Cystic Fibrosis-Related Diabetes

Cystic fibrosis related diabetes is diabetes caused by insulin deficiency from pancreatic damage in cystic fibrosis. It is distinct from type 1 and type 2 diabetes and strongly affects nutrition and lung function.

Prevalence rises with age: roughly 2% of children, about one fifth of adolescents and up to half of adults. Ketoacidosis is rare.

Risk factors are severe CFTR genotype, pancreatic insufficiency, female sex, cystic fibrosis liver disease, glucocorticoid use and lung transplantation.

Pathophysiology.

Fibrosis and fatty replacement of the pancreas destroy islets. Insulin secretion is delayed and reduced, first after meals, and the incretin effect is impaired.

Insulin resistance rises during infection and with steroids. Residual basal insulin explains the rarity of ketoacidosis, but glucagon response is impaired and hypoglycaemia is common.

Insulin deficiency is catabolic: it accelerates weight loss and lung function decline. Microvascular complications appear after about 10 years of diabetes. Macrovascular disease is rare.

• Often silent. Unexplained weight loss, falling lung function, delayed puberty or poor growth despite adequate enzymes and treatment.
• Polyuria or polydipsia may be absent. Hypoglycaemia occurs after meals or exercise.

• Annual 75 g (or 1.75 g/kg, maximum 75 g) oral glucose tolerance test from age 10 when clinically stable, at least 3 to 4 weeks after an exacerbation.
• Diabetes: 2-hour glucose 11.1 mmol/L or more or fasting glucose 7.0 mmol/L or more. Impaired glucose tolerance: 2-hour 7.8 to 11.0 mmol/L.
• HbA1c is insensitive for screening and is used only for monitoring. A value of 48 mmol/mol (6.5%) or more supports the diagnosis.
• Acute illness: diagnosis if fasting glucose is 7.0 mmol/L or more, or 2-hour post-meal glucose is 11.1 mmol/L or more on 2 days during steroids, intravenous antibiotics or enteral feeding. Retest when stable.
• Screen additionally before pregnancy, in pregnancy (12 to 16 weeks and 24 to 28 weeks), before lung transplant and when starting high dose steroids.

Differential diagnosis.

• Type 1 diabetes (autoantibodies present).
• Type 2 diabetes.
• Stress or steroid hyperglycaemia during exacerbations.
• Hyperglycaemia on enteral feeding, or post-transplant diabetes.

• Insulin is the treatment. Start mealtime rapid acting insulin with a carbohydrate ratio of about 1 unit for each 10 to 15 g, add basal insulin for fasting hyperglycaemia, and titrate to glucose. Starting at low doses limits hypoglycaemia.
• Oral agents are not first line, because they do not correct insulin deficiency and have limited evidence.
• Diet: high energy, high fat and salt as usual for cystic fibrosis. Do not restrict calories or carbohydrate. Take pancreatic enzymes with all meals and snacks.
• Increase insulin during infections and with steroid therapy, and reduce it as they settle.
• Modulator therapy (for example elexacaftor, tezacaftor and ivacaftor) may improve insulin secretion; review insulin doses after starting.
• Hypoglycaemia: 15 to 20 g oral glucose, repeat at 15 minutes; glucagon 1 mg intramuscularly (0.5 mg if under 25 kg) when unable to take oral intake.

Special groups. Pregnancy: pre-conception counselling, enzyme and nutrition optimisation, tight insulin titration, and frequent glucose checks. Post lung transplant: expect insulin requirement from steroids.

Monitoring. HbA1c every 3 months, with a target of 53 mmol/mol (7.0%) or under, individualised. After 5 years of diabetes: annual retinal screening and urine albumin to creatinine ratio, with blood pressure. Weight and lung function every visit.

Referral and escalation. Joint cystic fibrosis and diabetes team at diagnosis. Urgent review for ketosis (ketones 3.0 mmol/L or more) or glucose over 20 mmol/L with illness.