Exocrine pancreatic function tests - Gutgut.bmj.com/content/gutjnl/23/9/777.full.pdf · contamination of duodenal juice by gastric secretion present a minor problem. Duodenogastric

Gut, 1982, 23, 777-798

Progress report

Exocrine pancreatic function tests

Pancreatic disease may be classified as inflammatory, neoplastictraumatic, or genetic.1 According to the definition of Marseillesiinflammatory diseases may be subdivided into (1) acute pancreatitis, (2)relapsing acute pancreatitis, (3) relapsing chronic pancreatitis, and (4)chronic pancreatitis (Table 1). The first classification is primarily based onaetiological, the second on clinical and functional and/or morphologicalcriteria. For the diagnosis of pancreatic disease, pancreatic function testsare needed among other diagnostic procedures to assess the amount offunctional damage. As pancreatic function returns to normal after attacksof acute or relapsing acute pancreatitis, unlike what is found in the chronicform of the disease, pancreatic function tests are necessary to differentiatebetween acute and chronic presentations of the disease.

Since the pioneer work of Chiray et a13 and Lagerlof4 on the evaluationof the secretin test in pancreatic diseases, a variety of exocrine pancreaticfunction tests have been developed over the last 50 years. They may bedivided into the following categories (Table 2):1 Direct tests, in which pancreatic flow, bicarbonate, and enzymesecretion are measured in duodenal or pure pancreatic juice afterexogenous hormonal stimulation of the pancreas.2 Indirect tests, which make use of nutrients for endogenous stimulation ofpancreatic enzyme secretion.3 Faecal tests, which include microscopic inspection of stools andestimation of faecal trypsin, chymotrypsin, fat and nitrogen content.4 Serum enzyme or isoenzyme estimation, with or without previoushormonal stimulation.The purpose of this progress report is (1) to discuss current exocrine

pancreatic function tests with special reference to their practicability, (2)to state whether these tests are able to differentiate between impairmentof pancreatic function of diverse aetiology, and (3) to suggest possible waysof refining tubeless tests. Three excellent reviews have been published

Table 1 Classification ofpancreatic diseases

I Inflammatory III TraumaticAcute pancreatitis Non-penetrating or blunt traumasRelapsing acute pancreatitis Penetrating injuriesChronic relapsing pancreatitisChronic ('painless') pancreatitis IV Genetic

Cystic fibrosisII Neoplastic Hereditary and familial pancreatitis

Ductal originParenchymal origin (acinar cells)Islet cell origin

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Table 2 Exocrine pancreatic function tests

Direct testsDetermination in duodenal juice

Secretin testRapid intravenous injectionContinuous infusionAugmented secretin test

Secretin-CCK testRapid intravenous injection of CCKContinuous infusionSimultaneous intravenous injection of

both hormonesSequential administration of bothhormones

Secretin-caerulein testSecretin-bombesin testRadioselenium test

Determinations in pure pancreatic juiceViscosity measurementEnzyme measurement

Indirect testsTests requiring duodenal intubationLundh testSmall intestinal infusions

Tubeless testsNBT-PABA testPancreolauryl test

Faecal testsMicroscopic examinationTrypsin estimationChymotrypsin estimationFat and nitrogen determination

Enzyme estimations in serum, urine and parotid salivaEvocative testsTrypsin radioimmunoassayIsoamlyase determinationParotid saliva test

recently;1 5 6 they deal mainly with direct tests and older indirectpancreatic function tests such as the Lundh test and faecal enzymeestimations. These will therefore be referred to only briefly and the role ofmore recently developed tests, such as tubeless pancreatic function testsand serum enzyme estimations, will be more extensively discussed.

Direct tests

DETERMINATIONS IN DUODENAL JUICEThe major technical problems of measuring pancreatic volume,bicarbonate and enzyme contents in duodenal juice after stimulation of thepancreas are to prevent contamination by gastric juice and to overcome theloss of duodenal contents into the jejunum or by reflux into the stomach.6For intubation, double- or multiple-lumen tubes have been recom-

mended; these offer the possibility of separate collection of gastric juiceand balloons for occlusion of the pylorus and distal duodenum.7 8 In acomparative study the latter tube gave a higher percentage of recovery.9Alternatively, non-absorbable markers such as polyethylene glycol (PEG)or 57Co-labelled vitamin B12 (not allowed in several centres for legalreasons) have been recommended for calculating the loss of duodenaljuice. The data for recovery of investigations using these markers,however, differ considerably (for review see Worning10), and, unfor-tunately, are difficult or almost impossible to compare, as methods forintubation, position of patients, markers, their concentration, and infusionrate vary from study to study. Using PEG as a marker, recovery was veryhigh or almost complete in some studies,11-14 but amounted to only up to40% in others.15 16 This may be due to the position of the patient on his leftside,16 or to the advanced distal position of the tube.15 As it is almostimpossible to control adequate mixing of markers and duodenal juice, lowrecovery rates do not necessarily represent high losses of duodenalcontents. Until new technical improvements appear, the followingstatement of Wormsley6 should be accepted: a recovery rate of above 85%

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indicates that the collection technique is probably satisfactory and themagnitude of output of pancreatic juice can be satisfactorily inferred fromexperimental findings. Recovery of less than 85% means that the collectiontechnique needs to be modified.

In comparison, loss of duodenal contents into the stomach andcontamination of duodenal juice by gastric secretion present a minorproblem. Duodenogastric reflux is only rarely significant1 12 17 and gastricsecretion is low during pancreatic function tests. Errors in theinterpretation of duodenal contents of bicarbonate and pancreatic enzymescan be avoided by the use of indicators and by estimating bilirubin in thegastric aspirate.56

In some patients duodenal intubation for aspiration of duodenalcontents or pure pancreatic juice may be difficult. To make the procedureeasier diazepam may be given. Hyoscine butylbromide, however, shouldnot be used, as it reduces trypsin secretion into the duodenum and delaysthe appearance of both trypsin and bilirubin in duodenal aspirate.18

Secretin testTests of secretory capacity such as the secretin test are based on theassumption that a decrease in the capacity to secrete fluid, bicarbonate,and enzymes indicates pancreatic damage, and that the dose of stimulantwhich provides submaximal or maximal stimulation to normal glands alsoexerts the same effect on the diseased pancreas.6

After the evaluation of the secretin test by Lagerlof4' Dreiling and hiscolleagues,19-23 Sun and Shay,24 Burton et al,25 Petersen and Myren12 andother investigators (for review see 1 5 6 26) have provided moreinformation on the usefulness of the test. Secretin has been applied byrapid intravenous injection,4 25 27 subcutaneously, 28 and by continuousintravenous infusion.29-31 The results of these studies are difficult tocompare because the type of secretin preparation is important andpotency, dosage, and the test procedures used differed from study tostudy.' 5 6 26 When making comparisons it also has to be consideredwhether plastic material has been used for injections and especially forinfusions, because plastic surfaces are able to bind secretin. This bindingcan be abolished by dissolving secretin in serum albumin.32

Recently, the augmented secretin test (bolus intravenous test repeatedwith 4 clinical units/kg body weight intravenously) has been introduced andthis is said to enhance the accuracy of the standard function test.33 3 Theprocedure is of interest but needs to be further investigated.

Secretin-CCK (caerulein)-testAfter secretin administration, only a correct evaluation of the hydrokineticfunction of the pancreas may be expected, whereas the enzyme outputafter the secretin wash-out varies considerably and may even be normal inmany patients with chronic pancreatitis.26 CCK was therefore added to thetest procedure in order to assess the ecbolic pancreatic function.2526

Like secretin, CCK has also been given by different methods:5 26 as asingle intravenous injection before,35 6 with,37 and after25 36 38 secretin,or by continuous intravenous infusion alone,39 or in combination withsecretin.40 CCK may also be replaced by caerulein (Farmitalia, ResearchLaboratories, Milano, Italy) for testing the ecbolic function of the

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pancreas. It can be obtained in pure form and is cheaper than CCK. Whenit is combined with secretin infusion it provides a similar stimulation ofpancreatic enzyme secretion.41~3

False abnormal test results of the secretin-CCK-test caused by aninadequate contraction of the gallbladder after administration of thesesubstances are prevented by the intraduodenal application of dried ox bile(Kali-Chemie Pharma GmbH, Hannover, FRG) followed by anotherintravenous injection of secretin and CCK after the standard secretin-pancreozymin test.The most satisfactory stimulant or combination of stimulants for

measuring pancreatic secretory capacity and thus for separating normalfrom impaired pancreatic function has not yet been defined.6 A pilot studyhas been set up by the European Pancreatic Club to investigateinterlaboratory quality control of data in the secretin-pancreozymin test,but such great difficulties were initially found between the different centresinvolved in the study that rigorous and detailed standardisation of enzymeassays was introduced.46The substances used in this study are two synthetic secretin preparations

(Hoechst AG, Frankfurt/M, FRG, and Hoffmann-La Roche, Basel,Switzerland), and both preparations have been shown to have an effect onpancreatic secretion similar to that of natural secretin (GIH, Stockholm,14 an 4dgSweden) in man and dogs. Instead of CCK caerulein (Farmitalia,Milano, Italy) is applied. Markers are not used in this study.

Until the results of this pilot study are published, despite its limitationsof lack of standardisation and technical difficulties related to theperformance and requirement of analytical methods, the secretin-CCK-test remains the standard diagnostic method of detecting diffuse pancreaticdisease.1

In a recent survey of 2003 patients who were studied to evaluate thesecretin-CCK-test, false abnormal results were reported in 8% and falsenormal results in 6% of the patients.48 It is unlikely that these percentageswill be improved on because of the wide variation in normal pancreaticfunction.

Secretin-bombesin testAn intravenous infusion of bombesin has been found to stimulatepancreatic secretion, amylase and trypsin concentrations but notbicarbonate.49 The role of this procedure as an exocrine pancreaticfunction test still remains to be established.

Radioselenium testRadioactive labelled amino acids given intravenously are rapidly taken upby the acinar cells of the pancreas. Youngs et al reported a good correlationbetween the radioactivity of radioselenium present in the duodenalaspirate after stimulation with the Lundh test meal followed by anintravenous injection of (75Se) selenomethionine.50 Duodenal 75Se-activitygave good separation between normal subjects and patients with diseasesof the exocrine pancreas. The results of this study have been confirmed byothers estimating 75Se in basal51 or secretin-CCK-stimulated state,52 53whereas Brom et a154 reported that the Lundh test was superior to theradioselenium test.

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By an extension of the procedure of Youngs et also Shichiri et al"smeasured 75Se-radioactivity in the protein fraction of duodenal aspiratesafter stimulation with pancreozymin and secretin. They also found asatisfactory discrimination between normal control subjects and patientswith pancreatic diseases. It has been suggested that this test may becombined with a standard secretin-pancreozymin test, serum enzymeresponse to pancreozymin, and secretin and pancreatic scanning. Directmeasurements of enzyme activities after hormonal stimulation of thepancreas, however, is sufficiently simple and accurate and pancreaticisotope scanning is not worthwhile in the diagnosis of pancreatic disease.56Thus the additional or single measurement of 75Se-radioactivity confers noadvantage.

DETERMINATIONS IN PURE PANCREATIC JUICEViscosity measurementThe observation that duodenal secretion is more viscous in patients withchronic pancreatitis than in healthy controls led to the viscositymeasurement of pure pancreatic juice obtained after stimulation withsecretin (1 CU/kg body weight) via ERCP.s7 58 Viscosity was, indeed,significantly increased in the patients' group. In a similar study, viscosity ofduodenal juice was also significantly higher in patients with pancreaticinsufficiency after intravenous infusion of secretin and pancreozymin.59Unfortunately, neither group supplied data on the extent to which exocrinepancreatic function was impaired. It is possible that the increase inviscosity is due to protein precipitation in pancreatic secretion60 and that itoccurs only in advanced exocrine insufficiency. At present, this invasivetest offers too little information and additional studies are necessary todetermine whether viscosity measurement should become a supplementaryprocedure in the assessment of pancreatic function.

Enzyme measurementStudies of human pure pancreatic juice are technically demanding andinvasive. Endoscopic duct cannulation cannot guarantee completerecovery of pancreatic secretion and measurements of volume and outputmay be inaccurate.61 There is a considerable overlap in the values ofbicarbonate concentration: in some preliminary studies abnormally lowvalues were reported in patients with chronic pancreatitis,62 63 whereas inother studies normal values were found.61 4 In healthy control subjectsbicarbonate concentration was found to be higher in pure pancreatic juicethan in duodenal aspirates.65 In an extensive study by Denyer and Cotton6'volume, bicarbonate, and total protein concentrations were measured inpure pancreatic juice after bolus injection of 1, 4, and 70 CU secretin.There was a considerable overlap in all measured indices and noconvincing differences were found between normal subjects and patientswith chronic pancreatitis. It cannot be excluded, however, that thesepatients suffered only from mild to moderately severe exocrineinsufficiency, as only a few showed calcification on plain radiographs of theabdomen and none had overt diabetes mellitus.Although these studies are disappointing from the clinical point of view,

they are of interest for studying the physiology of pancreatic secretion and

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provide an ideal avenue61 for further detailed research into constituents ofpancreatic juice that may have diagnostic significance (see below).

Indirect testsTESTS REQUIRING DUODENAL INTUBATIONLundh testThe indirect pancreatic function test that is most widely used at present hasbeen described by Lundh66 and involves the endogenous stimulation of thepancreas by a test meal. The test procedure is simple: after intubation ofthe duodenum with a tube a test meal (300 ml) is given which contains 6%fat, 5% protein, and 15% carbohydrates. Duodenal contents are aspiratedeither in four consecutive 30-minute fractions or, more commonly, in asingle two-hour collection. Trypsin is the most frequently measuredenzyme, it is less sensitive to changes of pH and more discriminating thanlipase and phospholipase.67 Because all enzymes may be reduced,68however, it is recommended that at least two enzymes should be measured,preferably trypsin and lipase, to improve the reliability of the results.67

Recently, Bergstrom and Lundh showed that 300 ml water aloneprovided mean trypsin values in duodenal contents that were only slightlylower than those obtained with a test meal.69 The latter procedure,however, is still used by all investigators of the test.

Several groups have shown that the Lundh test is a simple and helpfultest in the diagnosis of chronic pancreatitis, particularly when associatedwith steatorrhoea - that is, severely impaired exocrine pancreaticfunction.7>76 James in 197377 found that the overall rate in the diagnosis ofchronic pancreatitis was 90% and that of pancreatic carcinoma 79%.

Several groups have compared the Lundh test with a direct pancreaticfunction test, the secretin or the secretin-CCK test (for review see also 77).The results showed considerable disagreement: in some studies there was agood correlation between both tests,76 78 especially in severe,79 but not inslight, exocrine insufficiency.80 Rolny and Jagenberg81 reported that theLundh test was much less sensitive than the secretin-CCK test. Braganzaand Rao82 found the opposite: that the indirect test was distinctly superior.This was partly because of the disproportionate reduction in trypticresponse to endogenous stimulation in chronic pancreatitis; it was only athird of the response to exogenous stimulation.Most investigators who favour the Lundh test stress that it is a simple.

physiological, and inexpensive test that is possible to6perform in mosthospitals. There are, however, certain disadvantages' which limit theusefulness of the test. (1) The test is based on the endogenous release ofsecretin and CCK. Thus, where there is mucosal damage - for example, incoeliac disease - the test may not be valid because of impaired hormonalrelease.83 Therefore the test cannot differentiate between malabsorptionof pancreatic or non-pancreatic origin. (2) Hormonal release depends onthe integrity of the gastroduodenal anatomy and the results may be difficultto interpret after operations such as Billroth II gastrectomy.85 (3) Volumeand bicarbonate secretory capacity cannot be assessed.

Small intestinal infusionsHydrochloric acid had been perfused into the jejunum to release secretin86and amino acids to release CCK.87 The response to this indirect

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stimulation was as high as to direct stimulants and was impaired in patientswith pancreatic disease.88 Both tests are at the moment primarily researchprocedures, however, and are still not standardised for clinical use.

TUBELESS TESTSGeneral principleIn tubeless pancreatic function tests, usually with a test meal forstimulation of pancreatic secretion, a compound is given which is split upinto two or more parts by pancreatic enzymes in the duodenum. One ofthese split products is readily absorbed in the small intestine, conjugated inthe liver, and excreted in the urine. The recovery rate in the urine within agiven time is taken as an index for pancreatic function. As the test resultmay be influenced by an impairment of absorption, liver function, andrenal excretion the test may be repeated on another day, this time applyingthe split product only.NBT-PABA testThis test is based on the specific hydrolysis of a synthetic tripeptide,N-benzoyl-L-tyrosyl-p-aminobenzoic acid (NBT-PABA) by chymotrypsinin the duodenum. The recovery rate of split PABA reflects intraluminalchymotrypsin activity. Thus, this oral pancreatic function test is essentiallyan indirect test of chymotrypsin secretion.The test procedure is not yet standardised but this may easily be

achieved when it becomes commercially available. Usually the peptide isapplied together with a test meal at a dosage between 150 mg and 2 g. Toincrease the sensitivity of the test it would seem to be logical to increase theapplied dose of NBT-PABA. A comparative investigation using 150 mgand 1 g NBT-PABA indeed showed an improvement in sensitivity.89 Thedosage cannot, however, be increased too much because after 4 g adecrease in PABA excretion has been observed,90 and probably theappropriate dosage is between 500 and 2000 mg NBT-PABA. The contentof the test meal does not seem to be of importance judging by the studiescarried out in man. It seems to be necessary, however, to give some sort ofstimulant to the pancreas, as the lowest sensitivity rate of the NBT-PABAtest was obtained in a study in which no stimulation of pancreatic secretionwas performed.91 Recent studies showed that the liquid test meal may bereplaced by a standard breakfast and additional meals may even be takenduring the period of urine collection without interfering with the test.90

In animal experiments the application of chymotrypsin-specificinhibitors (raw egg white) led to a better separation between normalcontrols and animals with pancreatic insufficiency.92To obtain an adequate diuresis, tea or mineral water is given at certain

intervals and PABA is measured in the urine collected for six, eight, ornine hours. A collection period of six hours is probably sufficient, becauseprolonging the test for up to nine hours did not improve its sensitivity.93Drugs such as sulphonamides, sulphonyl ureas, etc., or food ingredientssuch as prunes and cranberries interfere with the chemical determinationof aromatic amines and should be discontinued for two to three days andpancreatic enzyme substitution for five days before the test.

In animal experiments Imondi et al reported that the NBT-PABA testreflected the impairment of exocrine pancreatic function induced bypancreatic duct ligation.94 It was subsequently found to be a useful test for

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diagnosing pancreatic insufficiency in protein-deficient patas monkeys.95Since the first promising studies in man,9& 160 the NBT-PABA test has

been subjected to a considerable number of studies by differentgroups.8> 1 93101-108 With one exception,93 the sensitivity rate (trueabnormal results in patients with pancreatic insufficiency) was between 80and 100% compared with the secretin-pancreozymin test89 91 93 98 103-106or the Lundh test meal.90 99 101 102 In a recent review based on five years'experience with the test a sensitivity rate of 86.1% was given for chronicpancreatitis.90 While the sensitivity of the test seems to be good in severeand moderately severe exocrine insufficiency, it is not fully established incases with only slight impairment of pancreatic function, and seems to beinferior.

Comparative studies have been performed together with the pancreo-lauryl test (see below) and the estimation of chymotrypsin in stool. Theresults are inconsistent: faecal enzyme estimation was of higher diagnosticvalue than the NBT-PABA test in one study91 but not in anotherinvestigation.93 A third one reported that both function tests were of thesame sensitivity in severe exocrine insufficiency, whereas, in slightlyimpaired cases, the oral function test was superior.109

In addition to the studies in man, the NBT-PABA test has also beensuccessfully used in children to diagnose pancreatic insufficiency due tocystic fibrosis.110 111 Similar results were obtained by using 4-(N-acetyl-L-tyrosyl)amino benzoic acid as substrate in adults112 and children.'13

In a study of 353 patients the specificity (true normal results in patientswith non-pancreatic diseases) of the NBT-PABA test was found to be92.9% .9 This study did not include patients with renal insufficiency inwhom PABA excretion is reduced.102 As false abnormal test results havebeen reported, however, in patients with impaired liver function,104 108inflammatory bowel diseases,108 Billroth II gastrectomy108 (not found inother studies90 107), and diabetes mellitusl'4 105 the specificity may still beimproved by repeating the test using free PABA alone.114 Further studiesof the test's specificity are necessary, as PABA excretion has also beenfound after total pancreatectomy.93 9103 This may be due to a too-recentdiscontinuation of pancreatic enzyme therapy but also to an intactNBT-PABA absorption which has been reported in in vivolls and invitro116 animal experiments. It is therefore necessary to determine whethersuch an intact absorption is also possible in man to establish whether theNBT-PABA test offers quantitative or only qualitative assessment ofpancreatic function.At the moment the test seems to be a simple, non-invasive exocrine

pancreatic function test which is feasible in most hospitals and may even beused in outpatient departments provided that it is possible to guaranteeadequate urine collection. It is not intended to replace more sensitive andspecific, but also more invasive function tests such as the secretin-pancreozymin test but could be used as a screening procedure in placeswhere tests requiring more nursing or laboratory facilities are not possible.In addition to its diagnostic possibilities, the test may possibly be used tocontrol pancreatic enzyme therapy.117

Pancreolauryl testThe test compound, fluorescein dilaurate, a poorly water-soluble synthetic

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ester, is hydrolysed by the pancreas by specific arylesterases frompancreatic juice into lauric acid and free, water-soluble fluorescein. This isreadily absorbed in the small intestine, partly conjugated in the liver, andexcreted in the urine. The test procedure is standardised: on the first daythe test capsules are given orally in the middle of a standard breakfast (50 gwhite bread, 20 g butter, a cup of tea) which is followed by 1 1 of weak teabetween the third and fifth hour of the test. The urine is collected for 10hours. To evaluate individual absorption, conjugation, and excretion thetest is repeated on the third day using a control capsule which contains freefluorescein only. The recovery rate of both days is expressed as a ratio andtaken as an index of pancreatic function. Treatment with pancreaticenzymes or vitamin B2, which interfere with the fluorescein measurement,has to be discontinued five days before the test.Although this oral pancreatic function test was developed 11 years ago"8

it has only recently become commercially available (Temmler, Marburg,FRG) and there is little information on its sensitivity and specificity inpancreatic disease.

Kaffarnik et al found a confirmation of the final diagnosis in 93% of 255healthy controls and patients with different pancreatic diseases.1"9 In twopreliminary studies the sensitivity of the pancreolauryl test was distinctlyhigher in severe exocrine pancreatic insufficiency (estimated with thesecretin-pancreozymin test) compared with cases with only slightlyimpaired pancreatic function.109 110 A comparative study with the NBT-PABA test showed that both oral pancreatic function tests led to similarresults. 121By modifying test doses and fluid intake the pancreolauryl test has also

been adapted to children, in whom it was clearly able to differentiatebetween healthy controls and patients with pancreatic insufficiency due tocystic fibrosis.112

Like the NBT-PABA test the pancreolauryl test is a simple andnon-invasive tubeless function test. Its specificity should theoretically behigher because individual absorption, conjugation, and excretion areconsidered. Further experience, however, is obviously needed in a largernumber of patients with different pancreatic and other gastrointestinaldiseases to assess the sensitivity and specificity of the test. Like theNBT-PABA test, it remains to be determined whether there is anon-pancreatic hydrolysis of the ester, as some fluorescein excretion hasbeen measured even after total pancreatectomy.120

FAECAL TESTSMicroscopic examinationMicroscopic examination of stools may reveal meat fibres, neutral or splitfats as an index of malabsorption but cannot distinguish its aetiology. 123 124According to a recent report, qualitative faecal fat estimation by means ofSudan III staining and light microscopy is a highly sensitive test fordetecting steatorrhoea.125

Trypsin and chymotrypsin estimationThe development of synthetic low molecular substrates has made possiblethe specific titrimetric estimation of trypsin and chymotrypsin instools.'26 127 Both random samples127 and 24-hour collection of faeces128

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have been used. The test is obviously not invasive but is not popular withthe laboratory technicians and requires a titrimeter, which is not availablein all hospitals. Stool samples may be sent by post, however, to speciallyequipped centres without affecting test results. Pancreatic enzyme therapyhas to be discontinued five days before the test, while antibiotics may leadto false high faecal trypsin values.129

Several studies have shown that trypsin estimation has only a lowsensitivity.93 127 130 The sensitivity rate of chymotrypsin estimation isbetween 72 and 95% in severe and between 41 to 64% in slight exo-crine insufficiency demonstrated with the secretin-pancreozymintest.93 127 131 132 Studies of the specificity of the test are contradictory:whereas in some of them the rate was in the range of 90 to 100%,130 133 134false abnormal results were found in 29% of non-pancreatic diseases.135They are reported in non-pancreatic diarrhoea/steatorrhoea (low enzymeconcentration due to dilution), after Billroth II gastrectomy, and sprue(decreased liberation of hormones stimulating pancreatic secretion), afterreduced oral feeding, and in cachectic state (decreased pancreatic enzymesynthesis due to protein malnutrition) and in obstructive jaundice (lackingstimulation of bile). The test has also been successfully applied in childrenwith cystic fibrosis for the detection of pancreatic insufficiency.136 137From the present data chymotrypsin estimations in stools may be used as

a screening test for pancreatic insufficiency. An abnormal test result shouldbe taken as an index of pancreatic insufficiency when other causes ofmalabsorption can be ruled out. A normal result does not excludepancreatic diseases.Of special interest is the faecal enzyme estimation after stimulation of

the pancreas with secretin and CCK; the patient should first be purged toensure rapid intestinal transit of the enzymes. There was a good correlationbetween enzymes in duodenal aspirate and faeces.138

Faecal fat and nitrogen measurementSteatorrhoea and azotorrhoea occur when stimulated lipase output fallsbelow 10% of normal.139 The estimation of fat in stools collected for 72hours140 is a safe procedure for the diagnosis of steatorrhoea. It may beused as an index of pancreatic function when performed before and afterenzyme replacement therapy or as a control of the effect of the lattertherapy. It is also obviously not invasive but again is not popular withlaboratory technicians and requires some laboratory equipment. Attemptshave been made to replace this method by breath tests but the results arenot promising (for review see 141).

ENZYME ESTIMATION IN SALIVA, SERUM, AND URINEParotid saliva testIn acute experimental pancreatitis in rats, atrophy and reduction ofamylase content of parotid glands were found.'42 In dogs the sameexperimental condition induced degenerative changes of the parotid glandassociated with a marked decrease of maximal bicarbonate concentrationof parotid saliva.143 In man, a decrease of basal but not of stimulatedsalivary secretion was reported in chronic pancreatitis.144 In contrast,Kakizaki et al found that pilocarpine-stimulated volume, maximalbicarbonate concentration, and amylase content of the saliva of patients

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with pancreatic disorders were significantly lower than in patients withnon-pancreatic diseases.145 146 Therefore the parotid saliva test wasintroduced as allegedly superior to the secretin-pancreozymin test.146 Thetest procedure is simple and non-invasive. Parotid saliva is collected afterstimulation with pilocarpine hydrochloride (intramuscular injection) or byapplication of citric acid to the tongue. For evaluation volume,bicarbonate, amylase, and protein concentration and output are measured.The results of different studies are at variance. Some groups have

confirmed the results of Kakizaki et al, 147-149 whereas in two studies thesensitivity was very low'50 or practically zero.15' In both studies pancreaticinsufficiency had been demonstrated by the secretin-pancreozymin test.These data do not support the role of the parotid saliva test as a screeningtest for pancreatic function.

Evocative testsTo avoid duodenal intubation, the rise of serum amylase and lipase afterstimulation with secretin and/or pancreozymin has been used as an index ofpancreatic function. When the pancreas is normal, a negligible rise of bothenzymes is to be expected, whereas in pancreatic insufficiency, especiallyat an early stage, the rise has been reported to be significant. The validityof the test has been debated for many years. In his review on this subjectWormsley5 concluded that, in view, of the many factors other thanpancreatic diseases which can modify the values of both fasting andstimulated levels of pancreatic enzymes in the blood, the test is of limitedvalue. Two large studies published since then correlating the evocative testwith the secretin-pancreozymin test in patients with pancreatic andnon-pancreatic disease have shown that this test is neither sensitive norspecific and is not to be recommended.48 152

Immunoreactive serum trypsinRecently a radioimmunoassay for serum trypsin has been developed andrecommended for the diagnosis of chronic pancreatitis.153 Further investi-gations showed that radioimmunoreactive trypsin is not detectable aftertotal pancreatectomy.154 It increases in acute pancreatitis,15-acuteexacerbation of chronic pancreatitis,154 renal failure,156 157 and may alsobe raised in the presence of pancreatic cysts with hyperamylasaemia.154

Several studies have shown that the sensitivity of immunoreactive serumtrypsin is limited: chronic pancreatitis was confirmed in 33%,158 52%,15561%,'57 and 65%154 of the cases by low serum trypsin values. A review ofthe present experience leads to the conclusion that in approximately 60%of uncomplicated cases of chronic pancreatitis an abnormal serum trypsincan be expected.159 Therefore pancreatic insufficiency is not excluded bynormal values. The relatively high incidence of false normal test resultsmay be explained by the fact that, unlike amylase, serum trypsin tends tobe raised for a longer time after an acute attack of pancreatitis.Low serum trypsin values have been reported in some patients with

diabetes mellitus. Pancreatic function had, however, not been tested inthese cases.160161

Recently a raised ratio of trypsin to creatinine clearance (CrP/Ccr) hasbeen found in pancreatic carcinoma.162The ratio was normal in chronicpancreatitis and normal or raised in acute pancreatitis. Before the role of

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the trypsin radioimmunoassay can be finally evaluated more data on itssensitivity and specificity in chronic pancreatitis and pancreatic carcinomaare needed.

Isoamylase determinationDetermination of total amylase in serum and urine reveals normal values inchronic pancreatitis except during acute exacerbation of the disease. Aw etal163 could show by means of electrophoretic separation that pancreaticisoamylase is lowered in chronic pancreatitis. Since then, serum andurinary amylase have been fractionated by polyacrylamide gel electro-phoresis, Sephadex chromatography, electrophoresis, and isoelectricfocusing (for review see 164). As with any other serum enzyme estimation,isoamylase determinations are not invasive but need laboratory facilities.Some of these methods have been applied in the diagnosis of chronic

pancreatitis. Using agarose gel electrophoresis Skude and Eriksson165detected low pancreatic isoamylase values in 15 patients with advancedchronic pancreatitis. All had steatorrhoea. Using the same method Magidet al166 could show that the incidence of abnormal pancreatic isoamylaseincreased with the impairment of pancreatic function. Berk et al(chromatographic method)167 and Johnson and Levitt (isoelectricfocusing)1 reported that low isoamylase values support the diagnosis ofchronic pancreatitis, whereas normal values do not exclude the diagnosis.Though isoamylase determinations are helpful in the diagnosis of

unexplained hyperamylasaemia,169 the above-mentioned methods aremore or less restricted to specialised centres. Details of a new rapidmethod requiring simple photometric measurement have recently beenpublishedl'' 171 and it has already become commercially available(Phadebas, Uppsala, Sweden). An amylase inhibitor had been isolatedfrom wheat (Triticum aestivum) with a 100-fold higher specificity againstsalivary amylase than pancreatic isoamylase. Thus the test requires thephotometric measurement of total serum amylase with and without theinhibitor.

This is a simple method but further studies are needed to assess itsvalidity. A preliminary study showed a confirmation of pancreaticinsufficiency (secretin-pancreozymin test) in 70% of cases withuncomplicated pancreatitis.172 The test results of more demandingmethods, such as agarose gel electrophoresis165 and radioimmunoassay oftrypsin, were of slightly lower sensitivity.172 As with the trypsin-RIA,pancreatic isoamlyase estimations cannot be used for the diagnosis ofchronic pancreatitis during acute exacerbation of the disease.

DIFFERENTIATION BETWEEN DIFFERENT TYPES OF PANCREATICDISEASESUnfortunately, none of the above-mentioned pancreatic function testsis able to solve the main diagnostic problem: how to differentiatebetween pancreatic insufficiency due to chronic pancreatitis or to pan-creatic carcinoma. For this purpose, additional determinations in duodenalor, preferably, in pure pancreatic juice are necessary. These include,with different success rates, lactoferrin, 173-175 carcinoembryonicantigen.63 176 177 y-glutamyl transpeptidase,178 and cytology;177-180 thelatter may be also obtained by endoscopic retrograde brushing.181

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Sensitive function tests, however, will be able to decide whetherpancreatic function returns to normal182 183 and thus differentiate betweenacute or acute relapsing and relapsing chronic pancreatitis.There is some debate on whether, for the diagnosis of exclusion of

pancreatic diseases, a particular sequence of tests or, alternatively, abattery of more or less simultaneous diagnostic procedures should beapplied. We prefer the latter, as clinical experience has taught us thatsingle function tests or endoscopic/radiological examinations cannotexclude chronic pancreatitis or pancreatic carcinoma. Our diagnosticprocedure includes exocrine (secretin-pancreozymin test or, if this is notpossible, tubeless tests such as NBT-PABA test and PLT) and endocrine(oral glucose tolerance) function tests, plain radiographs of the abdomen,sonography (in case of enlargement of the pancreas with sonographicallyguided fine-needle puncture), and ERCP (in selected cases also PTC).

OUTLOOK FOR FURTHER PROGRESSDirect testsAt the moment, the secretin-pancreozymin or the secretin-caerulein testseems to be the safest procedure for the assessment of pancreatic function.To prove this, one must await the completion of the multicentre study ofthe European Pancreatic Club. It is hoped that results of this study will beavailable in the next two years and will decide whether the chosencombination is really the best and preferable to the single secretin test andalso which parameter(s) are the best for diagnosing pancreatic diseases.Furthermore, it will settle the long-lasting debate as to whether or not animpaired secretory rate and normal content of bicarbonate and enzymesmean the presence of pancreatic carcinoma, or whether a reduction ofbicarbonate and/or enzyme output and normal secretory rate should betaken as an indication of chronic pancreatitis. Finally, the study willpresent information upon whether bicarbonate or enzymes are reducedfirst in early chronic pancreatitis.

This study could also be used as a reference for large comparative studiesfor the evaluation of morphological methods such as sonography andcomputed tomography and especially ERCP. Several studies have shownthat pancreatic function is always impaired when ERCP shows abnormalfindings184-187 but others found in some cases abnormal ERCP resultscombined with normal pancreatic function.48 188 The study may showwhether these changes really are relevant or whether they are due toscarring as a result of acute attacks of relapsing acute pancreatitis and mayenable the interesting finding of the relationship between ductalobstruction and pancreatic secretion189 to be re-evaluated.

Finally, these comparative studies could help decide whether thosemorpholoqical findings not available at the time of the definition ofMarseilles should be included in a new definition of chronic pancreatitis.

'POOR MAN S' PANCREATIC FUNCTION TESTSIt is common experience that the incidence of pancreatic cancer andchronic pancreatitis (due to alcoholism) is increasing. There is, therefore, aneed for many hospitals and physicians in practice, and not just forspecialised centres, to be able to diagnose or exclude pancreatic disease,but highly sensitive pancreatic function tests are often beyond their

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resources. The role of faecal tests, especially of chymotrypsindeterminations in stools and fat estimation, has been fully established inrecent years. They are not often used, however, because they are eitherunpopular or time consuming or require special laboratory equipment.

Further progress may be made by proceeding with the evaluation ofserum enzyme estimation and tubeless pancreatic function tests. At themoment, serum enzyme estimations (trypsin-RIA, isoamylase) seem tosupply information when abnormal. It has yet to be demonstrated in largeseries whether they are specific, and to what extent pancreatic function hasto be impaired before these tests become abnormal.

Tubeless pancreatic function tests such as the NBT-PABA test and thepancreolauryl test have also to be studied further. It must first of all beestablished whether an intact absorption of the NBT-PABA-peptide or anon-specific hydrolysis of fluorescein dilaurate can occur in order to decidewhether these tests offer quantitative or only qualitative assessment ofpancreatic function. The pancreolauryl test then needs to be applied inmore cases with pancreatic and non-pancreatic diseases before it can finallybe evaluated. If both tests offer quantitative information, it should beestablished to what extent pancreatic function has to be impaired beforetubeless test results become abnormal. It would still be of interest,however, if the tests provide only qualitative assessment of pancreaticfunction for centres in which direct function tests are not available. As bothtests are based on different principles, it may be useful to combine them toincrease their sensitivity.'0 121

Further studies on tubeless tests should be directed to discoveringwhether the time of the urine collection may be shortened withoutimpairing the test result. This applies especially to the pancreolauryl test.In order to adapt the test to outpatient demands, attempts have been madeto estimate PABA in serum and to take the PABA concentration after onehour as an index of pancreatic function.190 If this finding could beconfirmed in larger studies and if the serum test has the same diagnosticvalue as the urine test, this would be of interest for outpatientdepartments, avoid the problem of renal excretion, and could possibly beused in combination with other tests such as xylose absorption or the oralglucose tolerance test.

Division of Gastroenterology and MetabolismDepartment of MedicineUniversity of GottingenGottingen, FRG

P G LANKISCH

Received for publication 17 September 1981

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Exocrine pancreatic function tests - Gutgut.bmj.com/content/gutjnl/23/9/777.full.pdf · contamination of duodenal juice by gastric secretion present a minor problem. Duodenogastric