Coeliac disease and pancreatic exocrine insufficiencyScheBo Biotech
However, evidence from a new study shows that around one third of these patients actually have a severe pancreatic exocrine insufficiency, which can be successfully managed by enzyme replacement therapy. This important finding can help substantially improve the quality of life of these patients.
Coeliac disease (CD) is a state of heightened immunological responsiveness to ingested gluten in genetically susceptible individuals.1 Classically, patients with CD present with gastrointestinal symptoms such as diarrhoea, iron deficiency anaemia or weight loss.
The diagnosis is made using a combination of clinical suspicion, positive immunological testing (particularly endomyseal [EMA] or tissue transglutaminase [TTG] antibodies), and distal duodenal biopsy which confirms the presence of villous atrophy. Recent population screening studies in Europe and the United States suggest that the prevalence of adult CD is in the magnitude of one per 100-200 individuals2-5 , which suggests CD is currently under diagnosed.
The treatment of CD involves maintaining a strict gluten free diet (GFD). However, a number of patients continue to complain of gastrointestinal problems (e.g. diarrhoea) despite adequate adherence to their diet. One possible explanation for this is exocrine pancreatic insufficiency. Dreiling first reported this association in 1957.6 His observation has subsequently been validated by other investigators using either direct or indirect tests of pancreatic function.7-13
More information about coeliac disease can be obtained from Coeliac UK at http://www.coeliac.co.uk/
Pancreatic function tests
Making the diagnosis of exocrine pancreatic insufficiency can be clinically difficult. This reflects the methodological limitations of direct and indirect pancreatic function tests. Quantifying the degree of pancreatic damage can be problematic, especially in the early stages, because not all the indirect tests are sensitive enough and the direct tests are too invasive and expensive to perform routinely.
Additionally, well recognised methods of classifying pancreatic damage, such as the Cambridge system,14 concentrate on morphological (i.e. structural) changes rather than alterations in pancreatic function. For these reasons there has been interest in the so-called indirect or “tubeless” tests as they are cheap, easy to perform and well accepted by the patients themselves.
Faecal pancreatic elastase-1
Elastase 1 is a proteolytic enzyme produced specifically by the pancreas. As it binds to bile salts it is not degraded in its passage through the gut, unlike other pancreatic enzymes.15 This results in concentrations 5-6 times higher in the faeces than those found in pancreatic juice.15-16 Furthermore, values are not affected by taking pancreatic enzyme replacement therapy when using the commercial test that utilizes monoclonal antibodies to human pancreatic elastase
- Studies have shown that measurement of faecal pancreatic elastase (FE1) correlates well with pancreatic output of elastase-1 and other enzymes such as amylase, lipase and trypsin.15,17 It has been well validated as an indirect means of assessing pancreatic function, by comparison against other indirect tests (such as faecal chymotrypsin,15,17-1913C mixed triglyceride breath test20-21 and pancreolauryl test18) and direct means (such as the secretin-caerulein test15-21 and endoscopic retrograde cholangiopancreatography [ERCP].16,18,23).
A value of FE1 <200 mg/g measured by ELISA is considered diagnostic of exocrine pancreatic insufficiency.24 The test just requires about a grape-sized stool sample, and only need be repeated when borderline. It is clinically practical as it is rapid, easy to handle, relatively cheap and there is little loss of immuno-activity when appropriately stored.15,17 Compared with other indirect tests FE1 appears to be highly sensitive and specific in detecting exocrine pancreatic insufficiency.20,25-27 Published sensitivities in severe insufficiency range from 82-100% but in the diagnostically more challenging mild to moderate disease, sensitivities range from 37-63%15-17,28 with one study claiming 100% in moderate disease.17
More information about the faecal pancreatic elastase test can be obtained at http://www.schebo.co.uk/gastro/en/index.html
Pancreatic function in paediatric patients with coeliac disease
There have been 5 studies assessing pancreatic function in paediatric patients with coeliac disease using FE1.19,22,29-31 These studies (ranging from 14-46 subjects) demonstrated that pancreatic insufficiency in children with coeliac disease may be highly prevalent at diagnosis. Some investigators suggested this may relate to the degree of mucosal villous atrophy and FE1 may increase once the mucosa has recovered on a GFD.30-31 These observations have not been described in an adult coeliac population and the largest case series was reported in 1998 (n=14).32 We have recently published a study assessing whether exocrine pancreatic insufficiency (using FE1) is a cause for persisting symptoms in adult CD patients.33 Furthermore, we examined the impact of pancreatic enzyme supplementation in adult coeliac patients with chronic diarrhoea.
We looked at 209 patients with CD and 50 chronic diarrhoea controls. The CD patients fell into three distinct subgroups; 1) newly diagnosed CD (n=57), 2) treated CD without diarrhoea (n=86) and 3) treated CD with diarrhoea (n=66). Each participant had baseline weight and stool frequency measured along with demographic information. A stool sample was taken for FE1 and current coeliac antibody status was ascertained to determine compliance with the GFD.
The prevalence of a low FE1 (<200 mg/g) across all the CD patients was 15%. It occurred in 30% of the patients with treated CD and persisting diarrhoea, compared to 10% in newly diagnosed CD patients, 6% in treated CD without diarrhoea, and just 4% in the non-CD controls with chronic diarrhoea (see graph 1).
The prevalence of reduced FE1 was statistically much higher in those patients with treated CD and persisting diarrhoea compared to all other CD groups (c2 p<0.0001) and controls (c2 p<0.0003). Interestingly, compliance with a GFD, as indicated by EMA and TTG antibodies, was similar (if anything, slightly better) in the CD patients with diarrhoea compared to those without symptoms.
When given pancreatic enzyme supplementation - three capsules of Creon 10,000* with each meal - eighteen out of twenty CD patients with diarrhoea (90%) had significant reduction in bowel frequency from 4 motions per day to 1 motion per day (p<0.001, graph 2).
Increases in weight were not significant. Repeat duodenal biopsy in 13/20 patient’s revealed improvement in their histological appearance. Subsequent follow-up of these patients for up to 24 months revealed continued benefit on pancreatic enzyme supplements.
A free download of the study abstract is available at http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2036.2006.03206.x
* Further information about Creon® is available at http://www.creoninfo.co.uk/pages/homepage.asp
Until now, there has been limited data regarding the prevalence of exocrine pancreatic insufficiency amongst adult patients with coeliac disease. Our data have shown that pancreatic insufficiency, demonstrated by low faecal pancreatic elastase-1 levels, is common in adult coeliac disease patients, especially those with persisting diarrhoea.
More specifically, we have shown that those patients may benefit from treatment with pancreatic enzyme supplementation. When faced with this clinical problem of ongoing gastrointestinal symptoms it is valuable to check the patients’ FE1 and prescribe enzyme replacement therapy when indicated.
- American Gastroenterological Association. American Gastroenterological Association medical position statement: Coeliac sprue. Gastroenterology 2001;120: 1522-5.
- Johnston SD, Watson RG, McMillan SA, Sloan J, Love AH. Prevalence of coeliac disease in Northern Ireland. Lancet 1997;350: 1370.
- Sanders DS, Patel D, Stephenson TJ, Milford-Ward A, McCloskey EV, Hadjivassiliou M, Lobo AJ. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003;4: 407-13.
- West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R, Reader R, Holmes GK, Khaw KT. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 2003;52(7): 960-5.
- Fasano A, Berti I, Geraduzzi T, Not T, Colletti RB, Drago S, Elitsur Y, Green PHR, Guandalini S, Hill ID, Pietzak M, Ventura A, Thorpe M, Kryszak D, Fornaaroli F, Wasserman SS, Murray JA, Horvath K. Prevalence of coeliac disease in at-risk and not-at-risk groups in the United States. Arch Intern Med 2003;163: 286-92.
- Dreiling DA. The pancreatic secretion in the malabsorption syndrome and related malnutrition states. J Mt Sinai Hosp NY 1957;24:243-50.
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- O'Mahony S, Howdle PD, Losowsky MS. Review article: management of patients with non-responsive coeliac disease. Aliment Pharmacol Ther 1996;10(5):671-80.
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- Löser C, Brauer C, Aygen S, Hennemann O, Folsh UR. Comparative Clinical Evaluation of the 13C-Mixed Triglyceride Breath Test as an Indirect Pancreatic Function Test. Scand J Gastroenterol 1998;33:327-334.
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- Hardt PD, Marzeion AM, Schnell-Kretschmer H, Wusten O, Nalop Zekorn T, Klor HU.Fecal elastase 1measurement compared with endoscopic retrograde cholangiopancreatography for the diagnosis of chronic pancreatitis. Pancreas 2002;25(1):e6-9.
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- Ammann RW, Akovbiantz A, Hacki W, Largiader F, Schmid M. Diagnostic Value of the Fecal Chymotrypsin Test in Pancreatic Insufficiency, Particularly Chronic Pancreatitis: Correlation with the Pancreozymin-Secretin Test, Fecal Fat Excretion and Final Clinical Diagnosis. Digestion 1981;21:281-289.
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- Carroccio A, Iacono G, Lerro P et al. Role of pancreatic impairment in growth recovery during gluten-free diet in childhood celiac disease. Gastroenterology1997;112(6);1839-44.
- Nousia-Arvanitakis S, Karagiozogiou-Lamboudes T, Aggouridaki C, Malaka-Lambrellis E, Galli-Tsinopoulou A, Xefteri M. Influence of jejunal morphology changes on exocrine pancreatic function in coeliac disease. J Pediatr Gastroenterol Nutr 1999;29(1):81-85.
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- Leeds JS, Hopper AD, Hurlstone DP, Edwards SJ, McAlindon ME, Lobo AJ, Donnelly MT, Morley S, Sanders DS. Is exocrine pancreatic insufficiency in adult coeliac disease a cause of persisting symptoms? Aliment Pharmacol Therap2007;25:265-71.
Dr John S Leeds, MB ChB (Hons), MRCP, and Dr David S. Sanders, MD, FRCP, FACG
Dr John Leeds is a doctor and researcher in the Gastroenterology and Liver Unit at the Royal Hallamshire Hospital, Sheffield ([email protected]). His main areas of interest and research are diseases of the pancreas and liver, and coeliac disease. His current medical research is looking at the implications of coeliac disease in Type 1 diabetes mellitus.
He is also investigating pancreatic function in a number of different patient groups, which has lead to the finding that some patients with diagnosed Irritable Bowel Syndrome (IBS) have pancreatic exocrine insufficiency.
He presented results at the 2007 annual scientific meeting of the British Society of Gastroenterology which showed that 6% of the diarrhoea-predominant IBS patients seen in hospital clinics had a severe lack of digestive enzymes. When treated with pancreatic enzyme replacement therapy, 95% of these patients benefited from a big reduction in the number of times they passed stools each day.
Dr David Sanders is a Consultant Gastroenterologist at the Royal Hallamshire Hospital ([email protected]) and an Honorary Reader in Gastroenterology with the University of Sheffield. He specialises in treating patients with coeliac disease and his research has been published in prestige international journals. Dr Sanders is currently Chairman of the Small Bowel and Nutrition section of the British Society of Gastroenterology, and an associate medical advisor for Coeliac UK.