Dr Kate Millar and Professor Michael Cummings present a summary of guidance that aims to help practitioners to identify and manage pancreatic exocrine insufficiency in people with diabetes

Dr Kate Millar

Dr Kate Millar

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Read this article to learn more about:

  • the spectrum of symptoms of pancreatic exocrine insufficiency (PEI)
  • the importance of diagnosing and treating gastrointestinal manifestations of PEI
  • the relationship between PEI and glycaemic control in people with diabetes.

COVID-19 considerations

Key points

Implementation actions for STPs and ICSs

Pancreatic exocrine insufficiency (PEI) is characterised by the secretion of insufficient pancreatic enzymes (consisting of amylase, proteases, and lipase) into the duodenum following a meal to maintain normal digestive processes.1,2 This results in abnormal food breakdown, leading to nutrient malabsorption and malnutrition.1,2

Some degree of biochemical pancreatic exocrine insufficiency (PEI) has been reported in around 50% of people with type 1 diabetes and 30–50% of people with type 2 diabetes,3 although the condition is not necessarily correlated with clinical symptoms. PEI is a functional state with a variety of underlying aetiologies in addition to diabetes mellitus, including cystic fibrosis, chronic pancreatitis, pancreatic cancer, pancreatic surgery, and coeliac disease.1,2 Symptoms exist on a spectrum ranging from mild to very severe with a complete absence of residual pancreatic enzyme activity.1,4

It is important to diagnose and treat PEI because it can be the reversible cause of unpleasant gastrointestinal (GI) symptoms for the patient and may result in nutrient malabsorption and vitamin deficiencies. Furthermore, in people with diabetes, there may be a relationship between PEI and glycaemic control. The Guidelines working party algorithm Gastrointestinal disorders in diabetes—could it be pancreatic exocrine insufficiency? was developed to improve awareness of PEI and enable its confident identification and management in primary care (see Figure 1).5

WPG - Pancreatic exocrine insufficiency

Figure 1: The Guidelines working party algorithm on PEI in diabetes5

Hambling C, Cummings M, Merriman H, Widdowson J. Gastrointestinal disorders in diabetes—could it be pancreatic exocrine insufficiency? In: Wilkhu P, editor. Guidelines—summarising clinical guidelines for primary care. 72nd edition. Chesham: MGP Ltd, 2019. pp. 73–76. Available at: www.guidelines.co.uk/diabetes/pancreatic-exocrine-insufficiency-guideline/454173.article

The aetiology of PEI in diabetes

The two distinct roles of the pancreas—the endocrine and exocrine roles—are functionally and anatomically closely related. Type 3c diabetes is diabetes due to pancreatic disease or injury, in which both endocrine and exocrine hormone production are affected. Type 3c diabetes is said to account for just under 10% of cases in people with diabetes in Western populations, and its most common cause is chronic pancreatitis.6 The aetiology of PEI differs between type 1 and type 2 diabetes, and several possible mechanisms have been described.3 These include diabetic neuropathy, lack of insulin as a trophic factor for exocrine tissue, dysregulation due to changes in the secretion and/or action of other islet hormones (including glucagon and somatostatin), and autoimmunity against endocrine and exocrine antigens (specific to type 1 diabetes).3 Occasionally, there may be a previously undiagnosed pancreatic disease, such as chronic pancreatitis (suggesting that the individual in fact has type 3c diabetes).3

Clinical features and assessment

The main symptoms of PEI at presentation are shown in Box 1. Although steatorrhoea and weight loss are the hallmark symptoms, they only occur in patients with severe or late-stage disease.5 In practice, the Bristol Stool Chart is a useful tool to assess diarrhoea, with scores of 5, 6, and 7 raising suspicion of the condition.5

Box 1: Main symptoms of PEI at first presentation5

Any combination of the following symptoms may suggest PEI:

  • abdominal pain or discomfort
  • bloating
  • flatulence
  • diarrhoea
  • weight loss[A]
  • steatorrhoea[A]
  • altered glycaemic control in patients with diabetes and GI symptoms.

[A] Typically only seen in patients with severe or late-stage disease.

PEI=pancreatic exocrine insufficiency; GI=gastrointestinal

Hambling C, Cummings M, Merriman H, Widdowson J. Gastrointestinal disorders in diabetes—could it be pancreatic exocrine insufficiency? In: Wilkhu P, editor. Guidelines—summarising clinical guidelines for primary care. 72nd edition. Chesham: MGP Ltd, 2019. pp. 73–76. Available at: www.guidelines.co.uk/diabetes/pancreatic-exocrine-insufficiency-guideline/454173.article

It is important to remember that GI symptoms occur frequently in people with diabetes—in one study, over 80% of patients with diabetes reported GI symptoms7 —and that these symptoms have a number of possible causes of which PEI is just one. Given their high symptom burden, it is important to ask patients about GI symptoms, because the information may not be volunteered or considered relevant by the patient or the healthcare professional conducting their diabetes management. An important function of the Guidelines working party algorithm on GI disorders in diabetes is to raise awareness of PEI as a recognised and treatable cause of such symptoms.5 Moreover, it provides a framework through which to consider differential diagnoses and the management pathway. See Box 2 for tips on implementation of the guidance in primary care.

Box 2: Tips for implementation in primary care

  • Enquire about GI symptoms at routine diabetes reviews—the Bristol Stool Chart may be a useful tool to help identify patients in whom there is clinical suspicion of PEI
  • To facilitate this, a prompt to enquire about GI symptoms should be included in the local diabetes review proforma
  • Educational support to community diabetes teams, including practice nurses and dietitians, should be provided to increase awareness and opportunities for patient identification.

GI=gastrointestinal; PEI=pancreatic exocrine insufficiency

Differential diagnosis

Differential diagnoses for GI disorders may be diabetes-related and include side-effects of antidiabetic medications (particularly metformin and glucagon-like peptide-1 [GLP-1] receptor agonists), gastroparesis and autonomic neuropathy affecting the bowel, and coeliac disease (which more commonly affects people with type 1 diabetes).5 Other differential diagnoses not specific to diabetes include irritable bowel syndrome, inflammatory bowel diseases, and bowel cancer.5 For this reason, clinical assessment/examination and baseline investigations in primary care are vital. Initial diagnostic investigations recommended in primary care include:

  • full blood count
  • urea and electrolytes
  • liver function tests
  • blood glucose
  • glycated haemoglobin (HbA1c)
  • tissue transglutaminase antibody
  • thyroid function
  • calcium and vitamin D levels
  • stool sample testing.

Further information on diagnostic investigations can be obtained from the Primary Care Society for Gastroenterology and from the NICE Pathways Gastrointestinal conditions overview.8

The diagnostic test for PEI involves the measurement of pancreatic enzymes in the stool, specifically elastase-1 (the faecal elastase-1 or FE-1 test).1 FE-1 is a reliable and easy test that requires one random stool sample; however, its results can be falsely positive in the presence of coexisting very watery diarrhoea.5 An FE-1 value <200 mcg/g is suggestive of PEI, with values of <100 mcg/g indicating more severe disease.5 A value of 200–250 mcg/g is considered borderline and retesting is recommended.5 The authors recommend testing two samples to confirm biochemical evidence of PEI.

As guided by clinical assessment and suspicion, other stool sample investigations for differential causes may include faecal occult blood test, culture, and calprotectin; the latter, if elevated, is suggestive of inflammatory bowel disease.5

Management in primary care and criteria for referral

If clinical history and FE-1 values indicate PEI, and providing there are no suspicions of another underlying cause or concerning features, a trial of pancreatic enzyme replacement therapy (PERT) in primary care is appropriate.5

Patients should be referred to a gastroenterologist for further pancreatic evaluations, such as endoscopic ultrasound, when other underlying causes are suspected.5 Specialist referral is also appropriate in the setting of other concerning features, including unexplained weight loss, GI bleeding, raised calprotectin levels, or a clinical history suggestive of gastroparesis.5 Patients with persistent loose stools that make FE-1 measurements unreliable should also be referred to a specialist.5

Once PEI is diagnosed, the goal of treatment is to normalise digestion and alleviate symptoms in addition to managing the underlying cause.9 Normalising digestion is achieved using PERT—this oral preparation is taken at mealtimes and with snacks, with the dose adjusted according to the fat content of the food and to clinical response. Dosage information on different PERT formulations can be obtained from the British National Formulary.9,10 A typical starting regimen that the authors frequently use in their clinical practice is 25,000 units of pancreatin with snacks and 40,000–50,000 units with meals.

Monitoring is based upon clinical response (symptoms, weight change, and markers of malnutrition) and, depending on these indicators, PERT doses should be up-titrated every 4–6 weeks.5 The drug works locally and remains within the GI tract; therefore, there is no set maximum dose.5 A retrospective study has shown that approximately 80% of patients with low FE-1 values respond to treatment with PERT.11 It is important to advise patients taking PERT on other general measures, including smoking cessation and reducing alcohol intake, and to assess levels of vitamin D and offer appropriate supplementation per national guidelines.11,12 In patients whose PEI fails to respond to adequate PERT dosing, additional acid suppression with a proton pump inhibitor may be beneficial by slowing down PERT degradation.9 In patients whose PEI shows no improvement, the diagnosis may need to be questioned—such patients should be referred to either a gastroenterologist or to a diabetologist with an interest in GI disorders/PEI.5

Glycaemic control in patients with diabetes and PEI

It has been shown that PERT enhances the release of the postprandial incretins glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 in patients with PEI, a process that is thought to be triggered by the improved absorption of nutrients.13 Secretion of GIP and GLP-1 leads to a slower rate of gastric emptying and stimulates the production of insulin, leading to a more controlled rise in postprandial glucose.13 This enhanced incretin response in patients with PEI treated with PERT may translate into improved glycaemic control, although this is an area where research for conclusive evidence is ongoing. Some studies have suggested that glycaemic control is enhanced in individuals with diabetes and PEI who are treated with PERT, based on reductions in HbA1c and hypoglycaemic episodes.14,15 PERT may also affect glycaemic control by improving the absorption of oral antidiabetic medications.5 From a practical perspective, the patient’s glycaemic response and blood glucose levels should be checked frequently during treatment, as doses of antidiabetic therapies such as sulfonylureas and insulin may need adjusting.5

Summary

Pancreatic exocrine insufficiency in diabetes often goes undiagnosed, but the symptoms are quick and straightforward to enquire about; therefore, it is essential to raise awareness of the condition among all healthcare professionals caring for people with diabetes. This is especially pertinent in primary care, given that this is where most diabetes consultations occur. PEI appears to be common in people both with type 1 and type 2 diabetes and could reasonably be considered another complication of the condition. Successful identification and treatment are important for the individual, as they can lead to a reduction in GI symptom burden, improvement in nutritional state and, potentially, improved glycaemic control.

Dr Kate Millar 

Specialty Registrar Diabetes and Endocrinology and NIHR Clinical Fellow, Portsmouth Hospitals NHS Trust

Professor Michael Cummings 

Consultant Physician Diabetes and Endocrinology, Portsmouth Hospitals NHS Trust

COVID-19 considerations

  • People with PEI and diabetes are at no greater risk from COVID-19 than people with diabetes and no PEI. Guidelines provided by the UK Government and Diabetes UK should be followed to minimise risk from COVID-19
  • Individuals with diabetes are particularly vulnerable to becoming seriously ill with COVID-19 as a result of difficulties managing their glucose levels, potentially leading to diabetic ketoacidosis. People with diabetes should follow the Diabetes UK and Trend UK sick day rules if they become unwell
  • People with diabetes are in the ‘clinically vulnerable group’, which means that they should stringently follow the relevant social distancing guidance. Some people with diabetes may be in the ‘clinically extremely vulnerable group’ (for example, those with cystic fibrosis-related diabetes) for whom shielding is recommended. Guidance on shielding is available for each of the four nations of the UK:
  • During the COVID-19 outbreak, although most routine appointments such as annual diabetes reviews in primary care have been cancelled or postponed, access to specialist care (for example, at diabetic foot or pregnancy clinics) has continued. Remote diabetes reviews have been facilitated by the use of technology enabling glucose data to be shared and viewed remotely. It is important to emphasise that, regardless of the COVID-19 pandemic, patients can and should access the emergency department and specialist input as needed
  • People with diabetes should be advised that there is no need to stockpile insulin, diabetes medicines, or technology supplies, which could in turn cause shortages and put other patients at risk. The Government has been working with industry and partners to monitor the impact of COVID-19 on the UK supply chain of medicines and technology and put measures in place to ensure their uninterrupted supply to UK patients
  • Data from NHS England show that the risk of dying from COVID-19 is higher for individuals with diabetes than those without the condition; among individuals hospitalised with COVID-19, people with type 1 diabetes are 3.5 times more likely to die, and people with type 2 diabetes twice as likely to die, than people without diabetes.16 However, age remains the strongest factor affecting baseline risk. Other important risk factors are ethnicity and body weight. To help reduce the individual risk of a person with diabetes, they should be advised and supported to keep their blood glucose levels within their target range as much as possible, follow healthy lifestyle advice, and practice weight management.

PEI=pancreatic exocrine insufficiency

Key points

  • Gastrointestinal symptoms in diabetes are common and may be caused by PEI, but this is often under-diagnosed
  • PEI is usually straightforward to diagnose and treat, but improved awareness among diabetes healthcare professionals and patients is key
  • Individuals with diabetes and PEI treated with PERT benefit from improvements in their gastrointestinal symptoms and nutritional state
  • There is ongoing research into the potential for PERT to improve glycaemic control.

PEI=pancreatic exocrine insufficiency; PERT=pancreatic enzyme replacement therapy

Implementation actions for STPs and ICSs

written by Dr David Jenner, GP, Cullompton, Devon

The following implementation actions are designed to support STPs and ICSs with the challenges involved with implementing new guidance at a system level. Our aim is to help you consider how to deliver improvements to healthcare within the available resources.

  • Consider establishing a joint diabetes and gastrointestinal multi-disciplinary team to review national guidance and coordinate a local response
  • Raise awareness of pancreatic exocrine insufficiency among primary care diabetes teams, who probably have limited knowledge in this area
  • Publish local guidelines and algorithms for the screening for, assessment of, and management of this condition; include trigger points for referral to specialist care using the algorithm in the article (Figure 1) as a reference point
  • Ensure direct access for faecal elastase testing for primary care
  • Update local formularies with choices for pancreatic enzyme replacement therapies.

STP=sustainability and transformation partnership; ICS=integrated care system

References

  1. Guts UK. Pancreatic exocrine insufficiency (PEI) and pancreatic enzyme replacement therapy (PERT). gutscharity.org.uk/advice-and-information/conditions/pancreatic-exocrine-insufficiency-pei-and-pancreatic-enzyme-replacement-therapy-pert/ (accessed 2 June 2020).
  2. Struyvenberg M, Martin C, Freedman S. Practical guide to exocrine pancreatic insufficiency—breaking the myths. BMC Med 2017; 15 (1): 29.
  3. Hardt P, Ewald N. Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes? Exp Diabetes Res 2011; 2011: 761950.
  4. Trend UK. Pancreatic exocrine insufficiency and diabetes. Brixworth: Trend UK, 2017. Available at: trend-uk.org/wp-content/uploads/2017/02/PEI-healthcare-leaflet-v8-approved.pdf
  5. Hambling C, Cummings M, Merriman H, Widdowson J. Gastrointestinal disorders in diabetes—could it be pancreatic exocrine insufficiency? In: Wilkhu P, editor. Guidelines—summarising clinical guidelines for primary care. 72nd edition. Chesham: MGP Ltd, 2019. pp. 73–76. Available at: www.guidelines.co.uk/diabetes/pancreatic-exocrine-insufficiency-guideline/454173.article
  6. Ewald N, Kaufmann C, Raspe A et al. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev 2012; 28 (4): 338–342.
  7. Bytzer P, Talley N, Leemon M et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med 2001; 161 (16): 1989–1996.
  8. NICE.Gastrointestinal conditions overview. NICE Pathways. pathways.nice.org.uk/pathways/gastrointestinal-conditions (accessed 2 June 2020).
  9. British National Formulary. Exocrine pancreatic insufficiency. bnf.nice.org.uk/treatment-summary/exocrine-pancreatic-insufficiency.html (accessed 2 June 2020).
  10. British National Formulary. Pancreatin. bnf.nice.org.uk/drug/pancreatin.html (accessed 2 June 2020).
  11. Campbell J, Sanders D, Francis K et al. Should we investigate gastroenterology patients for pancreatic exocrine insufficiency? A dual centre UK study. J Gastrointest Liver Dis 2016; 25 (3): 303–309.
  12. NICE. Vitamin D deficiency in adults—treatment and prevention. Clinical Knowledge Summary. cks.nice.org.uk/vitamin-d-deficiency-in-adults-treatment-and-prevention#!scenario (accessed 2 June 2020).
  13. Knop F, Vilsbøll T, Larsen S et al. Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. Am J Physiol Endocrinol Metab 2007; 292 (1): E324–E330.
  14. Ebert R, Creutzfeldt W. Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution. Diabetologia 1980; 19 (3): 198–204.
  15. Ewald N, Bretzel R, Fantus I et al. Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-centre trial. Diabetes Metab Res Rev 2007; 23 (5): 386–391.
  16. NHS England. NHS expands offer of help to people with diabetes during coronavirus outbreak. www.england.nhs.uk/2020/05/nhs-expands-offer-of-help-to-people-with-diabetes-during-coronavirus-outbreak/ (accessed 2 June 2020).