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Gastrointest Endosc 2002;56:218–224. Mori T, Kawara S, Shinozaki M et al. Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: a mouse fibrosis model. J Cell Physiol 1999;181:153–159. Müller MW, McNeil PL, Büchler MW, Friess H, Beger HG, Bockman DE. Membrane wounding and early ultrastructur- al findings. In: MW Büchler, W Uhl, H Friess, P Malfertheiner (eds) Acute Pancreatitis: Novel Concepts in Biology and Therapy. Oxford, Berlin: Blackwell Science, 1999:27–34. Qi Z, Atsuchi N, Ooshima A, Takeshita A, Ueno H. Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Natl Acad Sci USA 1999;96:2345–2349. Sanvito F, Nichols A, Herrera PL et al. TGF-beta-1 overexpres- sion in murine pancreas induces chronic-pancreatitis and to- gether with TNF-alpha, triggers insulin-dependent diabetes. Biochem Biophys Res Commun 1995;217:1279–1286. Slater SD, Williamson RC, Foster CS. Expression of trans- forming growth factor-beta(1) in chronic pancreatitis. Digestion 1995;56:237–241. Sparchez Z. Ultrasound-guided percutaneous pancreatic biopsy. Indications, performance and complications. Rom J Gastroenterol 2002;11:335–341. Sparmann G, Merkord J, Jaschke A et al. Pancreatic fibrosis in experimental pancreatitis induced by dibutyltin dichloride. Gastroenterology 1997;112:1664–1672. Van Laethem J-L, Deviere J, Resibois A et al. Localization of transforming growth factor b-1 and its latent binding protein in human chronic pancreatitis. Gastroenterology 1995;108:1873–1881. Van Laethem JL, Robberecht P, Resibois A, Deviere J. Trans- forming growth factor beta promotes development of fibro- sis after repeated courses of acute pancreatitis in mice. Gastroenterology 1996;110:576–582. Vogelmann R, Ruf D, Wagner M et al. Development of pan- creatic fibrosis in a TGFb1 transgenic mouse. Gastroen- terology 1999;116:A1174. Werz O, Brungs M, Steinhilber D. Purification of transforming growth factor beta 1 from human platelets. Pharmazie 1996;51:893–896. Yamanaka Y, Friess H, Büchler, Beger HG, Gold LI, Korc M. Synthesis and expression of transforming growth factor beta-1, beta-2, and beta-3 in the endocrine and exocrine pancreas. Diabetes 1993;42:746–756. Zech CJ, Helmberger T, Wichmann MW, Holzknecht N, Diebold J, Reiser MF. Large core biopsy of the pancreas under CT fluoroscopy control: results and complications. J Comput Assist Tomogr 2002;26:743–749. PART II 258 259 Because histology is usually not available for the diag- nosis of chronic pancreatitis, this is based on the demonstration of the morphologic and/or functional changes that typically develop over time in the course of the disease. Exocrine pancreatic function is impaired progressively as chronic pancreatitis develops. Thus, exocrine pancreatic dysfunction refers to a mild, mod- erate, or severe reduction of exocrine pancreatic func- tion. Finally, pancreatic function becomes insufficient to maintain normal digestive processes. Exocrine pancreatic insufficiency thus refers to the presence of maldigestion and malabsorption of nutrients as a con- sequence of primarily and/or secondarily impaired ex- ocrine pancreatic function. Thus the terms “exocrine pancreatic insufficiency” and “severe exocrine pan- creatic dysfunction” are synonymous. Exocrine pancreatic dysfunction is a frequent finding not only in chronic pancreatitis but also in most other diseases of the exocrine and endocrine pancreas, i.e., cystic fibrosis, pancreatic tumors, after acute necrotiz- ing pancreatitis and insulin-dependent diabetes mellitus. In addition, secondary exocrine pancreatic dysfunction frequently develops after gastrointestinal surgery (partial or total gastrectomy, duodenectomy). Functional evaluation of the exocrine pancreas may be important for supporting the diagnosis of pancreatic disease in cases of inconclusive morphologic findings on imaging methods. However, the most relevant role for functional evaluation of the pancreas is the detec- tion of primary or secondary pancreatic insufficiency in patients with known pancreatic disease or after gas- trointestinal surgery in order to aid in the indication of enzyme substitution therapy and to control the efficacy of this therapy. Exocrine pancreatic function may be evaluated by means of direct methods requiring duodenal intubation and noninvasive indirect methods (Table 31.1). The clinical usefulness of each of the available methods is related to factors like diagnostic accuracy, applicability to clinical routine, and cost. Direct pancreatic function tests, mainly the secretin–cholecystokinin test, are the gold standard for evaluation of exocrine pancreatic function. However, these tests are invasive, cumber- some, time-consuming, and expensive and thus limited to some specialized centers. Indirect pancreatic func- tion tests are more easily applicable to clinical routine and therefore more widely used. Among these are oral and breath tests that, together with fecal fat quantifica- tion, evaluate the digestive ability of the exocrine pancreas, and fecal tests that measure the activity or concentration of pancreatic enzymes in feces. The sen- sitivity and specificity of these indirect tests are variable and lower than those of the direct tests. Since the infor- mation provided by each test is different, it is important to select the optimal test to be performed in each clinical situation. In patients with clinical suspicion of chronic pancre- atitis but normal imaging, only the secretin–cerulein test is sufficiently sensitive to support the diagnosis of the disease. The development of endoscopic ultra- sonography, which has a very high sensitivity for the diagnosis of chronic pancreatitis, has further limited 31 Pancreatic function tests for diagnosis and staging of chronic pancreatitis, cystic fibrosis, and exocrine pancreatic insufficiency of other etiologies: which tests are necessary and how should they be performed in clinical routine? J. Enrique Domínguez-Muñoz PART II 260 the clinical usefulness of direct pancreatic function tests. Conversely, the diagnosis of primary or secondary exocrine pancreatic insufficiency and, in this context, the indication for or control of the efficacy of enzyme substitution therapy require a test able to detect maldigestion. It is easy to understand that in these two clinical situations the test to be used should have a very different sensitivity, highest in the former case, lowest in the latter (Fig. 31.1). In transitional situations, tests with an intermediate sensitivity may be useful for the screening of chronic pancreatitis in patients with a compatible clinical picture and for the long-term follow-up of patients with known chronic pancreatitis (Fig. 31.1). Direct tests Invasive pancreatic function tests are based on the di- rect measurement of pancreatic enzymes and bicarbon- ate output in samples of duodenal juice obtained after stimulation of the gland by intravenous administration of secretin and cholecystokinin (CCK) or cerulein (secretin–cholecystokinin test). Simple stimulation by intravenous secretin (secretin test) is used in the so-called endoscopic test, which is based on the mea- surement of bicarbonate concentration in endoscopy- guided aspirates of duodenal juice (see below). Finally, endogenous stimulation by a test meal (Lundh test) is no longer used because of a lower diagnostic accuracy. Since direct pancreatic function tests are invasive, cumbersome, time-consuming, nonstandardized, and expensive, and since the development of novel sensitive imaging methods (i.e., endoscopic ultrasonography) has markedly improved the diagnosis of chronic pan- creatitis, the usefulness of the secretin–cholecystokinin test is nowadays limited to its use as gold standard in the validation of new pancreatic function tests. Secretin–cholecystokinin test Method The secretin–cholecystokinin test protocol differs among centers. A double-lumen nasoduodenal tube should be placed for constant aspiration of gastric juice and complete and fractionated collection of duodenal juice on ice during continuous intravenous infusion of secretin and CCK or cerulein. The protocol recom- mended by our group is summarized in Fig. 31.2. Despite duodenal juice being continuously aspirated, collection may be incomplete. The amount of juice lost toward the jejunum may be calculated by constant duo- denal perfusion of a nonabsorbable dilution marker, usually polyethylene glycol. However, this requires a triple-lumen tube and further complicates the perfor- mance of the test. An additional problem is the variable inactivation of pancreatic enzymes within the collected duodenal juice despite the use of antiproteases and collection on ice. This may be overcome by the single quantification of zinc instead of bicarbonate and enzymes. Zinc secre- tion is linked to pancreatic proteases; it is easily quan- tifiable and very stable in duodenal juice. Our group has recently demonstrated that the secretin–cerulein test based on single quantification of zinc output is as Table 31.1 Pancreatic function tests. Direct tests Secretin–cholecystokinin test Endoscopic test Indirect tests Fecal fat quantification Fecal levels of pancreatic enzymes NBT-PABA test Pancreolauryl test Amino acid consumption test Breath tests ( 13 C-labeled substrates) HIGH LOW Sensitivity of the test to be used • Diagnosis of chronic pancreatitis in cases of inconclusive morphologic changes • Sereening of chronic pancreatitis in patients with compatible clinical symptoms • Long-term follow-up of patients with known chronic pancreatitis • Diagnosis of primary or secondary pancreatic insufficiency • Indication for and control of the efficacy of oral enzyme substitution therapy Figure 31.1 Indications for evaluation of exocrine pancreatic function. The sensitivity of the function test to be used varies according to the indication. CHAPTER 31 261 accurate as the test based on quantification of bicar- bonate and enzymes for evaluation of exocrine pan- creatic function. Interpretation The secretin–cholecystokinin test allows classification of the severity of exocrine pancreatic dysfunction (Table 31.2). The sensitivity and specificity of this test for the diagnosis of chronic pancreatitis both exceed 90% (Table 31.3). Endoscopic test The endoscopic pancreatic function test has been devel- oped in order to avoid the problems associated with the secretin–cholecystokinin test, i.e., intubation, dura- tion, and clinical applicability. It is based on the measurement of bicarbonate concentration and/or pancreatic enzyme activity in samples of duodenal juice obtained during upper gastrointestinal endoscopy after intravenous secretin stimulation. Method The protocol for the endoscopic pancreatic function test is based on the following four steps. 1 Standard endoscopy to the descending duodenum with the patient under conscious sedation. 2 Intravenous administration of secretin (1 U/kg or 0.2 mg/kg). 3 Endoscopic duodenal fluid collection at 0, 15, 30, 45, and 60 min after secretin injection. A short version of the test is based on the collection of duodenal juice for only 10 min. 4 Fluid analysis for bicarbonate concentration and/or pancreatic enzyme activity. Interpretation The peak bicarbonate concentration over 60 min is lower in patients with advanced chronic pancreatitis than in those with abdominal pain of extrapancreatic origin. Measurement of lipolytic activity in duodenal juice collected for 10 min after intravenous secretin is also significantly lower in patients with chronic pancre- atitis compared with patients with normal pancreas, but it is not accurate enough for routine clinical use. Calculation of bicarbonate and enzyme output Quantification of volume, bicarbonate concentration, and amylase, lipase and protease (trypsin, chymotrypsin, and/or elastase) activities Overnight fasting Placement of a double-lumen tube under fluoroscopic control, with the tip at the ligament of Treitz Continuous aspiration of gastric and duodenal juice Continuous intravenous infusion of secretin (1 U/kg per hour) and cerulein (100ng/kg per hour) over 90 min Sampling of duodenal juice in 10-min aliquots over the last 60 min of hormone infusion Figure 31.2 Secretin–cerulein test protocol. Table 31.2 Severity of exocrine pancreatic dysfunction based on the secretin–cholecystokinin test. Normal Normal output of enzymes and bicarbonate Mild dysfunction Secretion of enzymes and bicarbonate ≥ 75% of the lower limit of normal Moderate dysfunction Secretion of enzymes and bicarbonate 30–75% of the lower limit of normal Severe dysfunction Secretion of enzymes and bicarbonate < 30% of the lower limit of normal Table 31.3 Mean accuracy of exocrine pancreatic function tests for the diagnosis of chronic pancreatitis. Sensitivity (%) Specificity (%) Secretin–cholecystokinin 90 94 test Fecal chymotrypsin 57 88 Fecal elastase 70 85 Optimized serum 82 90 pancreolauryl test Although the endoscopic pancreatic function test is a promising procedure, it is far from being the current standard. Whether the peak bicarbonate concentra- tion, instead of output over time, is a reliable marker of exocrine pancreatic function is questionable. In fact, most experts in this field support bicarbonate and enzyme output and not concentration as the most reliable marker of exocrine pancreatic function. This is due to the inverse relationship between bicarbonate concentration and rate of juice secretion in response to secretin. In addition, the endoscopic pancreatic func- tion test requires the endoscope to be maintained in the duodenum for 1 hour, which is at least as uncomfort- able for patients as nasoduodenal tubing. Because of this, pharmacologic conscious sedation is required in the context of the endoscopic test, although the effect of these drugs on exocrine pancreatic function has not been specifically evaluated. All these facts hinder the clinical usefulness of the endoscopic pancreatic func- tion test. Indirect tests Indirect tests evaluate exocrine pancreatic function by quantifying either the digestive ability of the gland or levels of pancreatic enzymes in feces (Table 31.1). From a methodologic point of view, these tests can thus be classified as oral tests and fecal tests. In oral tests, a substrate is orally given together with a test meal. Pancreatic enzymes hydrolyze the substrate within the duodenum; the released metabolites are absorbed from the gut and can then be measured in serum, urine, or breath. Oral tests include the pancreolauryl test and different breath tests, mainly using 13 C-labeled sub- strates. Other tests like the NBT-PABA test and the amino acid consumption test are no longer commer- cially available and/or have insufficient diagnostic ac- curacy to be recommended for clinical use. Several extrapancreatic factors are known to limit the accuracy of oral pancreatic function tests, mainly those interfering with normal digestion (slow gastric emptying rate, decreased bile acid secretion) and in- testinal absorption (intestinal diseases) as well as those affecting the elimination of digestion products (renal insufficiency). Variability in gastric rate can be avoided to some extent by administration of metoclopramide or any other prokineticum in the context of the test. The potential negative role of renal disturbances is avoided by the quantification of digestion products in serum instead of urine. Fecal tests are based on the quantification of pan- creatic enzyme concentration (elastase) or activity (chymotrypsin) in feces. Enzymes are deactivated and diluted or concentrated to a variable degree during intestinal passage, which must be taken into account when interpreting test results. Exocrine pancreatic function can also be measured indirectly in feces by means of fecal fat quantification. The amount of fat eliminated within the feces indirectly reflects fat diges- tion and therefore pancreatic lipase secretion. Fecal tests Fecal fat quantification Fecal fat quantification using the classical Van de Kamer test is the gold standard for the diagnosis of steatorrhea. However, this test has several important disadvantages that limit its clinical applicability. Pa- tients must eat a standard diet containing 80–120 g of fat daily for five consecutive days. This is an important handicap since the majority of patients with chronic pancreatitis are alcoholics and thus have limited com- pliance. Furthermore, patients should collect the total amount of feces produced over the last 3 days of the diet. Again this is not easy for alcoholic patients. A 3- day collection is needed to reduce errors and variability that may occur if a shorter collection period is used. Patient compliance is not the only limitation of fecal fat quantification; so is the handling of stool samples in the laboratory. Stool samples collected over 3 days must be first homogenized and then processed man- ually, making this test unpleasant and cumbersome. A new methodology based on near-infrared reflectance analysis (NIRA) has greatly simplified the quantifica- tion of fat in stool and thus could make feasible the wide application of this test in clinical routine. Never- theless, the difficulties associated with patient com- pliance remain the same. Method In our laboratory, patients are instructed to eat a diet containing 92 g of fat for 5 days. Stool from the last three consecutive days is collected in three dif- ferent containers. The daily amount of fat excreted (g/day) is quantified based on fat concentration meas- ured by NIRA (g/100 g stool) and the total weight of the stool on each day. The mean of the three values obtained is considered as the result. PART II 262 Interpretation Following the test protocol described above, a fecal fat excretion below 7.5 g/day is consid- ered normal. Fat maldigestion indicating exocrine pan- creatic insufficiency is defined by a fecal fat excretion greater than 7.5 g/day. Interpretation of the test may be improved by keeping a record of all dietary intake over the 5-day period. In this way, fat intake can be deter- mined and thus the fractional fat absorption can be cal- culated. It should be noted that fecal fat quantification is a nonspecific pancreatic function test since any other cause of maldigestion (i.e., obstructive jaundice) or malabsorption (i.e., sprue, Crohn’s disease) may also induce abnormal fecal fat excretion. Fecal chymotrypsin activity Quantification of fecal chymotrypsin is a simple test and easy to apply to the clinical routine. This test is based on the enzymatic quantification of chymotrypsin activity in an isolated small stool sample. Because of this, fecal chymotrypsin has been widely introduced in clinical routine as an exocrine pancreatic function test. However, chymotrypsin is variably inactivated during intestinal passage in such a way that fecal chymotrypsin activity does not accurately reflect pancreatic secretion of the enzyme. In addition, dilution of the enzyme in patients with diarrhea of any etiology will also decrease the fecal activity of the enzyme. Because of this, and in order to maintain adequate specificity of the test, a low cut-off (3 U/g of stool) is generally accepted as the definition of an abnormal test. Patients with fecal chymotrypsin activity of less than 3 U/g of stool are thus considered as suffering from ex- ocrine pancreatic dysfunction, although the sensitivity obtained with the test is too low to recommend it for clinical practice. In fact, the test is not able to detect a single case of mild exocrine pancreatic dysfunction, and can only detect slightly more than half of those patients with moderate or severe dysfunction (Table 31.3). Last but not least, orally administered exogenous pancreatic enzymes as a treatment for exocrine pan- creatic insufficiency interact with the determination of chymotrypsin in stool and thus this therapy should be interrupted for at least the 48 hours preceding stool sample collection. This is not always easy to accomplish for patients with exocrine pancreatic insufficiency. In conclusion, and after taking into consideration all the aspects mentioned above, fecal chymotrypsin quan- tification should no longer be considered adequate for evaluating exocrine pancreatic function in clinical routine. Fecal elastase concentration Compared with chymotrypsin, pancreatic elastase is highly stable during gastrointestinal transit and the fecal concentration of this enzyme correlates signifi- cantly with the amount of enzyme secreted by the ex- ocrine pancreas. Furthermore, since the methodology used to quantify this enzyme is based on human- specific monoclonal antibodies, oral enzyme substitu- tion therapy does not interfere with the test. Therefore, interruption of this therapy previous to stool collection is not needed, which is an important advantage. Method Quantification of fecal elastase is performed in a single small stool sample by a specific enzyme immunoassay. Interpretation A fecal elastase concentration higher than 200 mg/g is considered normal. Concentrations lower than 50 mg/g are related to exocrine pancreatic insufficiency. Although fecal elastase quantification is not sensitive enough to detect patients with mild ex- ocrine pancreatic dysfunction, its sensitivity in cases of moderate to severe dysfunction is very high, reaching values close to 100%. The specificity of fecal elastase is also high, only limited by dilution in cases of watery diarrhea. Fecal elastase based on the use of human-specific monoclonal antibodies is therefore an excellent test for the diagnosis of exocrine pancreatic dysfunction in the context of chronic pancreatitis. Since this test is easy to apply to the clinical routine, it may be used as a first step in the study of patients with clinically suspected chronic pancreatic disease and for the follow-up of patients with known chronic pancreatitis. In situations of secondary exocrine pancreatic dysfunction (i.e., after gastrointestinal surgery), fecal elastase is useful for evaluating pancreatic secretion but not for detect- ing maldigestion. Oral tests Pancreolauryl test Fluorescein dilaurate is administered orally together with a standardized breakfast. A pancreas-specific cholesterol ester hydrolase acts on this compound CHAPTER 31 263 and water-soluble fluorescein is released and absorbed from the gut. Fluorescein can thus be measured in serum or urine after renal excretion. The advantage of this test is that it is easily applicable to the clinical routine and can be used not only for supporting the diagnosis of chronic pancreatitis but also for the follow-up of patients with this disease. The major dis- advantages of the test are the limiting factors of oral tests described above and a limited sensitivity for the early diagnosis of chronic pancreatitis. Method The standard test requires collection of urine over 10 hours after the ingestion of the standard break- fast and fluorescein dilaurate. The diuresis should be in- creased by the ingestion of at least 1500 mL of water during the test. In order to compensate for the variable intestinal absorption and renal excretion of the sub- strate, the test should be repeated 3 days later by giving fluorescein sodium as substrate. On both test days, urine fluorescein concentration is measured. Repetition of the test is not necessary if fluorescein concentration is measured in serum. Our group has op- timized the serum pancreolauryl test by administering intravenous metoclopramide just after the ingestion of the test meal in order to avoid potential problems related to gastric emptying. In addition, intravenous administration of secretin just before ingestion of the test meal significantly increases the sensitivity of the test by inducing a washout of stored pancreatic enzymes accumulated overnight. Finally, we have optimized the measurement of serum fluorescein concentration. The optimized serum pancreolauryl test protocol is summa- rized in Fig. 31.3. Potential adverse effects of metoclo- pramide and secretin present very rarely after a single dose. In our experience, transient mouth dryness is ob- served occasionally after metoclopramide administra- tion. A few patients suffer from nausea after secretin, which can be prevented by slow injection of the drug (over 2–3 min). Interpretation Results of the urine pancreolauryl test are expressed as the quotient between the urine fluores- cein concentration at day 1 (when fluorescein dilaurate is given as substrate) and that at day 2 (when fluorescein sodium is given as substrate). A quotient is considered as normal if higher than 30 and abnormal if lower than 20. Values between 20 and 30 are inconclusive. The peak serum fluorescein concentration is consid- ered as the result of the serum test. A peak greater than PART II 264 4.5 mg/mL indicates normal exocrine pancreatic func- tion. Mild to moderate exocrine pancreatic dysfunc- tion is defined by a peak between 2.5 and 4.5 mg/mL. A result below 2.5 mg/mL is observed in patients with severe pancreatic dysfunction. The accuracy of the optimized serum pancreolauryl test is much higher than the accuracy of the standard test in urine (Table 31.3). The sensitivity of the opti- mized serum test for the diagnosis of mild exocrine pan- creatic dysfunction is 75%, and for moderate or severe dysfunction is 100%. False-positive results can be ob- tained in patients with gastrointestinal extrapancreatic diseases leading to maldigestion of fluorescein dilau- rate (e.g., partial gastric resection with Billroth II anas- tomosis, obstructive jaundice) or to malabsorption of released fluorescein (e.g., sprue). 13 C-substrate breath tests Several substrates, mainly 13 C-labeled, have been used to evaluate exocrine pancreatic function by means of breath tests. In these tests, the labeled substrate is given orally together with a test meal. After intraduodenal hydrolysis of the substrate by specific pancreatic en- zymes, 13 C-marked metabolites are released, absorbed from the gut, and metabolized within the liver. As a con- sequence of hepatic metabolism, 13 CO 2 is released and Overnight fast Placement of an indwelling cannula in an antecubital vein Take basal blood sample (10 mL) Intravenous administration of secretin (1 U/kg body weight) over 2–3 min Ingestion of the test meal (40 g of white bread, 20g of butter, 200 mL of tea) together with 1 mmol fluorescein dilaurate spread on the bread together with the butter Intravenous metoclopramide administration (10 mg) Take blood samples (5 mL each) at 120, 150, 180 and 240 min after test meal ingestion Measurement of serum fluorescein concentration in all samples Figure 31.3 Optimized serum pancreolauryl test protocol. CHAPTER 31 265 thereafter eliminated with expired air (Fig. 31.4). The amount of 13 CO 2 expired, which indirectly reflects ex- ocrine pancreatic function, can be measured by means of mass spectrometry or infrared analysis. Most substrates used in breath tests, among them mixed 13 C-triglyceride, cholesteryl 13 C-octanoate, 13 C- hiolein, and 13 C-triolein, are hydrolyzed by pancreatic lipase. In this way pancreatic function breath tests should be seen as fat digestion tests and thus considered as an alternative to fecal fat quantification. The only breath test that has been optimized is the mixed 13 C-triglyceride ( 13 C-MTG) breath test. In our experience, this is the optimal substrate for the diagno- sis of fat maldigestion and thus the 13 C-MTG breath test has been developed as a simple alternative to fecal fat quantification. Method According to the protocol developed by our group, a total of 250 mg of 13 C-MTG is spread on a solid test meal containing 16 g of fat. Before the meal (basal sample) and in 30-min intervals for 6 hours after ingestion of the meal, breath samples are collected in 10-mL tubes. A single dose of a prokineticum (i.e., metoclopramide) is given orally 20–30 min before the meal in order to avoid potential problems related to gastric emptying. The amount of 13 CO 2 in breath samples is measured by mass spectrometry. The result of the test is expressed as the total amount of recovered 13 CO 2 over the 6 hours. Interpretation A 13 CO 2 below 58% indicates the pres- ence of fat maldigestion, with a sensitivity and specific- ity higher than 90%. The test is also highly accurate for the diagnosis of maldigestion in clinical situations of secondary exocrine pancreatic insufficiency, such as partial or total gastrectomy or duodenectomy. The 13 C-MTG breath test is a simple, noninvasive, and accurate method for the diagnosis of exocrine pan- creatic insufficiency. It is easily applicable to the clinical routine and can be repeated as often as necessary. In this way, the utility of the test is not only limited to the diag- nosis of exocrine pancreatic insufficiency but can also be extended to control of the efficacy of oral enzyme substitution therapy in these patients. Therefore, the 13 C-MTG breath test may play a relevant role in the management of patients with maldigestion secondary to chronic pancreatitis, cystic fibrosis, pancreatic can- cer, and after acute necrotizing pancreatitis or gastric or duodenal surgery. Summary A wide variety of tests are nowadays available for the evaluation of exocrine pancreatic function. The secretin–cholecystokinin test is still the gold standard, but its use is presently limited to the evaluation of new function tests in specialized centers. Quantification of pancreatic zinc output as a single marker may simplify the clinical applicability of this direct test. The optimized serum pancreolauryl test is the most sensitive tubuless pancreatic function test and probably 13 C-substrate 13 CO 2 13 CO 2 13 C-metabolites Figure 31.4 Basis of pancreatic function breath tests. Domínguez-Muñoz JE, Martínez S, Leodolter A, Malfertheiner P. Quantification of pancreatic zinc output as pancreatic function test: making the secretin–caerulein test applicable to clinical practice. Pancreatology 2004;4:57– 62. Gullo L. Value and clinical role of intubation tests in chronic pancreatitis. In: HG Beger, M Buchler, H Ditschuneit, P Malfertheiner (eds) Chronic Pancreatitis. Berlin: Springer- Verlag, 1990: 287–290. Lembcke B. Present and future of breath test in the diagnosis of pancreatic insufficiency. In: P Malfertheiner, JE Dominguez-Muñoz, HU Schulz, H Lippert (eds) Diagnostic Procedures in Pancreatic Disease. Berlin: Springer-Verlag, 1997: 261–271. Lembcke B, Grimm K, Lankish PG. Raised fecal fat concentra- tion is not valid indicator of pancreatic steatorrhea. Am J Gastroenterol 1987;82:526–531. Lembcke B, Braden B, Caspary WF. Exocrine pancreatic insufficiency: accuracy and clinical value of the uniformly labeled 13 C-hiolein breath test. Gut 1996;39:668–74. Leodolter A, Kahl S, Domínguez-Muñoz JE, Gerard C, Glasbrenner B, Malfertheiner P. Comparison of two tube- less function tests in the assessment of mild to moderate exocrine pancreatic insufficiency Eur J Gastroenterol Hepatol 2000;12:1335–1338. Löser C, Möllgaard A, Fölsch UR. Faecal elastase 1: a novel, highly sensitive and specific tubeless pancreatic function test. Gut 1996;39:580–586. Löser C, Brauer C, Aygen S, Hennemann O, Fölsch UR. Com- parative clinical evaluation of the 13 C-mixed triglyceride breath test as an indirect pancreatic function test. Scand J Gastroenterol 1998;33:327–334. Malfertheiner P, Büchler M. Correlation of imaging and function in chronic pancreatitis. Radiol Clin North Am 1989;27:51–64. Stein J, Purschian B, Bieniek U, Caspary WF, Lemcke B. Near- infrared reflectance analysis (NIRA): a new dimension in the investigation of malabsorption syndromes. Eur J Gas- troenterol Hepatol 1994;6:889–894. Stein J, Jung M, Sziegoleit A, Zeuzem S, Caspary F, Lembcke B. Immunoreactive elastase 1: clinical evaluation of a new noninvasive test of pancreatic function. Clin Chem 1996; 42:222–226. Vantrappen GR, Rutgeerts PJ, Ghoos YF, Hiele MI. Mixed triglyceride breath test: a noninvasive test of pancreatic lipase activity in the duodenum. Gastroenterology 1989; 96:1126–1134. Ventrucci M, Cipolla A, Ubalducci GM, Roda A, Roda E. 13 C-labelled cholesteryl octanoate breath test for assessing pancreatic exocrine insufficiency. Gut 1998;42:81–87. PART II 266 the most appropriate for the screening of chronic pan- creatitis in patients with clinical suspicion of the dis- ease. The urine pancreolauryl test can no longer be recommended because of its low sensitivity and the need to repeat the test twice three days apart. Fecal elastase quantification is the most adequate fecal test. It is clearly more accurate than fecal chy- motrypsin for evaluation of exocrine pancreatic func- tion and is easy to apply to the clinical routine. Therefore, fecal elastase may be applied as a first step in the study of patients with suspected chronic pancreati- tis and to aid in the differential diagnosis of chronic diarrhea. Fecal chymotrypsin activity is a nonsensi- tive pancreatic function test and can no longer be considered for clinical routine. The 13 C-MTG breath test appears to be an accurate alternative to fecal fat quantification for the diagnosis of maldigestion of any etiology. This is a simple and noninvasive method, easily applicable to the clinical routine, that can be repeated as frequently as needed and that is useful for the diagnosis of maldigestion as well as for optimization of enzyme substitution therapy in patients with primary or secondary exocrine pan- creatic insufficiency. Recommended reading DiMagno EP, Go VLW, Summerskill HJ. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973;288:813–815. Domínguez-Muñoz JE. Noninvasive pancreatic function tests. In: MW Büchler, H Friess, W Uhl, P Malfertheiner (eds) Chronic Pancreatitis: Novel Concepts in Biology and Therapy. Oxford, Berlin: Blackwell Publishing, 2002: 225–232. Domínguez-Muñoz JE, Malfertheiner P. Optimized serum pancreolauryl test for differentiating patients with and without chronic pancreatitis. Clin Chem 1998;44:869– 875. Domínguez-Muñoz JE, Pieramico O, Büchler M, Malfertheiner P. Clinical utility of the serum pancreolauryl test in diagnosing and staging of chronic pancreatitis. Am J Gastroenterol 1993;88:1237–1241. Domínguez-Muñoz JE, Hyeronimus C, Sauerbruch T, Malfertheiner P. Fecal elastase test: evaluation of a new noninvasive pancreatic function test. Am J Gastroenterol 1995;90:1834–1837. 267 In the initial stages of chronic pancreatitis, which generally last about 5 or 6 years, the disease is charac- terized by attacks of abdominal pain that recur at vari- able intervals during which the patient is pain-free. When the disease is more advanced, the pain tends to disappear, either spontaneously or following surgery, but other symptoms or complications may develop that can alter the course of the disease. In this chapter we discuss the role of the physician in management of this disease, particularly as regards follow-up and complications. What to do in the follow-up The clinical onset of chronic pancreatitis most com- monly occurs when the patient is in his thirties or for- ties. A typical patient with chronic pancreatitis is a male who is employed in a job that requires heavy labor and who generally (70–80% of cases) drinks alcohol to excess. In Italy, alcohol is by far the most frequent etiologic factor, present in 75–80% of patients with chronic pancreatitis who have an average daily con- sumption of 120–140 g of pure alcohol. Thus, the first and most important task for the physician is to con- vince the patient to stop drinking alcohol, informing him that if he does not do so there is little or no chance that his condition will improve, and that he may well also develop unpleasant complications. It should also be explained that if he ceases to drink, the attacks may become less frequent and eventually disappear. Unfor- tunately, not all patients quit drinking, some resuming once a painful attack has subsided (Table 32.1). A majority of individuals with chronic pancreatitis also smoke, and so another duty of the physician is to persuade the patient to quit this habit as well, even though it has not been clearly demonstrated that smok- ing has a pathogenetic role in chronic pancreatitis or that it can negatively influence progression of the disease. Pain, the most important symptom in chronic pan- creatitis, particularly in its initial stage, must be care- fully assessed and monitored in each patient. If the frequency and intensity of the painful attacks are re- duced by cessation of alcohol ingestion, the attacks are likely to eventually disappear, generally within the first 5 or 6 years of the disease; for these patients, surgical intervention is not indicated. Among our patients, roughly 50% fall into this category. If, on the contrary, the frequency and intensity of the painful attacks in- crease or remain high, surgery or, for a few selected patients, endoscopic intervention should certainly be considered, which is the case for about 50% of our patients. For most of the patients who undergo surgery, this generally occurs within 5 or 6 years of clinical onset. It is important to study exocrine and endocrine pan- creatic function from the initial stages of the disease, both to support the clinical diagnosis of chronic pan- creatitis and to guide its treatment. In studies that uti- lized duodenal intubation and prolonged maximal pancreatic stimulation, we showed that exocrine pan- creatic function is impaired in almost all patients with chronic pancreatitis, starting in the initial stages of the disease, at which point the functional impairment is generally mild or moderate. Although duodenal intu- bation is the more sensitive means of assessing exocrine pancreatic function, it is time-consuming and trouble- some and is no longer used in clinical practice. At pre- 32 Follow-up of patients with chronic pancreatitis: what to do and which complications can be expected Lucio Gullo and Raffaele Pezzilli [...]... pancreatitis and pancreatic pain Acta Chir Scand 1990;1 56: 261 – 265 Koliopanos A, Friess H, Roggo A, Zimmermann A, Büchler MW Cyclooxygenase-2 expression in chronic pancreatitis: correlation with stage of the disease and diabetes mellitus Digestion 2001 ;64 :240–247 Lankisch PG, Lohr-Happe A, Otto J, Creutzfeldt W Natural course of chronic pancreatitis Pain, exocrine and endocrine pancreatic insufficiency and prognosis... the procedure can be performed in 10 min under conscious sedation A prospective randomized comparison of EUS- and percutaneous CT-guided CPB for managing the pain of chronic pancreatitis showed that EUS-guided CPB provided more persistent pain relief than CT-guided block and was the preferred technique among the subjects studied The effect of EUS-guided CPB with bupivacaine and triamcinolone has been... clearance (%) Complete or partial pain relief (%) Need for surgery (%) Mean follow-up (months) 123 50 35 35 80 48 125 40 99 86 100 100 54 60 85 100 59 60 46 74 ND 44 64 ND 85 62 83 72 76 82 48* 80 8 12 14 3 10 4 13 20 14 20 23 27 40 7 29 30 32 10 100 NA 75 NA 86 NA 3 NA 44 12 * Patients with complete pain relief during follow-up NA, not addressed 282 CHAPTER 34 Early outcome of pancreatic ESWL in combination... H, Müller M, Wheatley AM, Beger HG Randomized trial of duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis Am J Surg 1995; 169 :65 69 Di Sebastiano P, Fink T, Weihe E et al Immune cell infiltration and growth-associated protein 43 expression correlate with pain in chronic pancreatitis Gastroenterology 1997;112: 164 8– 165 5 Ditschuneit H Treatment of pain... frequency of hospitalization before and 1, 3, and 6 years after endoscopic treatment was significantly reduced In selected cases, such as early stage of chronic pancreatitis and early-onset idiopathic chronic pancreatitis, pancreatic sphincterotomy in the absence of pancreatic duct stricture and dilation can be proposed as a treatment for reducing the frequency of pain and recurrence of pancreatitis... extracorporeal shock-wave lithotripsy (ESWL) and endotherapy for chronic calcific pancreatitis Study Year ESWL and endotherapy Delhaye 1992 Schneider 1994 Johanns 19 96 Costamagna et al 1997 Adamek et al 1999 Brand et al 2000 Farnbacher et al 2002 Kozarek et al 2002 ESWL alone Ohara Karasawa 19 96 2002 No of patients Fragmentation (%) Complete clearance (%) Complete or partial pain relief (%) Need for surgery... pancreatitis is performed according to the three-step ladder of the World Health Organization for the relief of cancer pain (Fig 33.1) The first step is for mild to moderate pain and consists of nonopioid analgesics The second step is for moderate to severe pain and a nonopioid analgesic is combined with a mild opioid, which is titrated until pain relief is satisfactory The third step is for severe pain and requires... Gansauge S, Beger HG Cyclooxygenase-2 is overexpressed in chronic pancreatitis Pancreas 2002;25: 26 30 Uhl W, Anghelacopoulos SE, Friess H, Büchler MW The role of octreotide and somatostatin in acute and chronic pancreatitis Digestion 1999 ;60 (Suppl 2):23–31 Warner TD, Guiliano F, Vojuovic I et al Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal... endoscopic and surgical therapy for chronic pancreatitis Endoscopy 2003;35:553–558 Farnbacher MJ, Shoen C, Rabenstein T et al Pancreatic duct stones in chronic pancreatitis: criteria for treatment intensity and succeess Gastrointest Endosc 2002; 56: 501–5 06 Francois E, Kahaleh M, Giovannini M EUS-guided pancreaticogastrostomy Gastrointest Endosc 2002; 56: 128–133 Gabbrielli A, Mutignani M, Pandolfi M et... generate and sustain the long-lasting pain syndrome in the natural history of chronic pancreatitis Based on current knowledge there are no gold standards for the therapy of chronic pancreatic pain A multidisciplinary approach based on individual pain history is recommended Recommended reading AGA technical review: treatment of pain in chronic pancreatits Gastroenterology 1998;15: 765 –7 76 CHAPTER 33 Andrén-Sandberg . with 2-[ 18 F]fluoro-2-deoxy- D-glucose for the differentiation of chronic pancreatitis and pancreatic cancer. Br J Surg 1999; 86: 194–199. Jaskiewicz K, Nalecz A, Rzepko R, Sledzinski Z. Immuno- cytes. Pharmazie 19 96; 51:893–8 96. Yamanaka Y, Friess H, Büchler, Beger HG, Gold LI, Korc M. Synthesis and expression of transforming growth factor beta-1, beta-2, and beta-3 in the endocrine and exocrine pancreas chronic-pancreatitis and to- gether with TNF-alpha, triggers insulin-dependent diabetes. Biochem Biophys Res Commun 1995;217:1279–12 86. Slater SD, Williamson RC, Foster CS. Expression of trans- forming