and treating CFRD. It will highlight newer data regarding early glucose and insulin secretion defects, mechanisms linking CFRD to worse outcomes, and recent advances in T2DM that may provide insights for CFRD; insulin secretion will be reviewed as background for these recent developments.

A detailed review of the present situation regarding the recognition and management of CFRD by recognised experts in the condition.

 

 

2013 Bridges N. Diabetes in cystic fibrosis. Paediatric Respiratory Reviews 2013; 14 Suppl 1:16-8. [PubMed]

Cystic fibrosis related diabetes (CFRD) is a common complication of cystic fibrosis, caused by a fall in insulin secretion with age in individuals with pancreatic insufficiency. CFRD is associated with worse clinical status and increased mortality. Treatment of CFRD with insulin results in sustained improvements in lung function and nutrition. While clinical experience with insulin treatment in CF has increased, the selection of who to treat and glycaemic targets remain unclear.

 

Dr Nicola Bridges is paediatric endocrinologist and Service Director for paediatric medical specialities at the Chelsea and Westminster Hospital, London. She provides endocrinological expertise for the children attending the paediatric CF clinic at the Royal Brompton Hospital, London.

 

 

2013 Kopp BT. Kirkby S. Hayes D Jr. Flanigan KM. Diabetic myonecrosis in a cystic fibrosis patient. Resp Care 2013; 58:e123-5. [PubMed]                                                                             The authors report the case of a 32-year-old with poorly controlled diabetes presenting with sub-acute leg pain and focal quadriceps tenderness. Neuromuscular testing and extensive workup revealed diabetic myonecrosis. To the authors’ knowledge, this is the first reported case of diabetic myonecrosis in a patient with CF, and highlights the need for pulmonary physicians to recognize this diabetic complication in CF patients, which is associated with a poor long-term prognosis and existing microvascular complications.

 

 

20014 Middleton PG. Wagenaar M. Matson AG. Craig ME. Holmes-Walker DJ. Katz T. Hameed S. Australian standards of care for cystic fibrosis related diabetes. Respirology 2014; 19:185-92.
[PubMed] 

This document seeks to combine various guidelines to provide an Australian approach to the management of CFRD and establish the guidelines within the Australian CF Standards of Care. It is intended that this document will provide assistance to doctors, nurses, dietitians, physiotherapists, diabetes educators and CF patients concerning the issues surrounding CFRD, and it will be reviewed and updated in 2016.

 

 

 
Burgess JC1, Bridges N2, Banya W3, Gyi KM4, Hodson ME1, Bilton D4, Simmonds NJ5.  HbA1c as a screening tool for cystic fibrosis related diabetes.  J Cyst Fibros. 2015 Apr 10. pii: S1569-1993(15)00068-5. doi: 10.1016/j.jcf.2015.03.013. [Epub ahead of print][PubMed]
Early diagnosis of cystic fibrosis (CF) related diabetes (CFRD) is important to improve outcomes. International guidelines recommend an oral glucose tolerance test (OGTT) for all CF patients aged ≥10years - this approach is controversial. The aim of this study was to develop an effective screening tool and reduce the need for a universal OGTT.
Adult CF patients (without CFRD) attending an annual review assessment were recruited prospectively (March 2009-July 2012) into two sequential studies - a primary investigative study followed by validation study. All patients underwent an OGTT and were simultaneously screened by predetermined biochemical/clinical criteria to identify their risk of CFRD. A sensitivity/specificity analysis was performed using the World Health Organisation diabetes criteria as gold standard; modifications were made to improve the screening tool's accuracy and determine the optimal screening thresholds. This was tested in the validation study.
429 patients (primary, n=94; validation, n=335: mean age=31.7±10.4(SD), 43% female, 77% on pancreatic supplements). Primary study: in predicting a positive OGTT, the test sensitivity was 66.7% and specificity 60%. HbA1c was carried over to the validation study as it was the most discriminative (optimal threshold ≥5.8% (40mmol/mol); receiver operating curve, ROC, score 0.60). Validation study: the number of patients with a normal, impaired and diabetic OGTT was 268(80%), 51(15.2%) and 16(4.8%), respectively. HbA1c provided a test sensitivity, specificity and ROC score of 93.8%, 53.0% and 0.73, respectively.
CONCLUSIONS:
The use of HbA1c≥5.8%(40mmol/mol) is an effective tool for CFRD screening and reduced the need for an OGTT by 50.7%.

 

Comment:  Marie-Angela Schnyder, Christian Benden, Christoph Schmid  HbA1c: An effective screening tool for cystic fibrosis related diabetes?  DOI: http://dx.doi.org/10.1016/j.jcf.2015.10.010
Caution “Overall, we concur that clinical criteria remain important in diagnostic strategies and treatment decisions, and that in CF patients in good clinical condition, low HbA1c could possibly serve as a tool to reduce the number of oGTTs; however, we strongly recommend oGTTs in patients with advanced CF lung disease and poor clinical condition with a high pretest probability of insulinopenia; since these patients may well benefit from insulin treatment, beyond the control of hyperglycaemia, ideally improving muscle and lung functions”

 

Comment:  John Widger, Shihab Hameed, Chee Y. Ooi, Charles VergeUsing HbA1c as a screening tool for Cystic Fibrosis Related Diabetes  DOI: http://dx.doi.org/10.1016/j.jcf.2015.10.009
Support “The HbA1c is a relatively cheap and simple one off blood test that would seem to fit the brief perfectly”.  


Uc A; Olivier AK; Griffin MA; Meyerholz DK; Yao J; Abu-El-Haija M; Buchanan KM; Vanegas Calderon OG; Abu-El-Haija M; Pezzulo AA; Reznikov LR; Hoegger MJ; Rector MV; Ostedgaard LS; Taft PJ; Gansemer ND; Ludwig PS; Hornick EE; Stoltz DA; Ode KL; Welsh MJ; Engelhardt JF; Norris AW. Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass.  Clin Sci 2015;  128(2):131-42.  25142104[PubMed]
Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis. The authors determined the structure of the endocrine pancreas in fetal, newborn and older CF and non-CF pigs and assessed endocrine pancreas function by intravenous glucose tolerance test (IV-GTT).
In fetal pigs, pancreatic insulin and glucagon density was similar between CF and non-CF. In newborn and older pigs, the insulin and glucagon density was unchanged between CF and non-CF per total pancreatic area, but increased per remnant lobular tissue in CF reflecting exocrine pancreatic loss. Although fasting glucose levels were not different between CF and non-CF newborns, CF newborns demonstrated impaired glucose tolerance and increased glucose area under the curve during IV-GTT. Second phase insulin secretion responsiveness was impaired in CF newborn pigs and significantly lower than that observed in non-CF newborns. Older CF pigs had elevated random blood glucose levels compared with non-CF.
In summary, glycaemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycaemia developed over time. Functional changes in CF pig pancreas were not associated with a decline in islet cell mass.
 
The authors conclude their results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.

 

 


Stecenko AA, Moran A. Update on cystic fibrosis-related diabetes. Curr Opin Pulm Med. 2010 Nov;16(6):611-5. doi: 10.1097/MCP.0b013e32833e8700. [PubMed]
The aim of this articis to provide a detailed review of recent publications on cystic fibrosis-related diabetes (CFRD) with a particular focus on the interplay between cystic fibrosis (CF) lung disease and diabetes.
CFRD is a form of diabetes that is distinct from type 1 or type 2 diabetes. CFRD remains very common and increases in prevalence with increasing age so that one in two middle-aged CF persons have CFRD. People with CFRD have lower lung function, worse nutrition, more frequent hospitalization, and worse mortality than CF people without diabetes. The excess mortality previously noted in women with CFRD compared with CF women without diabetes or CF men is much less apparent. CFRD is due to insulin deficiency and peripheral insulin resistance is much less a factor. Genetic susceptibility and oxidant stress are key risk factors for developing CFRD. The lung is the prime end organ target in CFRD and mortality is due to respiratory failure, not vascular complications. Insulin is the mainstay of therapy and early recognition and institution of therapy appear to improve health outcomes.
CFRD remains one of the most important co-morbidities in CF. Early recognition of the disease and therapeutic intervention may diminish the negative impact that diabetes has on lung health in CF. Although a clearer understanding of the role of oxidant stress and genetics in the pathogenesis of CFRD is being elucidated, much needs to be learned before more targeted, specific therapies can be developed for this distinct form of diabetes.

 


2015 Roberts R; Speight L; Lee J; George L; Ketchell RI; Lau D; Duckers J.  Retinal screening of patients with cystic fibrosis-related diabetes in Wales - a real eye opener.  J Cyst Fibros 2015; 14(2):282-4. [PubMed]
In the UK the National Screening Committee recommends annual retinal screening for all diabetic patients over the age of twelve years. Currently, patients on insulin therapy for Cystic Fibrosis-Related Diabetes Mellitus (CFRD) at the All Wales Adult Cystic Fibrosis Service, UK are invited for annual screening.  67 of the 228 (29%) patients attending the CF centre were receiving insulin therapy. Of the 43 who had retinal scans, 18 (42%) had evidence of retinopathy. Patients with retinopathy had a higher mean HbA1c (p=0.04), mean duration of diabetes and mean duration on insulin (p<0.001).
Almost half of the patients screened had evidence of retinopathy but over a third of the patients with CFRD did not attend screening appointments. Improving patient uptake of retinal scans will become increasingly important in an ageing CF population.
 

- A disappointing proportion of eligible patients attended for retinal screening particularly in view of the high percentage of retinopathy in those who did attend.

 

 

Uc A; Olivier AK; Griffin MA; Meyerholz DK; Yao J; Abu-El-Haija M; Buchanan KM; Vanegas Calderon OG; Abu-El-Haija M; Pezzulo AA; Reznikov LR; Hoegger MJ; Rector MV; Ostedgaard LS; Taft PJ; Gansemer ND; Ludwig PS; Hornick EE; Stoltz DA; Ode KL; Welsh MJ; Engelhardt JF; Norris AW.  Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass.  Clinical Science 2015; 128(2):131-42.[PubMed]
Glycaemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycaemia developed over time. It is interesting that functional changes in CF pig pancreas were not associated with a decline in islet cell mass. The results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.

 

 

 

 
2015 Knudsen KB, Mathiesen ER, Eriksen V, Skov M, Nielsen KG, Johannesen J, Pressler T.  The development of diabetes among Danish cystic fibrosis patients over the last two decades. Pediatr Diabetes. 2015 May;16(3):219-26. doi: 10.1111/pedi.12143. Epub 2014 Jun 1.
 [PubMed] 

Cystic fibrosis (CF)-related diabetes (CFRD) is correlated with age and has been associated with a decline in body mass index (BMI), pulmonary function, and survival. Over the last two decades, the focus has been on the early diagnosis and treatment of diabetes; therefore, in this study, we evaluated the status of the current clinical condition and survival in our CF population. In addition, we also aimed to investigate the incidence of diabetes among adolescence over time and to identify characteristics associated with early diabetes onset.
A retrospective chart review of a birth cohort consisting of 161 CF patients born between 1975 and 1994 and followed until 2011.
Over two decades, the incidence of CFRD among 11- to 16-year-old children remained unchanged at 12-14%, while the proportion of children with chronic pulmonary infection at age 10 declined from 31 to 8% (p < 0.001). Severe CF-mutation, i.e., group I and II mutations, were associated with diabetes (p = 0.003). Female gender was borderline associated with diabetes among adolescents (p = 0.06). No significant worsening in pulmonary function, BMI or survival was identified when comparing CFRD patients to CF patients without CFRD.
The incidence of diabetes among adolescence with CF in the Copenhagen clinic has not changed over the last two decades. Severe CF mutations are a risk factor for CFRD, and female gender is borderline associated with CFRD among adolescents. Pulmonary function, BMI and survival were comparable regardless of the onset