4 Diabetes mellitus and cystic fibrosis M A R G A R E T E. H O D S O N
Cystic fibrosis (CF) is a disease characterized by bronchopulmonary infection, pancreatic insufficiency and a high sweat sodium concentration. The clinical features are well recognized (Hodson et al, 1983; Lloyd-Still, 1983). In 1938, 80% of patients died within i year of birth but now many are surviving into adult life. There are estimated to be approximately 5000 children and 1500 adults with CF in the UK, and survival to 19 years is now 50% (British Paediatric Association, 1988). The prevalence of diabetes mellitus in patients with CF is much higher than in the general population. Estimates vary from 8-15% (Anderson, 1938; Rosan et al, 1962; di Sant Agnese and Davis, 1979; National Institute of Arthritis, Metabolism and Digestive Disease, 1979; Lebenthal et al, 1986; Rodman et al, 1986; Geffner et al, 1988; Knowles, 1988). In a survey of 448 patients with CF insulin-dependent diabetes developed in 7.6% of patients. Total glycosylated haemoglobin (HbA1) was significantly (p < 0.001) higher in the total CF population than in the general non-CF population (Finkelstein et al, 1988). It is well recognized that the incidence of diabetes mellitus in CF increases with age. About 27 % of children (Milner, 1969), and 57% of a wider age group (Rodman and Matthews, 1981) have impaired glucose tolerance. It has been estimated that 50% of CF patients over the age of 18 years have impaired glucose tolerance (National Institute of Arthritis, Metabolism and Digestive Disease, 1979). The author currently has on computer the records of 218 CF patients aged 15-65 years of whom 24 (11%) are diabetic. There are 12 males and 12 females. The prevalence with age is shown in Table 1. Diabetes mellitus was not found in 279 patients under the age of 119 years on the London Postgraduate Hospitals' computer. In 158 patients between 10 and 14 years it was found in 4%; in older patients diabetes was present in about 15%. Review of the records of 62 adult CF patients with diabetes mellitus who are, or have, attended the Royal Brompton Hospital Adult CF clinic over the last 25 years shows a peak age of onset between 15 and 24 years (Figure 1). PATHOLOGY The clinical features of diabetes mellitus in CF are different from those of either classical Type 1 (juvenile onset) or Type 2 (adult onset non-ketotic) Baillidre's Clinical Endocrinology and Metabolism-797 Vol. 6, No. 4, October 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1621-7 All rights of reproduction in any form reserved
798
M.E. HODSON Table 1. Prevalence of diabetes mellitus in CF patients with age. Age band (years)
Number of CF patients
0-4 5-9 10-14 15-19 20-24 25-29 30-34 ->35
:30 149 158 34 87 59 26 12
Number (%) with diabetes
0 0 7 3 7 8 4 2
(0) (0) (4) (9) (8) (14) (15) (17)
Data for 0-14 years taken from the London Postgraduate Hospitals' database, data for patients -> 15 years from the author's Brompton Hospital Adult CF Clinic.
diabetes. In CF the age of onset is usually 15-25 years, but this diabetes differs from the classical Type i diabetes in that it is not ketotic. It is of slow onset, there is a persistence of some insulin secretion and autoimmune factors are rarely present (Geffner et al, 1988). It is not associated with obesity, as is classical Type 2 diabetes, and indeed most patients are underweight. There may be hypoinsulinaemia as opposed to hyperinsulinaemia and insulin resistance. There is an associated exocrine pancreatic defect which does not occur in most patients with diabetes mellitus. Glucagon secretion is variable in CF diabetes and there may be hypoglucagonaemia or hyperglucagonaemia (Stahl et al, 1974; Redmond et al, 1977; Geffner et al, 1988).
30 O9 t-
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. . . . . . . .
O. 0
2::::::::
$ ..Q
E ,-n
.=
. . . . . . . .
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10
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10-14
15-19
N 20-24
25-29
30-34
35+
Age of onset of DM Figure 1. The age of onset of diabetes mellitus in 62 patients with cystic fibrosis.
DIABETES MELLITUS AND CYSTIC FIBROSIS
799
It has been suggested that diabetes mellitus in CF should be called insulin-requiring diabetes mellitus (IRDM) (Knowles, 1988) because of the differences from the classical Type 1 and Type 2 diabetes. However, this is not fully comprehensive as there are many patients who can be managed for a time on oral hypoglycaemic agents. Another alternative, CF-related diabetes (CFRD) is more appropriate (CF Foundation, 1990). Abdul-Karim et al (1986) studied the islets of Langerhans in adolescents. The mean percentage surface area occupied by insulin-producing cells (8.3%) in diabetic CF patients was significantly less than in CF patients with normal glucose tolerance (46.7%) and controls (53.4%). The mean percentage surface area occupied by glucagon-producing cells was similar in the three groups. L6hr et al (1989) studied the pancreases of 23 patients dying of CF (aged 5-22 years). The pancreases were either fibrotic ( n = 14) or lipatropic (n = 9). In all, irrespective of the dominating pattern, the islet system was affected by marked peri-insular and intra-insular sclerosis. There was a reduction of approximately 50% in insulin-producing cells in CF patients, This supported the concept that destruction of the exocrine tissue, with concomitant fibrosis and disorganization of the islets, gradually changes the proportional distribution of endocrine cells in favour of noninsulin-producing cells. This could explain the increasing incidence of diabetes mellitus in older patients. Basically there is a delay in peak insulin response to a glucose load (Handwerger et al, 1969; Wilmshurst et al, 1975; Lippe et al, 1977). Hartling et al (1988) confirmed that patients had lower insulin and C-peptide concentrations than controls 30 minutes after a glucose load, but the responses were sustained so that the area under the curve was comparable with controls. In contrast, they showed that the area under the pro-insulin curve was significantly higher in CF patients with impaired glucose tolerance than in controls and CF patients with normal glucose tolerance. The early diminished insulin response has been demonstrated with other islet 13-cell stimulators; intravenous glucose, arginine and tolbutamide (Wilmshurst et al, 1975; Redmond et al, 1977; Knopfle, 1985). There appears to be increased insulin sensitivity (Wilmshurst et al, 1975) and high insulin receptor binding (Lippe et al, 1980; Andersen et al, 1988). There may be true pancreatic hyposecretion of insulin in many patients with CF, whereas the peripheral sensitivity to insulin appears normal or enhanced. Increased prevalence of islet cell antibodies has been found in CF with impaired glucose tolerance (Stutchfield et al, 1988). It may be that the antibodies are formed in response to the damaged pancreatic tissue and further impair islet [3-cell function.
THE SPECIAL C H A L L E N G E S OF M A N A G I N G DIABETES
MELLITUS IN PATIENTS WITH CF Patients with CF usually malabsorb and this leads to malnutrition, in contrast to many non-CF diabetic patients who are overweight. Absorption
800
M . E . HODSON
of food is less efficient than in non-CF patients and absorption may be erratic, even when regular pancreatic supplements are given with all meals and snacks. Some very malnourished patients are fed overnight using gastrostomy tubes, making it necessary to control blood glucose concentrations very carefully at night as well as during the day. Occasional patients are on intravenous nutrition. Many CF patients have liver disease and others are taking corticosteroids which upset glucose metabolism. During periods of exacerbation of pulmonary infection patients often become too breathless to eat properly or to maintain regular exercise, which further complicates diabetes control. During pregnancy, lactation or surgery, such as pleurodesis or abdominal surgery, extra attention to the control of blood glucose is necessary. When a patient is having heart-lung transplantation for terminal respiratory failure, very great care is needed to control the blood glucose concentration. Immediately after transplantation, because of the high doses of steroids used peri-operatively, many previously non-diabetic CF patients develop diabetes mellitus which needs to be controlled using an insulin infusion. As the patient's condition improves this can be stopped and the patient changed to twice-daily insulin, and in some patients there is no need for any further treatment. All patients need careful and individual diabetic control. One of the biggest problems is that the dietary recommendations made for non-diabetic CF patients and for non-CF diabetic patients are very different--and the diabetic advice that is given to a CF diabetic patient has to be different from that given to other diabetic patients in the community. Confusion can occur if CF diabetic patients go to the local diabetic clinic and are seen by a junior member of staff who tries to manage them in the same way as other diabetic patients. The author thinks CF diabetic patients are best cared for within the context of the CF clinic where the doctor, nurses and dietitians are familiar with their problems. The exception is when an endocrinologist has taken a special interest in their condition and sees them personally at a diabetic clinic. This does, however, increase the number of hospital visits the patient has to make.
Symptoms Patients rarely present with severe hyperglycaemia or ketoacidosis. Most are diagnosed by routine out-patient screening which should include routine tests for the concentrations of 2-hour post-meal blood glucose and glycosylated haemoglobin. Sometimes patients present with weight loss, fatigue or an exacerbation of infection which fails to respond to their routine treatment.
Diagnosis Fasting blood glucose concentrations of > 8 mmol 1- 1 or a non-fasting blood glucose concentration of > 12 mmol 1- 1 on two occasions confirms the diagnosis. A glucose tolerance test is rarely indicated.
DIABETES MELLITUS AND CYSTIC FIBROSIS
801
TREATMENT
General considerations It is important to reassure a CF patient who has just had diabetes mellitus diagnosed that this is not uncommon in adult patients with CF. I make a point of emphasizing that diabetes in CF is different from the usual diabetes seen in young people and is easier to manage with less chance of serious complications. The aims of diabetes management in CF are summarized in Table 2. Good management necessitates a team approach with the doctor, nurse and dietitian working with the patient and the family. Table 2. Aims of diabetes management in cystic fibrosis patients, • • • • • • •
Control symptoms. Prevent hypoglycaemia. Encourage maintenance and increase in body weight. Obtain best control of blood glucose appropriate to the patient. Encourage self-reliance and self-care. Obtain the best quality of life. Prevent complications.
Diet I do not manage any CF patients with diabetes on diet alone. It would involve too great a reduction in their calorie intake and so their nutrition would suffer. All patients are given detailed dietetic advice and it is emphasized to them that this is not the same as is given in a routine diabetic clinic or in a booklet written for diabetic patients. The patient with CF has been on a high-calorie, high-protein diet for many years and now we are going to ask him to modify his diet yet again (Table 3). In practice we allow the patient to eat as much as he can and give enough insulin or oral hypoglycaemic agents to cover the food h~ eats. The only restriction is that we stop added sugar and ask them to use sugar-free drinks. We also change glucose polymer food supplements to more appropriate supplements. We encourage three meals a day with mid-morning, mid-afternoon and prebedtime snacks. Patients are encouraged to eat meat, fish, cheese, eggs, bread, potatoes and milk, and for snacks to include bread, yoghurt, plain biscuits, nuts and chocolate. It is important that patients continue to take their pancreatic enzymes with each meal and snack to obtain consistent absorption of food. Each patient should have sugar available as sugar lumps or glucose tablets, in case of hypoglycaemia. Patients are educated to take more calories when they are doing strenuous exercise, and to monitor glucose concentrations especially carefully when they have exacerbations of infections.
Oral hypoglycaemic agents Some CF patients have doubts about oral hypoglycaemic agents (Zipf, 1990), but the author finds that approximately half the adult CF patients
802
M.E. HODSON
Table 3. Contrast in dietary adviceroutinelygivento patientswith diabetes mel|itus and those with cysticfibrosis (adapted from Mueller, 1990). Diabetes mellitus
Cysticfibrosis
Energy
100% RDA or less if overweight
Fat Mono- and disaccharides Salt Snacks
30% calories or less Low intake
120-150% RDA (patients usually underweight) 30-40% calories Negligible restriction
Low intake Scheduled meal plan
Increased intake Ad-lib and as frequently as possible
RDA, recommendeddaily allowance.
with diabetes mellitus can be managed for a time, often a number of years, on oral hypoglycaemic agents. Some later require insulin and may require insulin for short periods during exacerbations of infections. The agent most commonly used is the sulfonylurea glibenclamide given once daily in doses of 2.5-15 mg. If this does not satisfactorily control the blood glucose concentration then insulin is usually required. M o s t patients requiring insulin are managed using two injections of soluble/isophane insulin. Occasionally a long-acting insulin in the morning and mealtime soluble insulin is required. During an exacerbation of infection or surgery, intravenous insulin by infusion may be needed. Patients are taught to measure their blood glucose concentration before meals using BM test strips. Those requiring insulin should test twice daily and those on oral agents on 2 days a week. The aim is to keep the pre-meal glucose in the range 3-7mmol1-1 and to keep glycosylated haemoglobin (HbAlc), which is tested in clinic, below 10% and preferably below 8.5%.
Psychological aspects Patients with CF have a very detailed treatment regimen, often consisting of twice-daily physiotherapy, nebulized antibiotics and bronchodilators, pancreatic enzymes, regular vitamin supplements and frequent hospital admissions for intravenous antibiotics. To add to this the measures needed for good diabetic control can, in some patients, seem altogether too much. Great care and much tact and sympathetic instruction is often needed to avoid the patient becoming depressed. If this happens they may ignore their diets, indulge in binges or omit their insulin. If a patient is nearing the end of his or her life, a suboptimal system of control may be acceptable. Patients who have been chronically ill for many years may have severe economic difficulties and this must be considered when dietary advice is given. It is surprising how bravely the majority of patients react to yet another problem to be mastered in their daily routine, and most comply excellently with treatment.
DIABETES MELLITUS AND CYSTIC FIBROSIS
803
SCREENING
In view of the high incidence of diabetes mellitus in adults with CF, each adult with CF should have tests for random 2-hour post-prandial blood glucose and glycosylated haemoglobin concentrations at least every 6 months during routine clinic visits. If there is weight loss, polyuria or an exacerbation of chest infection not responding to the usual treatment, then diabetes mellitus should be suspected and the appropriate tests performed.
COMPLICATIONS In theory these would include diabetic retinopathy, neuropathy and nephropathy and the macroangiopathies such as peripheral vascular disease, ischaemic heart disease and cerebro-vascular disease. It used to be thought that the complications of diabetes mellitus did not appear in CF patients. This was probably because they did not live long enough after the development of their diabetes. It is, however, true that CF patients rarely have any of the additional risk factors present in many other diabetic patients, such as hyperlipidaemia, obesity, smoking or hypertension. However, microangiopathic complications have now definitely been reported (Allen, 1986; Dolan, 1986; Rodman et al, 1986). An incidence as high as 21% of microangiopathy associated with poor compliance in patients with 10 years or more of diabetes has also been reported (Sullivan and Denning, 1989). In view of this it is now appropriate that regular screening of CF patients with diabetes for microangiopathic complications is carried out. This will include yearly ophthalmological and neurological examination and the measurement of creatinine clearance and urinary protein.
SUMMARY
There is a high prevalence of diabetes mellitus in patients with CF and this is likely to increase in the future as more patients are surviving into adult life. In view of this all CF clinics should routinely screen for diabetes mellitus. The prevalence of diabetes mellitus in adult CF patients is higher than in children, and the onset is commonly insidious. The diabetes seen in CF is not classical Type 1 diabetes or Type 2 diabetes and could more helpfully be called cystic fibrosis-related diabetes (CFRD). Treatment is by oral hypoglycaemic agents or insulin. It is not appropriate to control patients by diet alone. Dietary advice to CF diabetic patients is not the same as that given to non-CF diabetic patients. Microvascular complications have now been reported and careful monitoring of all CF patients with diabetes should be undertaken.
804
M.E. HODSON
REFERENCES Abdul-Karim FW, Dahms BB, Velasco ME & Rodman HM (1986) Islet of Langerhans in adolescents and adults with cystic fibrosis. Archives of Pathology and Laboratory Medicine 110: 602-606. Allen JL (1986) Progressive nephropathy in a patient with cystic fibrosis and diabetes. New England Journal of Medicine 315:764 (letter). Andersen O, Game S, Heilmann C et al (1988) Glucose tolerance and insulin receptor binding to monocytes and erythrocytes in patients with cystic fibrosis. Acta Paediatrica Scandinavica 77: 67-71. Anderson DH (1938) Cystic fibrosis of the pancreas and its relation to celiac disease. American Journal of Diseases of Children 56: 344-399. British Paediatric Association Working Party on Cystic Fibrosis (1988) Cystic fibrosis in the United Kingdom 1977-1985: an improving picture. British Medical Journal 297: 15991602. Cystic Fibrosis Foundation consensus conferences (1990) Vol. 1, section IV, pp 1-8. Cystic Fibrosis Foundation: USA. di Sant'Agnese PA & Davis PB (1979) Cystic fibrosis in adults; severity in five cases and a review of 232 cases in the literature. American Journal of Medicine 66: 121-132. Dolan TF (1986) Microangiopathy in the young adult with cystic fibrosis and diabetes mellitus. New England Journal of Medicine 314: 991-992. Finkelstein SM, Wielinski CL, Elliott GR et al (1988) Diabetes mellitus associated with cystic fibrosis. Journal of Pediatrics 112: 373-377. Geffner ME, Lippe BM, Maclaren NK & Riley WJ (1988) Role of autoimmunity in insulinopenia and carbohydrate derangements associated with cystic fibrosis. Journal of Pediatrics 112: 419-420. Handwerger S, Roth J, Gorden P e t al (1969) Glucose intolerance in cystic fibrosis. New England Journal of Medicine 281:451-460. Hartling SG, Garne S, Binder C et al (1988) Proinsulin, insulin and C-peptide in cystic fibrosis after an oral glucose tolerance test. Diabetes Research 7: 165-169. Hodson ME, Normal AP & Batten JC (1983) Cystic Fibrosis. London: Bailli~re Tindall. Knopfie G (1985) Endokrine Pankreasfunktion bei Mukoviszidoses. Klinische Pi~diatrie 197: 13-20. Knowles MR (1988) Diabetes and cystic fibrosis: new questions emerging from increased longevity. Journal of Pediatrics 112: 415-416. Lebenthal E, Lerner A & Heitlinger L (1986) The pancreas in cystic fibrosis. In Go VLW, Gardner JD, Brooks FP et al (eds) The Exocrine Pancreas, pp 783-817. New York: Raven Press. Lippe BM, Sperling MA & Dooley RR (1977) Pancreatic alpha and beta cell functions in cystic fibrosis. Journal of Pediatrics 90: 751-755. Lippe BM, Kaplan SA, Neufeld ND et al (1980) Insulin receptors in cystic fibrosis: increased receptor number and altered affinity. Pediatrics 65: 1018-1022. Lloyd-Still JD (1983) Textbook on Cystic Fibrosis. Bristol: John Wright. L6hr M, Goertchen P, Nizze H et al (1989) Cystic fibrosis associated islet changes may provide a basis for diabetes. An immunocytochemical and morphometrical study. Virchows Archiv (A) 414: 179--185. Milner AD (1969) Blood glucose and serum insulin levels in children with cystic fibrosis. Archives of Diseases of Childhood 44: 351-355. Mueller D (1990) Nutrition for CF patients with diabetes mellitus. Pediatric Pulmonology, supplement 5: 109-111. National Institute of Arthritis, Metabolism and Digestive Disease (1979) In Cystic Fibrosis; A Disease in Search of Ideas, Vol. 2, pp 33-34. Bethesda, Maryland: (Clinical Series, D H E U Publication no. NIHD 79-1643). Redmond AOB, Buchanan KD & Trimble ER (1977) Insulin and glucagon response to arginine infusion in cystic fibrosis. Acta Paediatrica Scandinavica 66: 199-204. Rodman HM & Matthews LW (1981) Hyperglycaemia in cystic fibrosis: a review of the literature and our own experience. In Warwick WJ (ed.) 1000 Years of Cystic Fibrosis, p 67. University of Minnesota.
DIABETES MELLITUS AND CYSTIC FIBROSIS
805
Rodman HM, Doershuk CF & Roland JM (1986) The interaction of two diseases: diabetes mellitus and cystic fibrosis. Medicine 65: 389-397. Rosan RC, Schwachman H & Kulezycki LL (1962) Diabetes mellitus and cystic fibrosis of the pancreas. American Journal of Diseases of Children 104: 625-634. Stahl M, Girard J, Rutishauser M e t al (1974) Endocrine function of the pancreas in cystic fibrosis; evidence for an impaired glucagon and insulin response following arginine infusion. Journal of Pediatrics 84: 821-824. Stutchfield PR, O'Halloran SM, Smith CS et al (1988) HLA type, islet cell antibodies and glucose intolerance in cystic fibrosis. Archives of Diseases of Childhood 63: 1234--1239. Sullivan MM & Denning CR (1989) Diabetic microangiopathy in patients with cystic fibrosis. Pediatrics 84: 642-647. Wilmshurst EG, Soeldner JS, Holsclaw DS et al (1975) Endogenous and exogenous insulin responses in patients with cystic fibrosis. Pediatrics 55: 75-82. Zipf WB (1990) Therapeutic options for the treatment of diabetes mellitus in cystic fibrosis. Pediatric Pulmonology, supplement 5: 111-114.
Cystic fibrosis (CF) is a disease characterized by bronchopulmonary infection, pancreatic insufficiency and a high sweat sodium concentration. The clinical features are well recognized (Hodson et al, 1983; Lloyd-Still, 1983). In 1938, 80% of patients died within i year of birth but now many are surviving into adult life. There are estimated to be approximately 5000 children and 1500 adults with CF in the UK, and survival to 19 years is now 50% (British Paediatric Association, 1988). The prevalence of diabetes mellitus in patients with CF is much higher than in the general population. Estimates vary from 8-15% (Anderson, 1938; Rosan et al, 1962; di Sant Agnese and Davis, 1979; National Institute of Arthritis, Metabolism and Digestive Disease, 1979; Lebenthal et al, 1986; Rodman et al, 1986; Geffner et al, 1988; Knowles, 1988). In a survey of 448 patients with CF insulin-dependent diabetes developed in 7.6% of patients. Total glycosylated haemoglobin (HbA1) was significantly (p < 0.001) higher in the total CF population than in the general non-CF population (Finkelstein et al, 1988). It is well recognized that the incidence of diabetes mellitus in CF increases with age. About 27 % of children (Milner, 1969), and 57% of a wider age group (Rodman and Matthews, 1981) have impaired glucose tolerance. It has been estimated that 50% of CF patients over the age of 18 years have impaired glucose tolerance (National Institute of Arthritis, Metabolism and Digestive Disease, 1979). The author currently has on computer the records of 218 CF patients aged 15-65 years of whom 24 (11%) are diabetic. There are 12 males and 12 females. The prevalence with age is shown in Table 1. Diabetes mellitus was not found in 279 patients under the age of 119 years on the London Postgraduate Hospitals' computer. In 158 patients between 10 and 14 years it was found in 4%; in older patients diabetes was present in about 15%. Review of the records of 62 adult CF patients with diabetes mellitus who are, or have, attended the Royal Brompton Hospital Adult CF clinic over the last 25 years shows a peak age of onset between 15 and 24 years (Figure 1). PATHOLOGY The clinical features of diabetes mellitus in CF are different from those of either classical Type 1 (juvenile onset) or Type 2 (adult onset non-ketotic) Baillidre's Clinical Endocrinology and Metabolism-797 Vol. 6, No. 4, October 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1621-7 All rights of reproduction in any form reserved
798
M.E. HODSON Table 1. Prevalence of diabetes mellitus in CF patients with age. Age band (years)
Number of CF patients
0-4 5-9 10-14 15-19 20-24 25-29 30-34 ->35
:30 149 158 34 87 59 26 12
Number (%) with diabetes
0 0 7 3 7 8 4 2
(0) (0) (4) (9) (8) (14) (15) (17)
Data for 0-14 years taken from the London Postgraduate Hospitals' database, data for patients -> 15 years from the author's Brompton Hospital Adult CF Clinic.
diabetes. In CF the age of onset is usually 15-25 years, but this diabetes differs from the classical Type i diabetes in that it is not ketotic. It is of slow onset, there is a persistence of some insulin secretion and autoimmune factors are rarely present (Geffner et al, 1988). It is not associated with obesity, as is classical Type 2 diabetes, and indeed most patients are underweight. There may be hypoinsulinaemia as opposed to hyperinsulinaemia and insulin resistance. There is an associated exocrine pancreatic defect which does not occur in most patients with diabetes mellitus. Glucagon secretion is variable in CF diabetes and there may be hypoglucagonaemia or hyperglucagonaemia (Stahl et al, 1974; Redmond et al, 1977; Geffner et al, 1988).
30 O9 t-
20 .#
. . . . . . . .
O. 0
2::::::::
$ ..Q
E ,-n
.=
. . . . . . . .
rff_~ff_if1~
10
Z
10-14
15-19
N 20-24
25-29
30-34
35+
Age of onset of DM Figure 1. The age of onset of diabetes mellitus in 62 patients with cystic fibrosis.
DIABETES MELLITUS AND CYSTIC FIBROSIS
799
It has been suggested that diabetes mellitus in CF should be called insulin-requiring diabetes mellitus (IRDM) (Knowles, 1988) because of the differences from the classical Type 1 and Type 2 diabetes. However, this is not fully comprehensive as there are many patients who can be managed for a time on oral hypoglycaemic agents. Another alternative, CF-related diabetes (CFRD) is more appropriate (CF Foundation, 1990). Abdul-Karim et al (1986) studied the islets of Langerhans in adolescents. The mean percentage surface area occupied by insulin-producing cells (8.3%) in diabetic CF patients was significantly less than in CF patients with normal glucose tolerance (46.7%) and controls (53.4%). The mean percentage surface area occupied by glucagon-producing cells was similar in the three groups. L6hr et al (1989) studied the pancreases of 23 patients dying of CF (aged 5-22 years). The pancreases were either fibrotic ( n = 14) or lipatropic (n = 9). In all, irrespective of the dominating pattern, the islet system was affected by marked peri-insular and intra-insular sclerosis. There was a reduction of approximately 50% in insulin-producing cells in CF patients, This supported the concept that destruction of the exocrine tissue, with concomitant fibrosis and disorganization of the islets, gradually changes the proportional distribution of endocrine cells in favour of noninsulin-producing cells. This could explain the increasing incidence of diabetes mellitus in older patients. Basically there is a delay in peak insulin response to a glucose load (Handwerger et al, 1969; Wilmshurst et al, 1975; Lippe et al, 1977). Hartling et al (1988) confirmed that patients had lower insulin and C-peptide concentrations than controls 30 minutes after a glucose load, but the responses were sustained so that the area under the curve was comparable with controls. In contrast, they showed that the area under the pro-insulin curve was significantly higher in CF patients with impaired glucose tolerance than in controls and CF patients with normal glucose tolerance. The early diminished insulin response has been demonstrated with other islet 13-cell stimulators; intravenous glucose, arginine and tolbutamide (Wilmshurst et al, 1975; Redmond et al, 1977; Knopfle, 1985). There appears to be increased insulin sensitivity (Wilmshurst et al, 1975) and high insulin receptor binding (Lippe et al, 1980; Andersen et al, 1988). There may be true pancreatic hyposecretion of insulin in many patients with CF, whereas the peripheral sensitivity to insulin appears normal or enhanced. Increased prevalence of islet cell antibodies has been found in CF with impaired glucose tolerance (Stutchfield et al, 1988). It may be that the antibodies are formed in response to the damaged pancreatic tissue and further impair islet [3-cell function.
THE SPECIAL C H A L L E N G E S OF M A N A G I N G DIABETES
MELLITUS IN PATIENTS WITH CF Patients with CF usually malabsorb and this leads to malnutrition, in contrast to many non-CF diabetic patients who are overweight. Absorption
800
M . E . HODSON
of food is less efficient than in non-CF patients and absorption may be erratic, even when regular pancreatic supplements are given with all meals and snacks. Some very malnourished patients are fed overnight using gastrostomy tubes, making it necessary to control blood glucose concentrations very carefully at night as well as during the day. Occasional patients are on intravenous nutrition. Many CF patients have liver disease and others are taking corticosteroids which upset glucose metabolism. During periods of exacerbation of pulmonary infection patients often become too breathless to eat properly or to maintain regular exercise, which further complicates diabetes control. During pregnancy, lactation or surgery, such as pleurodesis or abdominal surgery, extra attention to the control of blood glucose is necessary. When a patient is having heart-lung transplantation for terminal respiratory failure, very great care is needed to control the blood glucose concentration. Immediately after transplantation, because of the high doses of steroids used peri-operatively, many previously non-diabetic CF patients develop diabetes mellitus which needs to be controlled using an insulin infusion. As the patient's condition improves this can be stopped and the patient changed to twice-daily insulin, and in some patients there is no need for any further treatment. All patients need careful and individual diabetic control. One of the biggest problems is that the dietary recommendations made for non-diabetic CF patients and for non-CF diabetic patients are very different--and the diabetic advice that is given to a CF diabetic patient has to be different from that given to other diabetic patients in the community. Confusion can occur if CF diabetic patients go to the local diabetic clinic and are seen by a junior member of staff who tries to manage them in the same way as other diabetic patients. The author thinks CF diabetic patients are best cared for within the context of the CF clinic where the doctor, nurses and dietitians are familiar with their problems. The exception is when an endocrinologist has taken a special interest in their condition and sees them personally at a diabetic clinic. This does, however, increase the number of hospital visits the patient has to make.
Symptoms Patients rarely present with severe hyperglycaemia or ketoacidosis. Most are diagnosed by routine out-patient screening which should include routine tests for the concentrations of 2-hour post-meal blood glucose and glycosylated haemoglobin. Sometimes patients present with weight loss, fatigue or an exacerbation of infection which fails to respond to their routine treatment.
Diagnosis Fasting blood glucose concentrations of > 8 mmol 1- 1 or a non-fasting blood glucose concentration of > 12 mmol 1- 1 on two occasions confirms the diagnosis. A glucose tolerance test is rarely indicated.
DIABETES MELLITUS AND CYSTIC FIBROSIS
801
TREATMENT
General considerations It is important to reassure a CF patient who has just had diabetes mellitus diagnosed that this is not uncommon in adult patients with CF. I make a point of emphasizing that diabetes in CF is different from the usual diabetes seen in young people and is easier to manage with less chance of serious complications. The aims of diabetes management in CF are summarized in Table 2. Good management necessitates a team approach with the doctor, nurse and dietitian working with the patient and the family. Table 2. Aims of diabetes management in cystic fibrosis patients, • • • • • • •
Control symptoms. Prevent hypoglycaemia. Encourage maintenance and increase in body weight. Obtain best control of blood glucose appropriate to the patient. Encourage self-reliance and self-care. Obtain the best quality of life. Prevent complications.
Diet I do not manage any CF patients with diabetes on diet alone. It would involve too great a reduction in their calorie intake and so their nutrition would suffer. All patients are given detailed dietetic advice and it is emphasized to them that this is not the same as is given in a routine diabetic clinic or in a booklet written for diabetic patients. The patient with CF has been on a high-calorie, high-protein diet for many years and now we are going to ask him to modify his diet yet again (Table 3). In practice we allow the patient to eat as much as he can and give enough insulin or oral hypoglycaemic agents to cover the food h~ eats. The only restriction is that we stop added sugar and ask them to use sugar-free drinks. We also change glucose polymer food supplements to more appropriate supplements. We encourage three meals a day with mid-morning, mid-afternoon and prebedtime snacks. Patients are encouraged to eat meat, fish, cheese, eggs, bread, potatoes and milk, and for snacks to include bread, yoghurt, plain biscuits, nuts and chocolate. It is important that patients continue to take their pancreatic enzymes with each meal and snack to obtain consistent absorption of food. Each patient should have sugar available as sugar lumps or glucose tablets, in case of hypoglycaemia. Patients are educated to take more calories when they are doing strenuous exercise, and to monitor glucose concentrations especially carefully when they have exacerbations of infections.
Oral hypoglycaemic agents Some CF patients have doubts about oral hypoglycaemic agents (Zipf, 1990), but the author finds that approximately half the adult CF patients
802
M.E. HODSON
Table 3. Contrast in dietary adviceroutinelygivento patientswith diabetes mel|itus and those with cysticfibrosis (adapted from Mueller, 1990). Diabetes mellitus
Cysticfibrosis
Energy
100% RDA or less if overweight
Fat Mono- and disaccharides Salt Snacks
30% calories or less Low intake
120-150% RDA (patients usually underweight) 30-40% calories Negligible restriction
Low intake Scheduled meal plan
Increased intake Ad-lib and as frequently as possible
RDA, recommendeddaily allowance.
with diabetes mellitus can be managed for a time, often a number of years, on oral hypoglycaemic agents. Some later require insulin and may require insulin for short periods during exacerbations of infections. The agent most commonly used is the sulfonylurea glibenclamide given once daily in doses of 2.5-15 mg. If this does not satisfactorily control the blood glucose concentration then insulin is usually required. M o s t patients requiring insulin are managed using two injections of soluble/isophane insulin. Occasionally a long-acting insulin in the morning and mealtime soluble insulin is required. During an exacerbation of infection or surgery, intravenous insulin by infusion may be needed. Patients are taught to measure their blood glucose concentration before meals using BM test strips. Those requiring insulin should test twice daily and those on oral agents on 2 days a week. The aim is to keep the pre-meal glucose in the range 3-7mmol1-1 and to keep glycosylated haemoglobin (HbAlc), which is tested in clinic, below 10% and preferably below 8.5%.
Psychological aspects Patients with CF have a very detailed treatment regimen, often consisting of twice-daily physiotherapy, nebulized antibiotics and bronchodilators, pancreatic enzymes, regular vitamin supplements and frequent hospital admissions for intravenous antibiotics. To add to this the measures needed for good diabetic control can, in some patients, seem altogether too much. Great care and much tact and sympathetic instruction is often needed to avoid the patient becoming depressed. If this happens they may ignore their diets, indulge in binges or omit their insulin. If a patient is nearing the end of his or her life, a suboptimal system of control may be acceptable. Patients who have been chronically ill for many years may have severe economic difficulties and this must be considered when dietary advice is given. It is surprising how bravely the majority of patients react to yet another problem to be mastered in their daily routine, and most comply excellently with treatment.
DIABETES MELLITUS AND CYSTIC FIBROSIS
803
SCREENING
In view of the high incidence of diabetes mellitus in adults with CF, each adult with CF should have tests for random 2-hour post-prandial blood glucose and glycosylated haemoglobin concentrations at least every 6 months during routine clinic visits. If there is weight loss, polyuria or an exacerbation of chest infection not responding to the usual treatment, then diabetes mellitus should be suspected and the appropriate tests performed.
COMPLICATIONS In theory these would include diabetic retinopathy, neuropathy and nephropathy and the macroangiopathies such as peripheral vascular disease, ischaemic heart disease and cerebro-vascular disease. It used to be thought that the complications of diabetes mellitus did not appear in CF patients. This was probably because they did not live long enough after the development of their diabetes. It is, however, true that CF patients rarely have any of the additional risk factors present in many other diabetic patients, such as hyperlipidaemia, obesity, smoking or hypertension. However, microangiopathic complications have now definitely been reported (Allen, 1986; Dolan, 1986; Rodman et al, 1986). An incidence as high as 21% of microangiopathy associated with poor compliance in patients with 10 years or more of diabetes has also been reported (Sullivan and Denning, 1989). In view of this it is now appropriate that regular screening of CF patients with diabetes for microangiopathic complications is carried out. This will include yearly ophthalmological and neurological examination and the measurement of creatinine clearance and urinary protein.
SUMMARY
There is a high prevalence of diabetes mellitus in patients with CF and this is likely to increase in the future as more patients are surviving into adult life. In view of this all CF clinics should routinely screen for diabetes mellitus. The prevalence of diabetes mellitus in adult CF patients is higher than in children, and the onset is commonly insidious. The diabetes seen in CF is not classical Type 1 diabetes or Type 2 diabetes and could more helpfully be called cystic fibrosis-related diabetes (CFRD). Treatment is by oral hypoglycaemic agents or insulin. It is not appropriate to control patients by diet alone. Dietary advice to CF diabetic patients is not the same as that given to non-CF diabetic patients. Microvascular complications have now been reported and careful monitoring of all CF patients with diabetes should be undertaken.
804
M.E. HODSON
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