Gastrointestinal Disorders in Diabetes—Could it be Pancreatic Exocrine Insufficiency?

This management algorithm was developed by a multidisciplinary expert panel: Hambling C et al with the support of a grant from Mylan Ltd. See end of summary for full disclaimer.

In this algorithm:

• Pancreatic exocrine insufficiency in diabetes
• Differential diagnosis
• Assessment in primary care
• Referral criteria
• Management
• Glycaemic control.

Assessment of Gastrointestinal Disorders in Patients with Diabetes

Pancreatic Exocrine Insufficiency in Diabetes

• Pancreatic exocrine insufficiency (PEI) is characterised by a deficiency of three major groups of pancreatic enzymes (amylase, protease, lipase):
  • this results in impaired digestion, with abnormal food breakdown, leading to nutrient malabsorption and malnutrition
• Some degree of PEI has been reported in 50% people with type 1 and 30–50% people with type 2 diabetes:
  • co-existing PEI in people with either type 1 or type 2 diabetes is likely to be a different clinical entity to pancreatic diabetes (sometimes referred to as type 3c diabetes)
  • 5–10% of people with diabetes in Western populations have type 3c diabetes, or diabetes associated with chronic pancreatitis, which is often misclassified as either type 1 or type 2 diabetes:
    • type 3c diabetes is diabetes due to pancreatic disease or injury so both endocrine and exocrine hormone production are affected

Differential Diagnosis

• Gastrointestinal (GI) symptoms are commonly attributed to GI side-effects of diabetes medications, particularly metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors:
  • if symptoms persist despite stopping the medication or reducing the dose, consider an alternative cause for these symptoms
• Box 1, below, shows the clinical features suggestive of PEI:
  • steatorrhoea and weight loss typically occur only in severe cases or late-stage disease and their absence does NOT exclude a diagnosis of PEI
  • rectal bleeding and blood in the stool are not due to PEI and should be considered red flag signs warranting specialist referral
  • diarrhoea and scores of 5, 6 or 7 on the Bristol Stool Chart are consistent with PEI
• A differential diagnosis should consider:
  • conditions associated with diabetes:
    • GI side-effects associated with diabetes medications (see above)
    • autonomic neuropathy affecting the bowel
    • coeliac disease*
  • conditions in the general population and not specific to diabetes:
    • irritable bowel syndrome
    • inflammatory bowel diseases
    • bowel cancer
    • coeliac disease*

*Coeliac disease, although common in the general population, more commonly affects people with type 1 diabetes

Assessment in Primary Care

• Faecal elastase-1 <200 µg/g is suggestive of PEI, with values <100 µg/g indicating more severe disease. A value of 200–250 µg/g is considered borderline with retesting recommended:
  • FE-1 may be reduced in patients diagnosed with coeliac disease or IBS suggesting PEI may be the cause of symptoms in these patients or the patient may have both conditions
  • be aware that this measure can be unreliable if the patient has very loose stools
  • if the patient has persistent, very loose and prolonged stools, refer to GI services
• Elevated calprotectin levels may be suggestive of inflammatory bowel disease
• Test for vitamin D deficiency by measuring serum 25 hydroxyvitamin D (25OHD) levels (if available):
  • consult national and local guidelines
  • consider vitamin D replacement therapy alongside pancreatic enzyme replacement therapy (PERT) where indicated in line with guideline recommendations
• Availability of DEXA scans is variable, but if available, may be warranted as these patients may be at risk of reduced bone mineral density

Referral Criteria

• If clinical history and FE-1 levels indicate PEI and no other underlying cause other than diabetes is present, the patient can be treated in primary care:
  • if the patient does not respond to treatment, refer to specialist (gastroenterologist or diabetologist with an interest in GI disorders/PEI)
• Where other underlying causes are suspected, refer patients to gastroenterologist for tests such as endoscopic ultrasound to identify pancreatic disease, or other pancreatic imaging:
  • a referral is also appropriate if PEI is suspected but the patient has persistent loose stools that make FE-1 measurements unreliable
• The following may require specialist referral:
  • unexplained weight loss, gastrointestinal bleeding, raised calprotectin levels, or a clinical history suggestive of gastroparesis

Management

• Pancreatic enzyme replacement therapy (PERT) should be titrated upwards every 4–6 weeks depending on the patient’s clinical response:
  • take with meals or immediately before eating
  • see BNF for dosage information
  • there is no maximum dose specified as the drug works within the gastrointestinal tract
  • patients should be monitored for clinical response (e.g. improvement in symptoms, weight, nutritional status)
• Advise on smoking cessation, reducing alcohol intake, and/or vitamin D supplementation if appropriate
• A healthy diet is recommended—altering fat content in the diet is controversial, therefore, refer patient to a dietician for expert advice

Glycaemic Control

• PERT can affect glycaemic control pathways via:
  • altered action of the hormones leptin and incretins on glucose homeostasis; for example it may improve the incretin response to food and consequently lower blood glucose levels
  • improving absorption of oral diabetes medication
• The patient’s glycaemic response and blood glucose levels should be checked frequently during treatment as the dose of the diabetes medication may need adjusting (especially sulphonylureas and insulin).