Pancreatic exocrine insufficiency (PEI)develops when less than 10 per cent

of functioning pancreas remains. It is char-acterised by deficiency or absence of pan-creatic enzymes – amylase, lipase andproteases. Clinical symptoms includechronic abdominal pain, cramps and steat-orrhoea, eventually leading to malnutritionand weight loss. Despite several testsavailable to diagnose this condition, noneis 100 per cent specific and sensitive.

EpidemiologyIn the UK about 11 000 patients developPEI each year from various causes.1 Theoverall prevalence of chronic pancreatitis(CP) in the Western world is 27.4 cases per100 000 population.2 Some 50–80 percent of patients with CP develop PEI with anaverage interval of 5–10 years from diag-nosis of alcoholic CP.3 In non alcohol-relatedpancreatitis the progression to PEI is slower.

CausesThe most common cause of PEI in adultsis chronic pancreatitis (4000 new casesper year) followed by pancreatic carci-noma, pancreatic resection and acute,severe necrotising pancreatitis. In children,the most common cause is cystic fibrosis(CF). Effective pharmacological therapy ofchildren with CF has enabled many to liveinto adult life with PEI.

The most common cause of chronicpancreatitis in industrialised nations isexcess alcohol consumption. Other lesscommon causes include untreated coeliacdisease, small bowel Crohn’s disease,hereditary pancreatitis, IgG4-related sys-temic disease, so-called tropical pancre-atitis, obstructive chronic pancreatitis,hyperlipidaemia, chronic renal failure,hyperparathyroidism and postradio/chemotherapy pancreatitis.

Rare causes include Shwachman-Diamond syndrome, Johanson-Blizzardsyndrome, Pearson syndrome andHIV/AIDS.

Clinical featuresThe most common clinical symptom of PEIis steatorrhoea. The pancreas has a largereserve capacity and more than 90 per centof the pancreatic acini must be destroyed

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Diagnosis and management ofpancreatic exocrine insufficiencyMayur Kumar MRCP and Mark Wilkinson MD, FRCP

Managing pancreaticexocrine insufficiency effec-tively is challenging for bothspecialist and primary-carephysicians. This review sum-marises current methodsemployed to diagnose andtreat PEI effectively and pre-vent complications.

Figure 1. Abdominal CT scan of patient with chronic calcific pancreatitis with typical pancreatic ductal calcifications and atrophy of the pancreas

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before steatorrhoea results.4 Steatorrhoeais characterised by voluminous, yellowish,foul-smelling stool with a daily stool weightof over 200g containing more than 7g offat. Abdominal cramps and excess flatusare common. Eventually weight loss andmalnutrition occurs. Vitamin D deficiency israre, but osteopenia and osteoporosis maydevelop secondary to steatorrhoea.

Diagnostic testsSeveral diagnostic tests exist to diagnosechronic pancreatitis and PEI, but none is100 per cent sensitive or specific for thecondition.

Direct tests Direct hormone-stimulated pancreaticfunction tests (PFTs) are the most sensitiveand specific tests for assessing pancreaticexocrine function and provide a gold stan-dard. They involve gastric and duodenalintubation (Dreiling tubes) and iv injectionof secretin or cholecystokinin followed bycollection and analysis of the resultingpancreatic secretions.

Direct tests are most useful in patientsin whom radiological investigations areinconclusive. Unfortunately, they are inva-sive, unpleasant, take about two to threehours and the laboratory techniquesrequired for fluid analysis are not univer-sally available. Direct PFTs are thereforerarely performed.5

Indirect testsSeveral indirect tests have been developedto diagnose chronic pancreatitis and PEI toovercome the complexity, lack of availabilityand discomfort of direct tests. These testscan measure pancreatic enzymes in bloodor stool. A general criticism of these tests islow sensitivity for mild/moderate disease.They include: faecal chymotrypsin, faecalelastase, serum trypsin and 13C breath test.

Faecal chymotrypsin assay has a sen-sitivity for advanced disease of 50–80 percent, increasing to 80–90 per cent in cysticfibrosis, with a specificity of 50–100 percent.6

Faecal elastase Pancreatic elastase-1is a pancreas-specific protease that is min-imally degraded during intestinal transit.The concentration of faecal elastase instool is measured by ELISA (enzyme-linkedimmunosorbent assay) and a faecal elas-tase less than 100µg per g of stool indi-cates severe PEI. Values over 200µg arenormal. Sensitivity varies between 0 and65 per cent for mild disease to between33 and 100 per cent for severe CP.

Faecal elastase requires only a singlestool sample without the need for prolongedurine collections and is recommended bythe British Society of Gastro enterology asthe test of first choice in patients with steat-orrhoea. Most centres in the UK now per-form a faecal elastase test to diagnose PEI.

Serum trypsin test The serum trypsinassay is a simple and convenient test. Lowlevels – <20ng per ml – are specific for CP,but are sensitive only for advanced dis-

ease. This is a radioimmunoassay test andtakes a few days for results to be available.

13C breath tests Breath tests using13C isotopes are available to diagnosePEI. Sensitivities of 85–100 per cent havebeen reported with specificity >90 per centwith high fat intake. 13C breath tests canbe used to measure response to pancre-atic enzyme replacement therapy (PERT).20

These tests, which require a mass spec-trometer, are however inappropriate inpatients with diabetes, liver disease or obe-sity and are not widely available in the UK.

Endoscopic pancreatic function tests(ePFT)Recently, simplified tests of pancreatic func-tion have been developed to improve acces-sibility in patients undergoing endoscopy.These include the secretin ePFT and aspi-ration of pancreatic fluid at endoscopic ret-rograde cholangiopancreatography (ERCP).7

The ePFT is most useful in patientswith a suspicion of CP but with minimal orequivocal radiographic abnormalities. Adisadvantage is the requirement forendoscopy and/or ERCP, with their atten-dant costs and risks.

Combined endoscopic ultrasoundEUS/ePFT A combination of structural andfunctional testing can be performed usingEUS. This involves EUS following secretinstimulation, with collection of duodenalfluid and analysis of bicarbonate and pan-creatic enzymes.

Combined EUS/ePFT is a novel diag-nostic tool and provides complementaryfunctional and structural information forthe evaluation of CP and pancreatic func-tion in one session, but routine use needsvalidation in larger studies.8,9

Secretin MRCPConventional CT (see Figure 1) and mag-netic resonance cholangiopancreatogra-phy (MRCP) can diagnose chronicpancreatitis reliably but cannot assesspancreatic function. Hence secretin MRCPhas been introduced to measure the func-tional status of the pancreas.

Secretin-stimulated pancreatic secre-tion with measurement of duct dilatationand filling of the duodenum is used toassess exocrine function and correlateswell with faecal elastase-1 and urinary pan-creolauryl levels in diagnosing PEI.10,11 Both

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Table 1. Causes of pancreatic exocrine insufficiency1

Pancreatic parenchymal diseaseschronic pancreatitispostnecrotising acute pancreatitiscystic fibrosispancreatic cancers/tumoursIgG4 autoimmune pancreatitis

Extrapancreatic diseasescoeliac diseaseinflammatory bowel diseasediabetes mellitusZollinger-Ellison syndrome

Postsurgical statesgastric resectionWhipple’s pancreaticoduodenectomyshort bowel syndromebariatric surgeries

KEY POINTS

n PEI develops in most patients with chronic pan-creatitis

n faecal elastase tests are now performed inmost centres to diagnose PEI

n ePFT and secretin MRCP tests can diagnose PEImore accurately and may become more widelyavailable

n PERT remains the mainstay of treatment

n nonenteric-coated preparations may also bebeneficial in reducing pain

n high doses are employed: starting doses in adultsare usually 25 000–40 000IU per main meal

n fat-soluble vitamin levels should be monitored

structural and functional components ofthe pancreas are assessed noninvasively.

All of the above tests have some valuein diagnosing PEI but none is of the requiredspecificity or sensitivity for reliable diagno-sis, so a combination of tests is used in clin-ical practice to diagnose and manage PEI.

Management of pancreaticexocrine insufficiencyEffective management of PEI remains achallenge and needs a multidisciplinaryapproach involving dietitians, primary-care physicians and specialist gastro -enterologists.

Lifestyle modificationsPatients should refrain from drinking alco-hol and stop smoking. This improves bothCP pain and PEI.20 Dietary fat restriction to<20g per day is the initial approach tomanaging steatorrhoea, but this may leadto restricted consumption and deficiencyof fat-soluble vitamins. Diet should bereviewed regularly and nutritional statusassessed by experienced dietitians.

Currently the mainstay of treatment isPERT.

Pancreatic enzyme replacement therapy Patients with steatorrhoea, weight lossand faecal fat excretion of greater than15g per day need PERT. PERT (non entericcoated preparations) may also be benefi-cial in reducing pain in CP patients througha negative feedback mechanism by inhibit-ing cholecystokinin release,12 although theevidence is mixed. A few small randomisedcontrolled trials13 have shown benefit inpain reduction, but a meta-analysis14 of sixrandomised controlled trials showed nobenefit. Our experience suggests thatusing nonenteric coated enzyme prepara-tions has a role in pain reduction in CPpatients with PEI.

The main aim of PERT is to simulatethe physiological response of the pancreasto food and thus aid more normal diges-tion, especially of fats. PERT is alsobelieved to improve quality of life.

Porcine pancreatin preparations arethe most widely used, but other prepara-tions are available by special order if thereare cultural or religious issues with pig-related products. Table 2 summarises thevarious preparations available in the UK.

Most products have a similar enzyme con-stitution, but the formulations differ instrength.

The dosage of pancreatic enzymepreparations is individually tailored. A rea-sonable starting dose for adults is25 000–40 000IU of lipase per mainmeal. The dosage for light meals or snacksdepends on their size but should be atleast 10 000IU. In children, doses are cal-culated based on body weight or onamount of fat intake. The maximum dailydose in children is limited to 10 000IU oflipase per day to prevent fibrosingcolonopathy, which is reported with higherdoses.19,20 To ensure that they are wellmixed with the food in the stomach, pan-creatin preparations should be taken dur-ing or immediately after meals.

Unsuccessful responses can be man-aged by dose escalation or the addition ofproton pump inhibitors (PPIs) or H2-antag-onists to prevent acid inactivation oflipase. Success to therapy is usually meas-ured by improvement in patient symptoms;however, faecal fat measurement and 13Cbreath tests can be used to measure suc-cess objectively.

Patient education is vital for successwith this therapy. The following adviceshould be provided to patients who arestarted on PERT:1

1. enzymes to be taken with all meals andsnacks; sporadic intake should be avoided2. doses should be titrated according toresponse3. concomitant PPI/H2-antagonist use ifinadequate response4. do not crush or chew enteric-coated

enzymes preparations to avoid mouth irri-tation and sores5. avoid antacids containing magnesiumand calcium as they can reduce effec-tiveness6. warn against potential side-effects suchas bloating, abdominal cramps, diarrhoea,headache, dizziness and mouth and peri-anal soreness. These symptoms are usu-ally transient and treatable with simplemeasures discussed above.

Fibrosing colonopathy has beenreported in paediatric CF patients takinghigh doses of pancreatic enzymes.17 This isthought to be secondary to the methacrylicacid co-polymer used in some brands ofenteric-coated preparations, although anautoimmune process has been postulatedtoo.18Newer products such as enzyme gran-ules and mini-microspheres have not beenassociated with this complication.

The US Cystic Fibrosis Foundation con-sensus guidelines recommend thatdosages should be limited to 500–2500lipase units per kg per meal, <10 000lipase units per kg per day or <4000 lipaseunits per g dietary fat per day.19

Hypersensitivity reactions such as skinallergy, allergic rhinitis and rarely anaphy-laxis have been reported, but these areuncommon.

PERT is generally considered safe,even in high doses.

Fa-soluble vitamin deficiency in PEIMalabsorption of fat-soluble vitamins (A, D,E and K) is frequently present in patientswith PEI but often undiagnosed. Vitamin Ddeficiency is common in CF patients with

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Table 2. Pancreatic enzyme supplements available (MIMS March 2013)

Formulation Brand name

Nonenteric-coated formulationspowder Pancrex V Powdergranules Pancrex Granulescapsules Pancrex V Capsules

Enteric-coated formulationsgranules Creon Microtablets Pancrex V Tablets

Pancrex V Forte Tabletscapsules Creon 10000, 25000, 40000

Nutrizym 22Pancrease HL

pancreatic insufficiency. Latent vitamin Aand E deficiency is reported even inpatients on PERT.15,16

Monitoring of fat-soluble vitamin levelsand adequate replacement are essentialin the management of PEI patients.

ConclusionPEI develops in almost all patients with CPand the average time to develop symptomscan vary from 5 to 10 years. Diagnosing PEIaccurately remains a challenge and noneof the currently available tests is 100 percent sensitive or specific, leading todelayed diagnosis in some cases. Indirecttests are currently used to diagnose PEI,but newer tests such as ePFT and secretinMRCP may be more widely available infuture and diagnose PEI more accurately.

The main aim of treatment is to reducesteatorrhoea and prevent malnutrition andweight loss. PERT remains the mainstay oftreatment.

References1. Imrie CW, et al. Aliment Pharmacol Ther2010;32 Suppl 1:1–25. doi: 10.1111/j.1365–2036. 2010.04437.x.2. Sleisenger and Fordtran’s gastrointestinaland liver disease: pathophysiology, diagnosis,management. 8th ed. Saunders, Philadelphia.3. Layer PH, et al. Pancreas 1996;12(3):318–20.4. Thomas PD, et al. Gut 2003;52(Suppl V):v1–v15.5. Stevens T, et al. World J Gastro enterol 2011;17(35):3957–61.6. Lieb JG II, et al. World J Gastroenterol 2008;14(20):3149–58. PMCID: PMC2712845.7. Law R, et al. Gastrointest Endosc 2012;75(4):764–8. 8. Stevens T, et al. Dig Dis Sci 2010;55(9):2681–7. Epub 2010 Jan 26.9. Gardner TB, et al. Pancreas 2012;41(2):290–4.10. Gillams A, et al. Abdom Imaging 2008;33(4):469–73.11. Manfredi R, et al. Radiol Med 2012;117(2):282–92. Epub 2012 Jan.

12. Gachago C, et al. World J Gastroenterol2008;14:3137–48.13. Isaksson G, et al. Dig Dis Sci 1983;28:97.14. Brown A, et al. Am J Gastroenterol 1997;92:2032–5.15. Dutta SK. et al. Ann Intern Med 1982;97(4):549–52.16. Nakamura T, et al. Acta Gastroenterol Belg1996; 59(1):10–14.17. FitzSimmons SC, et al. N Engl J Med 1997;336(18):1283–9.18. Lee J, et al. Arch Dis Child1997;77(1):66–70.19. Stallings VA, et al. J Am Diet Assoc 2008;108(5):832–9.20. Löhr J–M, et al. United Eur Gastroent J2013; 1:79–83.

Declaration of interestsNone to declare.

Dr Kumar is specialist registrar in gastroenterology and Dr Wilkinson isconsultant gastroenterologist at Guy’sand St. Thomas’ Hospital, London

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