Refer to: Goff JS: Pancreatic exocrine function testing (Medical Medical Progress Progress). West J Med 135:368-374, Nov 1981

Pancreatic Exocrine Function Testing JOHN S. GOFF, MD, Denver

It is important to understand which pancreatic function tests are available and how to interpret them when evaluating patients with malabsorption. Available direct tests are the stimulation test, the Lundh test meal, and measure- ment of serum or fecal . Indirect tests assess pancreatic exocrine function by measuring the effect of pancreatic secretion on various nutrients. These include triglycerides labeled with carbon 14, cobalamin labeled with cobalt 57 and cobalt 58, and para-aminobenzoic acid bound to a dipeptide. Of a/l these tests the secretin stimulation test is the most accurate and reliable if done by experienced personnel. However, the indirect tests are simpler to do and appear to be comparable to the secretin test at detecting pancreatic exocrine insufficiency. These indirect tests are becoming clinically available and clinicians should familiarize themselves with the strengths and weak- nesses of each.

EXOCRINE FUNCTION of the is required initiated. If pancreatic insufficiency is suspected, for of fat, protein and carbohydrates. it is important to confirm the diagnosis by ob- For efficient digestion the pancreas must secrete jective testing. Many tests have been designed to bicarbonate as well as enzymes. Because the major assess pancreatic exocrine secretion; unfortu- enzymes secreted by the pancreas (amylase, tryp- nately, some of the traditional tests are difficult to sin, chymotrypsin and lipase) are denatured by carry out and the results often are misleading.'-3 acid or the combination of acid and pepsin, Therefore, any clinician who deals with malab- maldigestion can occur if bicarbonate secretion is sorptive disorders should understand which pan- diminished, even though the enzymes are present creatic function tests are available and how to in adequate concentrations. Impaired secretion of best interpret the results. This review attempts to pancreatic enzymes, bicarbonate, or both, results place into perspective the traditional pancreatic either from diffuse destruction of the gland (usu- exocrine function tests and explore newer tests. ally the result of chronic relapsing pancreatitis) The pancreatic function tests described below or from obstruction of the main duct in the head are classified as direct or indirect. The direct tests of the pancreas by carcinoma or stricture. measure pancreatic secretion in response to phar- It is often difficult to determine the cause of macological or physiological stimulants, whereas a patient's malabsorption by history or physical the indirect tests assess pancreatic secretion by examination, but it is desirable to make a specific measuring its effect on ingested nutrients. diagnosis so that appropriate therapy can be From the Division of Gastroenterology, Department of Medi- Direct Tests of Pancreatic Exocrine Function cine, University of Colorado School of Medicine, Denver. Reprint requests to: John S. Goff, MD, Division of Gastro- The secretin stimulation and Lundh tests are enterology, Department of Medicine, University of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262. the oldest and most studied of the pancreatic

368 NOVEMBER 1981 * 135 * 5 PANCREATIC EXOCRINE FUNCTION TESTING a nonabsorbable marker, such as polyethylene ABBREVIATIONS USED IN TEXT glycol or bromsulphalein'0; the opening of this BT-PABA = N-benzoyl-N-tyrosyl para-amino- tube must be proximal enough to the collection benzoic acid port of the first tube so there will be adequate CCK = mixing of the marker substance with the pan- C02 = carbon dioxide IF = intrinsic factor creatic secretions before aspiration. The marker substance is introduced at a known concentration and rate. The concentrations of the marker, bi- exocrine function tests. In these tests one measures carbonate and enzymes in the collected duodenal the volume of fluid, enzymes and bicarbonate juice are then determined, and from simple mathe- secreted into the after a pancreatic matical equations the output of pancreatic enzymes stimulus. Another direct test of pancreatic secre- and bicarbonate can be calculated.10'11 Before the tion is the measurement of stool concen- nonabsorbable marker technique (which does not trations. The measurement of trypsin or isoam- require the complete collection of duodenal juice) ylase activity in serum also has been used to was used, incomplete collection was a major cause assess pancreatic function more or less directly. of erroneous results. After a control period of infusion of the marker Secretin Test and aspiration of duodenal content (usually half The stimulants of the pancreas used in the an hour), the is administered. If volume secretin test are intravenously injected gastro- and bicarbonate production are to be measured, intestinal .4 Formerly, crude prepara- pure secretin from the Karolinska Institute in tions of secretin were used for this purpose, but Sweden should be used (usual dose is 0.5 to 1.0 it was discovered that these contained cholecys- CU per kg of body weight per hour). The syn- tokinin (CCK) as well as secretin. Secretin stimu- thetic octapeptide of CCK sincalide (Kinevac), the lates bicarbonate and water secretion by the active portion of the CCK molecule, is the most pancreas, whereas CCK stimulates enzyme (protein) satisfactory and least expensive preparation avail- secretion. Now that essentially pure enzyme prep- able for the stimulation of pancreatic enzyme arations are available, one can test separately for secretion. The usual dose of CCK is 50 jg per kg water and bicarbonate secretion, on the one hand, of body weight per hour administered by con- or enzyme secretion, on the other hand, depend- tinuous infusion. Duodenal juice is collected by ing on which hormone is used.6 7 By simulta- gravity drainage in iced tubes at 15-minute inter- neously administering secretin and CCK, both kinds vals for 11/2 hours after the stimulants are given. of secretory response can be measured. Different The secretin test has several drawbacks: (1) the amounts of the hormones have been used alone length of the procedure, (2) the necessity for or in various combinations, either as bolus injec- nasogastric intubation, which frequently is poorly tions or as continuous infusions, to determine the tolerated by the patient and (3) radiation exposure optimal dose for distinguishing normal from ab- during placement of the tube. Nevertheless, when normal pancreatic function.8'9 The best results careful attention is given to all procedural details, have been reported with the use of submaximal 90 percent accuracy in differentiating normal from doses of the hormones given by continuous infu- abnormal pancreatic function can be attained.4 3 sion.3 Lundh Test The secretin test requires the passage of a triple lumen tube by mouth or nose into the In the Lundh test the stimulus to pancreatic and duodenum, or a double lumen tube secretion is a standardized liquid meal ingested by into the duodenum and a separate single lumen the patient after a tube has been passed into the tube into the antrum of the stomach. The gastric duodenum.'2-'4 The constituents of this meal tube is necessary for the removal of gastric acid cause the duodenum to secrete the hormones CCK and pepsin so that enzymes secreted into the and secretin, which in turn stimulate pancreatic duodenum will not be denatured. The first of the secretion. The meal also distends the stomach, duodenal tubes is used for collecting duodenal producing pancreatic secretion via nervous system content; its distal opening usually is placed near reflexes. Even though this test sometimes is re- the angle of Treitz by fluoroscopic guidance. The ferred to as an indirect method of pancreatic second duodenal tube is used for the infusion of stimulation, it is in fact the physiological way in

THE WESTERN JOURNAL OF MEDICINE 369 PANCREATIC EXOCRINE FUNCTION TESTING which the, pancreas is stimulated. The effect of The Lundh meal test is simpler and cheaper to the stimulant (food) on enzyme and bicarbonate do than is the secretin test, but it still requires secretion is measured directly in the aspirated nasogastric intubation, prolonged careful monitor- duodenal juice. ing and the need for expert handling of the col- The Lundh test also requires duodenal intuba- lected specimens. Because data produced by the tion. Traditionally, a single lumen tube is placed Lundh test may be less accurate or more difficult so that its distal opening is near the angle of to interpret, the secretin test is recommended as Treitz. The patient then drinks a 300-ml liquid the best available direct test of pancreatic exocrine meal (5 percent protein, 6 percent fat and 15 function. percent carbohydrate), and duodenal contents are aspirated at 15-minute intervals for two hours. Fecal Enzyme Assays The duodenal juice is assayed for bicarbonate Because feces are relatively easy to obtain from and enzyme concentrations. The test can distin- patients, many workers have attempted to corre- guish between normal and abnormal pancreatic late pancreatic exocrine function with the con- function found in pancreatic cancer or pancreatic centration of enzymes present in stool speci- insufficiency with an accuracy of 75 percent to mens.'7 8 Measurement of chymotrypsin is the 90 percent, depending on the type of disease least variable, but the range of values obtained is present (patients with pancreatic cancer may have so great that the test is not a reliable measure of normal or decreased outputs of enzymes and pancreatic secretion and is no longer used in bicarbonate, depending on the location of the adults. tumor) .14 In the standard Lundh meal technique, because Serum Enzyme Assays of uncertainty about completeness of duodenal Serum amylase and lipase concentrations can aspiration and because a marker is not used, only be measured easily, but values do not correspond enzyme concentrations rather than enzyme output with the amount of pancreatic exocrine function. can be determined. Furthermore, in comparison One study has reported decreased pancreatic with the secretin test, there is an increased poten- isoamylase concentrations in the serum of patients tial in the Lundh test for acid and pepsin to enter with cystic fibrosis and pancreatic insufficiency, the duodenum, which might lead to more variable but at present this method has little clinical use- values for measured enzyme concentrations be- fulness because of the difficulty in distinguishing cause of denaturation. Gastric acid entering the pancreatic from salivary amylase.19 duodenum also prevents accurate measurement Trypsin is difficult to measure in serum because of bicarbonate secretion. Because the Lundh meal of the presence of inhibitors, but recently workers relies on endogenous hormones to stimulate pan- in England have developed a radioimmunoassay creatic secretion, there are situations (for example, for serum trypsin. Although serum trypsin values after Billroth II gastrectomy or in celiac disease) are low in pancreatic insufficiency, they can also when test results may suggest decreased pan- be low in chronic pancreatitis unassociated with creatic exocrine function while actually indicating exocrine insufficiency.20 21 No improvement in poor physiological stimulation of the pancreas."," distinguishing normal pancreatic function from Thus, the results may show an important patholog- pancreatic insufficiency has been achieved when ical process but may be misinterpreted clinically. serum trypsin is measured after food-induced The secretin test has stood the test of time. The stimulation of pancreatic secretion.22 In summary, use of nonabsorbable markers to enable quantita- serum enzyme levels do not appear to be useful tion of secretion has made the test reasonably in diagnosing exocrine insufficiency. reproducible and sensitive for quantitation of pancreatic exocrine function. However, the ex- Indirect Tests of Pancreatic Exocrine Function tent of its use is limited by its complexities. Fat Absorption Ideally, the test should be done only by well- Triglyceride absorption requires hydrolysis of trained personnel who are familiar with tube the lipid by pancreatic lipase, solubilization by placement, sample collection and enzyme assays. bile acids and uptake by epithelial cells of the As a general rule, the test is indicated too infre- small bowel mucosa. After absorption, some of quently to warrant its use outside of large, special- the fatty acids are metabolized to carbon dioxide ized centers. (CO,) which is excreted through the lungs. Tni-

370 NOVEMBER 1981 * 135 * 5 PANCREATIC EXOCRINE FUNCTION TESTING glyceride absorption can be quantitated by radio- the fatty acid 3H can be absorbed by the active-labeled triglyceride tests. Initially, triolein, intestinal mucosa directly. Theoretically, the 14C a triglyceride composed of glycerol and three to 3H ratio should be 1.0 or close to it if pan- molecules of the long-chain fatty acid oleate, was creatic function is normal. A decrease in the ratio labeled with iodine 131.23 The alteration of the suggests the presence of pancreatic insufficiency. triglyceride by iodination and in vitro and in vivo By contrast, fat malabsorption secondary to a loss of the iodine 131 from the fatty acid resulted deficiency in bile acids or intestinal mucosal in a poor correlation between estimates of stool abnormalities impairs the absorption of the tri- fat excretion and triolein 1 131 absorption, and the glyceride 14C and fatty acid 3H about equally, test was abandoned. More recently, triglycerides leaving the ratio unaffected. Unfortunately, Euro- labeled with carbon 14, such as triolein 14C, pean studies using this method have not consis- tripalmitin 14C and trioctanoin 14C, have become tently distinguished normal pancreatic function available.24-26 Absorption of ingested triolein 14C from patients with pancreatic insufficiency.28'29 (the 14C is the carboxyl carbon on the oleic acid) The second modification of the triolein 14C test can be easily assessed by measuring the appear- is administration of triolein 14C together with ance of 14CO0 in the breath. The authors of a pancreatic extract to patients who have low 14C02 large study at the Mayo Clinic, who investigated excretion values when the triolein 14C is given the use of several fatty acids for detecting fat alone.30 Preliminary experience with this approach malabsorption, concluded that triolein 14C was has been promising, although in a few patients the most reliable agent for use in distinguishing with nonpancreatic malabsorption, a substantial normal nonobese patients from those with steator- increase in 14CO2 excretion after ingestion of pan- rhea.25 However, the accuracy of the radioactive- creatic extract was recorded. labeled triglyceride tests is compromised in pa- At present, the triolein 14C breath test appears tients who have altered fat metabolism (due to to be about as sensitive and specific as the meas- fever, hyperthyroidism, obesity or diabetes) or urement of stool fat in the diagnosis of fat mal- who are given glucose, which inhibits fat metabo- absorption. The time requirement of only 6 hours lism during the test.27 instead of 72 hours and the advantage of not Carrying out a triolein 14C breath test is simple. having to collect or analyze stool are important The patient ingests 5 juCi of triolein 14C and 25 points favoring use of the breath test.25 The agents grams of Lipomul (emulsified corn oil) and then for doing the study are available, and the test exhales into vials containing 1.0 mmole of can be set up in any hospital; however, it must Hyamine (a C02-trapping agent) in methanol. be pointed out that most nuclear medicine de- Each vial contains phenolphthalein, which turns partments do not routinely have the liquid scintil- from pink to colorless as the Hyamine is neutral- lation spectrometers needed for detecting 14C. The ized by combining with the exhaled CO2; this accuracy of the two-part tests in a large popula- color change signifies accurately when the CO2 tion still needs to be determined before it can be collection is complete. The peak of the radioactive recommended as a routine method for detecting excretion usually occurs within six hours from the pancreatic insufficiency. time of ingestion of the triolein 14C. The peak excretion has been shown to correlate best with BT-PABA Test the presence or absence of steatorrhea. N-benzoyl-N-tyrosyl para-aminobenzoic acid The triolein 14C breath test cannot be used to (BT-PABA) is the combination of para-aminoben- differentiate fat malabsorption due to pancreatic zoic acid (PABA) and a chymotrypsin-sensitive insufficiency from that due to any other cause. In dipeptide. When BT-PABA enters the duodenum this respect the test is similar to the measurement the dipeptide is separated from the PABA by pan- of stool fat. Two modifications intended to make creatic chymotrypsin. The free PABA is readily the test more specific for pancreatic disease have absorbed and transported to the where it is been described. In the first, the ratio of 14C to 3H conjugated. Most of the conjugated PABA iS in the serum is measured after the ingestion of the excreted into the urine where it can be measured triglyceride labeled with carbon 14 and the fatty by a simple colorimetric technique. acid labeled with tritium (3H).28,29 Absorption The BT-PABA test has been studied extensively of the fatty acid 14C requires hydrolysis of the in Europe, Japan and the United States.3135 Some triglyceride 14C by pancreatic lipase, whereas reports have suggested that the test is 80 percent

THE WESTERN JOURNAL OF MEDICINE 371 PANCREATIC EXOCRINE FUNCTION TESTING sensitive and 90 percent specific for detecting stomach; in the alkaline duodenum, with the aid pancreatic insufficiency or, pancreatic cancer. of pancreatic enzymes, the cobalamin transfers to However, results of the BT-PABA test do not always IF; the IF-cobalamin complex is then absorbed correlate with those of the secretin test, and values across the terminal .38-40 The transfer of in groups of normal subjects and patients with cobalamin to IF is a necessary step because cobal- pancreatic insufficiency often overlap. Several amin bound to R-protein cannot be absorbed by variables can influence the results of the BT-PABA the ileum. test: (1) whether the BT-PABA iS given with a This model is consistent with the well-recog- liquid meal or alone, (2) the presence of abnormal nized observation41'42 that in as many as 50 per- small bowel mucosa, (3) the presence of cirrhosis, cent of patients with pancreatic insufficiency, co- (4) the presence of abnormal renal function, balamin is not absorbed normally. (5) the acidity of the stomach and (6) ingestion The pancreatic Schilling test is based on the by the patient of substances that can interfere with requirement for pancreatic enzymes in the absorp- the assay for PABA, such as sulfonamides, thia- tion of cobalamin.43 The test is carried out by zides, furosemide, acetaminophen, chlorampheni- simultaneously giving the patient 57Co-cobalamin- col, prunes or cranberries.34'36 To circumvent IF, 58Co-cobalamin-R-protein, cobinamide and IF these problems, a two-stage test has been de- by mouth. Cobinamide is an analogue of cobal- vised.37 On day one, free PABA (680 mg) is in- amin that irreversibly binds to R-protein; it is gested by the patient, and PABA excreted in urine given to prevent endogenous R-protein from dis- during the next 6 to 24 hours is measured. On associating the exogenous cobalamin 57Co from IF. the next day the patient ingests an equivalent The free IF is given to assure that sufficient IF amount of PABA as BT-PABA, and the excretion will be present to bind to the cobalamin 58Co in of PABA iS compared with that of the first day. By the duodenum once the cobalamin has been re- determining the ratio of PABA excreted after ad- leased from R-protein by pancreatic enzymes. The ministration of the two molecular forms, many patient also receives 1,000 jug of unlabeled cobal- of the variables mentioned above can be elimi- amin intramuscularly, as in the standard Schilling nated. Preliminary results with the test are encour- test, to saturate binding sites and, thereby, en- aging. Further, it is easy to carry out and does hance urinary excretion of absorbed radioactive not subject the patient to radiation exposure, thus cobalamin. The patient collects his or her urine making it safe for use in pregnant women and for 24 hours, and the radioactivity of the 57Co children. and 58Co in the urine is counted (both isotopes are gamma emitters but have different energy Pancreatic Schilling Test emission peaks) (Figure 1). The most recently developed test of pancreatic When this test was carried out on 26 healthy exocrine function is based on new information subjects at this institution, it was found that the about the absorption of cobalamin (vitamin B12). ratio of 58Co to 57Co excreted in the urine was The traditional model for cobalamin absorption near 1.0. This result presumably reflects the simi- includes intrinsic factor (IF) and the ileal mucosa: lar absorption and excretion of cobalamin that cobalamin binds to IF in the stomach, and the occurs in the presence of a normally functioning complex is absorbed across the terminal ileum. pancreas irrespective of whether the cobalamin Recently, it has been discovered that another is bound to R-protein or to IF. In 15 patients glycoprotein, R-protein, is present in gastric juice, with pancreatic insufficiency, the ratio of 58Co to bile and saliva.38'39 R-protein in an acid environ- 57Co excretion was much less than 1.0, presum- ment binds cobalamin with a 150-fold higher ably reflecting the decreased absorption of co- affinity than does IF; in an alkaline environment, balamin 58Co bound to R-protein that occurs when as in the normal duodenum, R-protein binding to pancreatic proteases are deficient. There was no cobalamin is only three times greater than IF overlap of ratios in the normal group with those binding. Pancreatic enzymes can partially degrade of the patients who had pancreatic insufficiency. R-protein, thereby further reducing the ability of Pancreatic insufficiency was confirmed in all the the glycoprotein to bind to cobalamin.38 IF iS patients by the secretin test, and none of the resistant to pancreatic enzyme activity. Thus, a normal subjects had steatorrhea. new model for cobalamin absorption has been If further studies confirm the findings of this proposed: Cobalamin binds to R-protein in the initial investigation, the pancreatic Schilling test

372 NOVEMBER 1981 * 135 * 5 PANCREATIC EXOCRINE FUNCTION TESTING FATE OF IF-Cbl FATE OF R-Cbl

Figure 1.-A model of the dual-label pancreatic Schilling test. The drawing on the left (under fate of IF-Cbl) illustrates how cobalamin (Cbl) bound to IF (intrinsic factor) is handled in normal subjects and in patients with pancreatic insufficiency. The IF-Cbl passes through the gut and is absorbed in the terminal ileum regardless of pancreatic function. Note that R-protein (R) is prevented from interacting with the IF-Cbl by cobinamide (Cbl), a cobalamin analogue with a higher affinity for R-proteiin than cobalamin. The other two drawings illustrate the different handling of cobalamin bound to R-protein (R-Cbl) in both normal subjects and patients. In normal persons R-protein must be degraded by pancreatic enzymes before the cobalamin can be bound to intrinsic factor and transported to the ileum for absorption. However, in patients with decreased pancreatic exocrine function the R-protein remains bound to the cobalamin and cannot be absorbed by the terminal ileum. Thus, if IF-Cbl and R-Cbl are labeled with different isotopes, the differential handling can be easily detected by collecting the patient's urine. may prove to be the most accurate indirect test pitals do not have the proper equipment for carry- of pancreatic exocrine function available. The use ing it out. The pancreatic Schilling test may be of the excretion ratio of 58Co to 57Co eliminates the simplest and most reliable, but it is not yet false-positive results created by abnormal absorp- commercially available. The BT-PABA test will tion of cobalamin secondary to intestinal mucosal soon be available in this country, and I expect disease, by abnormal excretion because of renal that it will be one of the indirect tests of pancreatic insufficiency or by incomplete collection of urine function most widely accepted for clinical use in because each of these factors affects the excretion the near future. This will be especially beneficial of cobalamin 58Co and cobalamin 57Co equally, to smaller, community hospitals that do not now leaving the ratio unchanged. In the future the have the facilities required for reliably conducting ability to provide all the ingested ingredients as the complicated secretin stimulation test. will make the test similar to capsules technically REFERENCES the dual-labeled Schilling tests used at present. 1. Dreiling DA: Pancreatic secretory testing in 1974. Gut 16: nuclear medicine should be 653-657, Aug 1975 Thus, any department 2. Gyr NE: Tests of Exocrine Pancreatic Function. Hans Huber able to do the pancreatic Schilling test. Publishers, Bern, Switzerland, 1975 3. Arvanitakis C, Cooke AR: Diagnostic test of exocrine pan- creatic function and disease. Gastroenterology 74:932-948, May 1978 Conclusion 4. Dreiling DA: The early diagnosis of pancreatic cancer. Scand J Gastroent 5(Suppl 6):115-122, 1970 exo- 5. Wormsley KG: Further studies of the response to secretin Among the available tests of pancreatic and pancreozymin in man. Scand J Gastroent 6:343-350, 1971 crine function, the secretin test is the most ac- 6. Escourrou J, Flexinos J, Ribet A: Biochemical studies of pancreatic juice collected by duodenal aspiration and endoscopic curate, provided that it is done carefully by cannulation of the main pancreatic duct. Am J Dig Dis 23:173- 177, Feb 1978 well-trained personnel. Triolein 14C is available, 7. Rinderknecht H, Renner IG, Douglas AP, et al: Profiles of pure pancreatic secretions obtained by direct pancreatic duct can- but not enough data have been accumulated on nulation in normal healthy human subjects. Gastroenterology 75: the modifications described above to advocate 1083-1089, Dec 1978 8. Gullo L, Costa PL, Lab6 G: A comparison between injection that this test can be used for routine detection and infusion of pancreatic stimulants in the diagnosis of exocrine pancreatic insufficiency. Digestion 18:64-69, 1978 of pancreatic insufficiency. Moreover, many hos- 9. Clain J, Bank S, Barbezat GO, et al: A comparison between

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Acta Chir Scand 231(Suppl):1-83, 1958 nostic value of the oral pancreatic function test. Scand J Gastro- 16. DiMagno EP, Go VLW, Summerskill WHJ: Impaired chole- enterol 14: 183-187, 1979 cystokinin-pancreozymin secretion, intraluminal dilution and mal- 34. Masuda M: Pancreatic Function Diagnostant. New York, digestion of fat in sprue. Gastroenterology 63:25-32, Jul 1972 Igaku-Shein, 1980 17. Ammann RW, Tagwecher E, Kashwagi H, et al: Diagnostic 35. Gyr K, Stalder GA, Schiffmann I, et al: Oral administration value of fecal chymotrypsin and trypsin assessment for detection of a chyniotrypsin-labile -A new test of exocrine pan- of pancreatic disease. Am J Dig Dis 13:123-146, Feb 1968 creatic function in man (PFT). Gut 17:27-32, Jan 1976 18. Haverback BJ, Oyce BJ, Gutentag PJ, et al: Measurement 36. Cathcart-Rake W, Porter R, Whittier F, et al: Effect of of trypsin and chymotrypsin in stool. Gastroenterology 44:588- diet on serum accumulation and renal excretion of aryl acids and 597, 1963 secretory activity in normal and uremic man. Am J Clin Nutr 19. Taussig LM, Wolf RO, Woods RE, et al: Use of serum 28:1110-1115, Oct 1975 amylase isoenzymes in evaluation of pancreatic function. Pediatrics 37. Mitchell CJ, Hiumphrey CS, Bullen AW, et al: Improved 54:229-234, Aug 1974 diagnostic accuracy of a modified oral pancreatic function test. 20. Elias E, Redshaw M, Wood T: Diagnostic importance of Scand J Gastroenterol 14:737-741, 1979 changes in circulating concentrations of immunoreactive trypsin. 38. Allen RH, Seetharam B, Podell E, et ;l: Effect of pro- Lancet 2:66-68, Jul 9, 1977 teolytic enzymes on the binding of cobalamin to R protein and 21. Bloom SR, Adrian TE, Besterman HS, et al: Plasma trypsin intrinsic factor. J Clin Invest 61:47-54, Jan 1978 in the diagnosis of steatorrhea due to chronic pancreatitis. Gastro- 39. Allen RH, Seetharain B, Allen NC, et al: Correction of enterology 74:1012, 1978 cobalamin malabsorption in pancreatic insufficiency with a cobala- 22. Lake-Bakaar G, McKavanagh S, Redshaw M, et al: Serum min analogue that binds with high affinity to R protein but not to immunoreactive trypsin concentration after a Lundh meal-Its intrinsic factor. J Clin Invest 61:1628-1634, Jun 1978 value in the diagnosis of pancreatic disease. J Clin Pathol 32:1003- 40. Marcoullis G, Parmentier Y, Nicolas JP, et al: Cobalamin 1008, Oct 1979 malabsorption due to nondegradation of R-protein in the human 23. Stanley MM, Thannhauser SJ: The absorption and disposi- intestine. J Clin Invest 66:430-440, Sep 1980 tion of orally administered 1311 labeled neutral fat in man. J Lab 41. Matuchansky C, Rambaud JC, Modigliani R, et al: Vitamin Clin Med 34:1634-1639, 1949 B12 malabsorption in chronic pancreatitis. Gastroenterology 67: 24. Kaihara S, Wagner RN Jr: Measurement of intestinal fat 406-407, Aug 1974 absorption with carbon-14 labeled tracers. J Lab Clin Med 71: 42. Toskes PP, Hansell J, Cerda J, et al: Vitamin B12 malab- 400-411, Mar 1968 sorption in chronic pancreatic insufficiency-Studies suggesting 25. Newcomer AD, Hofman AF, DiMagno EP, et al: Triolein the presence of a pancreatic "intrinsic factor." N Engl J Med 284: breath test: A sensitive and specific test for fat malabsorption. 627-632, Mar 25, 1971 Gastroenterology 76:6-13, Jan 1979 43. Brugge WR, Goff JS, Allen NC, et al: Development of a 26. Levy-Gigi C, Mandelowitz N, Peled Y, et al: Is the fat dual label Schilling test for pancreatic exocrine function based on breath test effective in the diagnosis of fat malabsorption and the differential absorption of cobalamin bound to intrinsic factor pancreatic disease? Digestion 18:77-85, 1978 and R protein. Gastroenterology 78:937-949, May 1980

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