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13C-Mixed Triglyceride Breath Test to Assess Oral Enzyme Substitution Therapy in Patients With Chronic Pancreatitis
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5:484 – 488
13C-Mixed
Triglyceride Breath Test to Assess Oral Enzyme Substitution Therapy in Patients With Chronic Pancreatitis
J. ENRIQUE DOMÍNGUEZ–MUÑOZ, JULIO IGLESIAS–GARCÍA, MARÍA VILARIÑO–INSUA, and MARTA IGLESIAS–REY Department of Gastroenterology and Foundation for Research in Digestive Diseases, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
See Dimcevski G et al on page 1546 for companion article in the April 2007 issue of Gastroenterology. Background & Aims: Malnutrition persists in most patients with chronic pancreatitis despite an adequate clinical response to oral pancreatic enzyme substitution therapy. Our aims were to analyze the accuracy of the 13C-mixed triglyceride breath test as a tool for evaluating the effect of enzyme therapy on fat digestion in chronic pancreatitis, and to analyze the impact of modifying the therapy according to the breath test on patients’ nutritional status. Methods: The accuracy of the breath test for monitoring the effect of therapy was evaluated prospectively in 29 patients with maldigestion secondary to chronic pancreatitis by using the coefficient of fat absorption as the gold standard. Therapy was modified to obtain a normal breath test result in a further 20 chronic pancreatitis patients with malnutrition despite an adequate clinical response to the enzyme therapy; the impact of this therapeutic modification on patients’ nutritional status was evaluated. Results: The coefficient of fat absorption and breath test results were similar when assessing fat absorption before and during treatment. Modification of the enzyme therapy to normalize fat absorption as assessed by the breath test in the second group of 20 patients was associated with a significant increase of body weight (P < .001), and serum concentrations of retinol binding protein (P < .001) and prealbumin (P < .001). Conclusions: The 13C-mixed triglyceride breath test is an accurate method to evaluate the effect of enzyme therapy on fat digestion. This method is simpler than the standard fecal fat test to assess therapy in patients with pancreatic exocrine insufficiency. Normalizing fat absorption improves nutrition in these patients.
P
ancreatic exocrine insufficiency with maldigestion is a major consequence of chronic pancreatitis. Approximately 50% of patients with chronic pancreatitis develop maldigestion at a median time of 10 to 12 years from onset of the disease, and few patients do not develop clinically relevant exocrine insufficiency at later stages.1 Although clinical consequences of maldigestion secondary to chronic pancreatitis are poorly studied, it generally is accepted that this complication plays an important prognostic role. Together with the well-known malnutrition-related health problems, maldigestion secondary to chronic pancreatitis is associated with life-threatening complications such as cardio-
vascular events, which have been related to abnormally low plasma levels of high-density lipoprotein C, apolipoprotein A-I, and lipoprotein A.2 An appropriate maldigestion therapy therefore becomes crucial to reduce the morbidity and mortality associated with chronic pancreatitis. Treatment of pancreatic exocrine insufficiency clearly is indicated in cases of symptomatic steatorrhea or steatorrhea of more than 15 g/day.3 The therapy of choice in these cases is based on the oral administration of pancreatic enzyme supplements. Because of problems related to acid-mediated inactivation of lipase and the need for an adequate gastric mixture and emptying of enzymes with the nutrients, enteric-coated minimicrospheres are generally the preferred pharmacologic formulation of pancreatic enzymes.4 –7 Because of the absence of objective and easily applicable methods to establish the adequate dose of oral pancreatic enzymes for each individual patient, this dose usually is calculated with the goal of avoiding diarrhea and weight loss.3 However, up to 70% of patients with chronic pancreatitis-related maldigestion have abnormally low nutritional parameters (mainly serum levels of fat-soluble vitamins) despite adequate clinical control with enzyme substitution therapy.8 Based on this finding, the concept has developed that enzyme substitution therapy should be given with the aim of normalizing fat digestion and absorption, and not only to obtain a clinical response. Fecal fat quantification is considered the gold standard for evaluating fat digestion in the context of chronic pancreatitis.9 This method, however, is too cumbersome and unpleasant to be applied widely in clinical practice to optimize enzyme substitution therapy. We previously optimized, standardized, and validated a 13C-mixed triglyceride (13C-MTG) breath test as an easy and accurate alternative to fecal fat quantification for detecting fat maldigestion.10 Taking this background into account, the present study was performed with the following aims. First, to evaluate the accuracy of the 13C-MTG breath test to assess the efficacy of oral pancreatic enzyme substitution therapy in patients with pancreatic exocrine insufficiency secondary to chronic pancreatitis; and, second, to evaluate the impact of optimizing the therapy of maldigestion in each individual patient according to the breath test result on the patients’ nutritional status. Abbreviations used in this paper: CFA, coefficient of fat absorption; CRR, cumulative recovery rate; MTG, mixed triglyceride; PhU, pharmacology units; RBP, retinol binding protein. © 2007 by the AGA Institute 1542-3565/07/$32.00 doi:10.1016/j.cgh.2007.01.004
April 2007
Methods Two consecutive prospective studies were performed to evaluate the accuracy and the clinical usefulness and impact of the 13C-MTG breath test as a tool for assessing and optimizing oral enzyme substitution therapy in patients with chronic pancreatitis.
Accuracy of the 13C-Mixed Triglyceride Breath Test for Evaluating the Effect of Enzyme Therapy on Fat Digestion In this prospective study, 29 patients (mean age, 51 y; range, 27– 85 y; 21 men) previously diagnosed with pancreatic exocrine insufficiency secondary to alcohol-related chronic pancreatitis were included. The coefficient of fat absorption (CFA) was evaluated as the gold standard before and after 2 weeks of oral pancreatic enzyme substitution therapy by near-infrared– based fat quantification in stool samples collected over the last 72 hours of a 5-day period of standardized diet containing 100 g of fat/day.11 The CFA was calculated as follows: CFA ⫽ (fat intake [g/day] ⫺ fecal fat excretion [g/day]) ⫻ 100/fat intake (g/day). Based on the definition of steatorrhea as a daily fecal excretion higher than 7.5 g, a CFA higher than 92.5% was considered normal. A 13C-MTG breath test was performed as previously described10 on the day before starting pancreatic enzyme therapy (basal), and on the last day of the 2-week period of enzyme substitution therapy. For the breath test, 250 mg of mixed 13C-triglyceride (Eurisotop, Cedex, France) was given orally together with a standard solid test meal containing 16 g of fat (2 slices of toasted white bread, 20 g butter, and 200 mL water) after an overnight fast. The substrate was spread on the butter for an optimal mixture. Metoclopramide 10 mg was given orally 30 minutes before the breath test to avoid potential problems related to gastric emptying. Breath samples were collected in Exeteiner (Labco Ltd, High Wycombbe, United Kingdom) tubes before ingestion of the test meal and at 15-minute intervals for 6 hours. The quotient 13CO2/12CO2 was measured in each breath sample by mass spectrometry (BreathMat, Finnigan, Germany) and the global 6-hour cumulative recovery rate (CRR) of 13CO2 was considered as the result of the test. Based on previous studies performed by our group in patients with chronic pancreatitis with and without steatorrhea, a 13CO2-CRR of less than 58% detects fat maldigestion with sensitivity and specificity higher than 90%.10 For therapy, 40,000 Pharmacology units (PhU) lipase in the form of enteric-coated minimicrospheres (4 capsules of Creon 10,000; Solvay Pharmaceuticals, Hannover Germany) were given orally for 2 weeks along with each of the 3 main daily meals (1 capsule just before meals, 2 during the meals, and 1 just after the meals).12 The same enzyme dose also was given orally along with the test meal for the last 13C-MTG breath test. The distribution of data was analyzed by the Kolmogorov– Smirnov test. Based on that, results of fat absorption and the breath test are shown as the mean and SD; results in figures are shown as individual values, mean and 25th–75th percentiles. Oral enzyme-mediated improvement of fat absorption, as measured by fecal fat quantification and the breath test, is shown as the median and 95% confidence interval. Quantitative and qualitative variables were compared statistically by the Student t test for related samples and the Fisher exact test, respectively.
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Use and Clinical Impact of the 13C-Mixed Triglyceride Breath Test to Assess Enzyme Substitution Therapy In this prospective, comparative, paired study, 30 consecutive patients (mean age, 55 y; range, 32–76 y; 23 men) newly diagnosed with steatorrhea secondary to alcohol-related chronic pancreatitis, who did not participate in the previous study, were included. If required, patients were treated initially with pancreatic enzymes in the form of enteric-coated minimicrospheres at a dose that avoided diarrhea and weight loss. Of the 30 patients, 7 with a daily fecal fat excretion of less than 15 g, who did not suffer from diarrhea, and who had a stable body weight did not receive any substitution therapy. Of the remaining 23 patients, 14 were treated with enzymes at a dose of 20,000 PhU lipase per meal, and the remaining 9 were treated with enzymes at a dose of 40,000 PhU lipase per meal. Seven patients had endocrine pancreatic insufficiency requiring insulin therapy and 9 had pancreatic calcifications as shown by abdominal ultrasound. After 1 year of follow-up evaluation, those patients with persistent abnormal nutritional status, as defined by low serum levels of retinol-binding protein (RBP), underwent modification of the therapy to normalize fat digestion as evaluated by the 13C-MTG breath test described previously. With this aim, the enzyme dose was increased gradually in 20,000 PhU lipase/meal measures, starting with 20,000 PhU lipase/meal up to a maximum of 60,000 PhU lipase/meal. Esomeprazole 40 mg (Nexium; AstraZeneca, Mölndal, Sweden) was added as a single daily dose before breakfast in patients with an abnormal breath test result despite enzyme substitution therapy at the dose of 60,000 PhU lipase per meal. The breath test was repeated 1 week after each therapy modification until a normal test result was obtained. The nutritional status was evaluated before and 1 year after optimization of the therapy by quantifying the body weight and serum levels of RBP (normal, ⬎3 mg/dL) and prealbumin (normal, ⬎21 mg/dL). Data are shown as mean and SD; results in figures are shown as individual values, mean and 25th–75th percentiles. A statistical comparison was performed by using the Student t test for related samples.
Ethical Considerations Studies were conducted in accordance with the current guidelines of good clinical practice. The study protocols were approved by the Regional Committee for Ethics and Clinical Research. Patients participated voluntarily in the study after the investigator explained it properly. A written, dated, and signed informed consent was obtained from all subjects before entry into the study.
Results Accuracy of the 13C-Mixed Triglyceride Breath Test for Evaluating the Effect of Enzyme Therapy on Fat Digestion CFA increased significantly from 80.8% ⫾ 11.0% before enzyme substitution therapy to 93.5% ⫾ 3.4% during therapy (P ⬍ .001) (Figure 1). Similarly, 13CO2-CRR in the context of the 13C-MTG breath test increased from 23.3% ⫾ 15.9% before therapy to 61.5% ⫾ 16.7% during therapy (P ⬍ .001) (Figure 1). The absolute improvement of fat digestion obtained by enzyme
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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 4
Figure 1. Coefficient of fat absorption (%) and 13CO CRR (%) in the context of the 13C-MTG 2 breath test in patients with pancreatic exocrine insufficiency secondary to chronic pancreatitis. Individual values, mean (horizontal line), and 25th–75th percentiles (box) before (basal) and during enzyme substitution therapy (treatment) are shown. The lower limits of normal are shown as a dotted line.
substitution therapy was 11.0% (1.1%–39.4%) and 32.9% (8.4%– 79.1%), as measured by fecal fat quantification and 13C-MTG, respectively. All patients had abnormal CFA and 13CO2-CRR before therapy (Figure 1). CFA normalized during enzyme substitution therapy in 18 patients (65.5%), whereas the breath test result normalized in 15 patients (51.7%) (P⫽NS) (Figure 1).
Use and Clinical Impact of the 13C-Mixed Triglyceride Breath Test to Assess Enzyme Substitution Therapy Of the 30 consecutive patients with chronic pancreatitis-related maldigestion who were treated with pancreatic enzymes at a median dose of 20,000 PhU lipase (range, 0 – 40,000 PhU lipase) for 1 year to avoid diarrhea and weight loss, 20 had persistent malnutrition defined as an abnormally low serum
Figure 2. 13CO2 CRR (%) in the 13C-MTG breath test in patients with chronic pancreatitis–related pancreatic exocrine insufficiency during therapy with oral pancreatic extracts. Results (individual data; mean, horizontal line; 25th–75th percentiles, box) before and after therapeutic modification are shown. The lower limit of normal is shown as a dotted line.
concentration of RBP. With this therapy all 20 patients had an abnormal breath test result. The breath test result normalized in all patients after increasing the enzyme dose to a median of 40,000 PhU lipase per meal (14 patients required 40,000 PhU lipase/meal and 6 patients required 60,000 PhU lipase/meal) and giving a proton pump inhibitor to 3 of the patients (Figure 2). After 1 year of this treatment, body weight increased significantly from 67.5 ⫾ 12.4 kg to 71.8 ⫾ 12.6 kg (P ⬍ .001) (Figure 3). Similarly, serum RBP levels increased significantly from 2.4 ⫾ 0.6 mg/dL to 3.1 ⫾ 0.6 mg/dL (P ⬍ .001) and reached normal values in 14 patients (70%) (Figure 4A), and serum prealbumin levels increased significantly from 20.7 ⫾ 4.1 mg/dL to 25.2 ⫾ 3.1 mg/dL (P ⬍ .001) and became normal in all 20 patients (Figure 4B).
Figure 3. Body weight (kg) in patients with chronic pancreatitis–related pancreatic exocrine insufficiency during therapy with oral pancreatic extracts. Results (individual data; mean, horizontal line; 25th–75th percentiles, box) before and after therapeutic modification are shown.
April 2007
Figure 4. Serum levels of (A) RBP and (B) prealbumin in patients with chronic pancreatitis–related pancreatic exocrine insufficiency during therapy with oral pancreatic extracts. Results (individual data; mean, horizontal line; 25th–75th percentiles, box) before and after therapeutic modification are shown. The lower limits of normal are shown as a dotted line.
Discussion In this study we corroborate previous findings that fat malabsorption of exocrine pancreatic insufficiency can be corrected3,12–17 and that a breath test can be used to assess the response to enzyme therapy.12,17–22 Important findings of our study are that the 13C-MTG breath test is a simple, accurate, alternative method to the quantitative fecal fat test to assess correction of fat malabsorption during therapy, and that 1 year after correction of fat malabsorption nutrition improved, manifested by significant weight gain, and increased serum concentrations of RBP and prealbumin. Pancreatic exocrine insufficiency with maldigestion develops in most patients with chronic pancreatitis over time, which
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leads to a situation of malnutrition that may have important prognostic consequences.1,2 The impact of malnutrition on the prognosis of chronic pancreatitis has been poorly investigated. Nevertheless, and independently of its cause, malnutrition is associated with severe complications and a high risk of death.23 Actually, maldigestion has been shown to be associated with a higher risk of life-threatening cardiovascular events in patients with chronic pancreatitis, which seems to be related to abnormally low plasma levels of high-density lipoprotein C, apolipoprotein A-I, and lipoprotein A.2 Therefore, therapy of pancreatic exocrine insufficiency should normalize digestion and ensure a normal nutritional status, and not just improve symptoms. Enteric-coated minimicrospheres have been developed to facilitate an adequate intragastric mixture of the exogenous enzymes with the meal and simultaneous gastric emptying of the enzymes with the chyme.7,13 With the same objective, the administration schedule of oral pancreatic enzymes should be optimized, and enzyme intake distributed with meals is preferred to intake before meals.12 In addition, inhibition of gastric acid secretion occasionally is required to enhance the effect of orally ingested enzymes, either by avoiding acid-mediated lipase inactivation14 –16 or by facilitating enzyme release from the microspheres within the proximal intestine.17 The efficacy of oral pancreatic enzymes usually is assessed in individual patients by a simple clinical evaluation of steatorrhea-related symptoms.3 In our previous experience, which is confirmed in the present study, about two thirds of patients with maldigestion secondary to chronic pancreatitis have abnormally low nutritional parameters despite adequate clinical control during treatment with oral pancreatic enzyme supplements.8 Therefore, oral pancreatic enzyme substitution therapy cannot be optimized correctly based simply on clinical evaluation (absence of weight loss, diarrhea, and other steatorrhearelated symptoms). From a clinical and therapeutic point of view, fat maldigestion, which appears to develop once pancreatic lipase secretion is less than 10% of normal, is more relevant than protein and carbohydrate maldigestion.24,25 Enzyme substitution therapy in patients with pancreatic exocrine insufficiency thus should be able to normalize fat digestion and absorption. Evaluation of the CFA after fecal fat quantification generally is accepted as the gold standard for fat digestion analysis.9 This method, however, is too cumbersome and unpleasant to be applied widely in clinical practice. Different breath tests thus have been developed to evaluate fat digestion and absorption by using 13Clabeled substrates such as mixed triglycerides,26 hiolein,27 triolein,21 and cholesteryl-octanoate.28 The 13C-labeled mixed triglyceride breath test recently was optimized by our group for the diagnosis of fat maldigestion secondary to chronic pancreatitis.10 This test is simple, easily applicable to clinical routine, and, thus, repeatable as frequently as needed. We and others previously have used different breath tests for monitoring enzyme replacement treatment of pancreatic exocrine insufficiency secondary to chronic pancreatitis,12,17,18 cystic fibrosis in children19,20 and in adults,21 after pancreatic surgery,22 and in pancreatic cancer.29 Although comparative studies between different breath tests in this setting are lacking, the 13C-MTG appears to be superior to cholesteryl 13C-octanoate for the diagnosis of fat maldigestion.30 The present study confirms that the 13C-MTG breath test is highly accurate for
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evaluating the efficacy of oral pancreatic enzyme substitution therapy, and therefore it is ready to substitute fecal fat quantification in clinical routine. In summary, the breath test result is consistently abnormal in patients with malnutrition despite a theoretically adequate enzyme substitution therapy based on clinical response. Modifying the enzyme substitution therapy to normalize the breath test result is associated with normalization of the nutritional status in most patients. In conclusion, therapy for maldigestion in patients with chronic pancreatitis requires normalizing fat digestion and absorption, which may be evaluated easily by the 13C-MTG breath test. This therapeutic approach may lessen morbidity and prolong survival. References 1. Layer P, Yamamoto H, Kalthoff L, et al. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994;107:1481131487. 2. Montalvo G, Zorreéis M, Carroccio A, et al. Lipoproteins and chronic pancreatitis. Pancreas 1994;9:137–138. 3. Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep 2001;3:101–108. 4. Dutta SK, Rubin J, Harvey J. Comparative evaluation of the therapeutic efficacy of a pH-sensitive enteric coated pancreatic enzyme preparation with conventional pancreatic enzyme therapy in the treatment of pancreatic exocrine insufficiency. Gastroenterology 1983;84:476 – 482. 5. Kühnelt P, Mundlos S, Adler G. The size of enteric coated microspheres influences the intraduodenal lipolytic activity. Z Gastroenterol 1991;29:417– 421. 6. Meyer JH, Elashoff J, Porter-Fink V, et al. Human postprandial gastric emptying of 1–3 millimeter spheres. Gastroenterology 1988;94:1315–1325. 7. Domínguez-Muñoz JE, Birkelbach U, et al. Effect of oral pancreatic enzyme administration on digestive function in healthy subjects: comparison between two enzyme preparations. Aliment Pharmacol Ther 1997;11:403– 408. 8. Iglesias-García J, Vilariño-Insua M, Iglesias-Rey M, et al. Oral pancreatic enzyme supplementation in patients with exocrine pancreatic insufficiency: is it enough to evaluate clinical response? Gastroenterology 2003;124(Suppl 1):A-632. 9. Domínguez-Muñoz JE. 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? In: Domínguez-Muñoz JE, ed. Clinical pancreatology for practising gastroenterologists and surgeons. Oxford: Blackwell Publishing, 2005:259 –266. 10. Iglesias-García J, Vilariño M, Iglesias-Rey M, et al. Accuracy of the optimized 13C-mixed triglyceride breath test for the diagnosis of steatorrhea in clinical practice. Gastroenterology 2003;124 (Suppl 1):A-631. 11. Stein J, Purschian B, Bieniek U, et al. Near-infrared reflectance analysis (NIRA): a new dimension in the investigation of malabsorption syndromes. Eur J Gastroenterol Hepatol 1994;6:889 – 894. 12. Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, et al. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther 2005;21:993–1000. 13. Halm U, Loser C, Lohr M, et al. A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency. Aliment Pharmacol Ther 1999;13:951–957.
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14. Regan PT, Malagelada JR, DiMagno EP, et al. Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 1977;297:854 – 858. 15. Durie PR, Bell L, Linton W, et al. Effect of cimetidine and sodium bicarbonate on pancreatic replacement therapy in cystic fibrosis. Gut 1980;21:778 –786. 16. Bruno MJ, Rauws EA, Hoek FJ, et al. Comparative effects of adjuvant cimetidine and omeprazol during pancreatic enzyme replacement therapy. Dig Dis Sci 1994;39:988 –992. 17. Domínguez-Muñoz JE, Iglesias-García J, Iglesias-Rey M, et al. Optimizing the therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor to enteric-coated pancreatic extracts. Gut 2006;55:1056 –1057. 18. Mundlos S, Kuhnelt P, Adler G. Monitoring enzyme replacement treatment in exocrine pancreatic insufficiency using the cholesteryl octanoate breath test. Gut 1990;31:1324 –1328. 19. De Boeck K, Delbeke I, Eggermont E, et al. Lipid digestion in cystic fibrosis: comparison of conventional and high-lipase enzyme therapy using the mixed-triglyceride breath test. J Pediatr Gastroenterol Nutr 1998;26:408 – 411. 20. Braden B, Picard H, Caspary WF, et al. Monitoring pancreatin supplementation in cystic fibrosis patients with the 13C-Hiolein breath test: evidence for normalized fat assimilation with high dose pancreatin therapy. Z Gastroenterol 1997;35:123–129. 21. Ritz MA, Fraser RJ, Di Matteo AC, et al. Evaluation of the 13Ctriolein breath test for fat malabsorption in adult patients with cystic fibrosis. J Gastroenterol Hepatol 2004;19:448 – 453. 22. Bruno MJ, Borm JJ, Hoek FJ, et al. Comparative effects of entericcoated pancreatin microsphere therapy after conventional and pylorus-preserving pancreatoduodenectomy. Br J Surg 1997;84: 952–956. 23. Mason JB. Nutritional assessment and management of the malnourished patient. In: Feldman M, Friedman LS, Brandt LJ, eds. Gastrointestinal and liver disease. 8th ed. Philadelphia: Saunders-Elsevier, 2006:319 –355. 24. 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. 25. Lankisch PG, Lembcke B, Wengen G, et al. Functional reserve capacity of the exocrine pancreas. Digestion 1986;35:175–181. 26. Vantrappen GR, Rutgeerts PJ, Ghoos YF, et al. Mixed triglyceride breath test: a noninvasive test of pancreatic lipase activity in the duodenum. Gastroenterology 1989;96:1126 –1134. 27. Lembcke B, Braden B, Caspary WF. Exocrine pancreatic insufficiency: accuracy and clinical value of the uniformly labelled 13CHiolein breath test. Gut 1996;39:668 – 674. 28. Ventrucci M, Cipolla A, Ubalducci GM, et al. 13C labelled cholesteryl octanoate breath test for assessing pancreatic exocrine insufficiency. Gut 1998;42:81– 87. 29. Perez MM, Newcomer AD, Moertel CG, et al. Assessment of weight loss, food intake, fat metabolism, malabsorption, and treatment of pancreatic insufficiency in pancreatic cancer. Cancer 1983;52:346 –352. 30. Iglesias-García J, Vilariño-Insua M, Lourido MV, et al. Development of a breath test for the diagnosis of steatorrhea. Gastroenterology 2002;122(Suppl 1):A-52.
Address requests for reprints to: Dr J. Enrique Domínguez–Muñoz, Department of Gastroenterology, University Hospital of Santiago de Compostela, C/ Choupana, s/n, 15706-Santiago de Compostela, Spain. e-mail: enriquedominguezmunoz@fienad.com; fax: (34) 981951-365. Supported by a grant from the Health Institute Carlos III, Spanish Ministry of Health (G03/156), and the Foundation for Research in Digestive Diseases.
13C-Mixed
Triglyceride Breath Test to Assess Oral Enzyme Substitution Therapy in Patients With Chronic Pancreatitis
J. ENRIQUE DOMÍNGUEZ–MUÑOZ, JULIO IGLESIAS–GARCÍA, MARÍA VILARIÑO–INSUA, and MARTA IGLESIAS–REY Department of Gastroenterology and Foundation for Research in Digestive Diseases, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
See Dimcevski G et al on page 1546 for companion article in the April 2007 issue of Gastroenterology. Background & Aims: Malnutrition persists in most patients with chronic pancreatitis despite an adequate clinical response to oral pancreatic enzyme substitution therapy. Our aims were to analyze the accuracy of the 13C-mixed triglyceride breath test as a tool for evaluating the effect of enzyme therapy on fat digestion in chronic pancreatitis, and to analyze the impact of modifying the therapy according to the breath test on patients’ nutritional status. Methods: The accuracy of the breath test for monitoring the effect of therapy was evaluated prospectively in 29 patients with maldigestion secondary to chronic pancreatitis by using the coefficient of fat absorption as the gold standard. Therapy was modified to obtain a normal breath test result in a further 20 chronic pancreatitis patients with malnutrition despite an adequate clinical response to the enzyme therapy; the impact of this therapeutic modification on patients’ nutritional status was evaluated. Results: The coefficient of fat absorption and breath test results were similar when assessing fat absorption before and during treatment. Modification of the enzyme therapy to normalize fat absorption as assessed by the breath test in the second group of 20 patients was associated with a significant increase of body weight (P < .001), and serum concentrations of retinol binding protein (P < .001) and prealbumin (P < .001). Conclusions: The 13C-mixed triglyceride breath test is an accurate method to evaluate the effect of enzyme therapy on fat digestion. This method is simpler than the standard fecal fat test to assess therapy in patients with pancreatic exocrine insufficiency. Normalizing fat absorption improves nutrition in these patients.
P
ancreatic exocrine insufficiency with maldigestion is a major consequence of chronic pancreatitis. Approximately 50% of patients with chronic pancreatitis develop maldigestion at a median time of 10 to 12 years from onset of the disease, and few patients do not develop clinically relevant exocrine insufficiency at later stages.1 Although clinical consequences of maldigestion secondary to chronic pancreatitis are poorly studied, it generally is accepted that this complication plays an important prognostic role. Together with the well-known malnutrition-related health problems, maldigestion secondary to chronic pancreatitis is associated with life-threatening complications such as cardio-
vascular events, which have been related to abnormally low plasma levels of high-density lipoprotein C, apolipoprotein A-I, and lipoprotein A.2 An appropriate maldigestion therapy therefore becomes crucial to reduce the morbidity and mortality associated with chronic pancreatitis. Treatment of pancreatic exocrine insufficiency clearly is indicated in cases of symptomatic steatorrhea or steatorrhea of more than 15 g/day.3 The therapy of choice in these cases is based on the oral administration of pancreatic enzyme supplements. Because of problems related to acid-mediated inactivation of lipase and the need for an adequate gastric mixture and emptying of enzymes with the nutrients, enteric-coated minimicrospheres are generally the preferred pharmacologic formulation of pancreatic enzymes.4 –7 Because of the absence of objective and easily applicable methods to establish the adequate dose of oral pancreatic enzymes for each individual patient, this dose usually is calculated with the goal of avoiding diarrhea and weight loss.3 However, up to 70% of patients with chronic pancreatitis-related maldigestion have abnormally low nutritional parameters (mainly serum levels of fat-soluble vitamins) despite adequate clinical control with enzyme substitution therapy.8 Based on this finding, the concept has developed that enzyme substitution therapy should be given with the aim of normalizing fat digestion and absorption, and not only to obtain a clinical response. Fecal fat quantification is considered the gold standard for evaluating fat digestion in the context of chronic pancreatitis.9 This method, however, is too cumbersome and unpleasant to be applied widely in clinical practice to optimize enzyme substitution therapy. We previously optimized, standardized, and validated a 13C-mixed triglyceride (13C-MTG) breath test as an easy and accurate alternative to fecal fat quantification for detecting fat maldigestion.10 Taking this background into account, the present study was performed with the following aims. First, to evaluate the accuracy of the 13C-MTG breath test to assess the efficacy of oral pancreatic enzyme substitution therapy in patients with pancreatic exocrine insufficiency secondary to chronic pancreatitis; and, second, to evaluate the impact of optimizing the therapy of maldigestion in each individual patient according to the breath test result on the patients’ nutritional status. Abbreviations used in this paper: CFA, coefficient of fat absorption; CRR, cumulative recovery rate; MTG, mixed triglyceride; PhU, pharmacology units; RBP, retinol binding protein. © 2007 by the AGA Institute 1542-3565/07/$32.00 doi:10.1016/j.cgh.2007.01.004
April 2007
Methods Two consecutive prospective studies were performed to evaluate the accuracy and the clinical usefulness and impact of the 13C-MTG breath test as a tool for assessing and optimizing oral enzyme substitution therapy in patients with chronic pancreatitis.
Accuracy of the 13C-Mixed Triglyceride Breath Test for Evaluating the Effect of Enzyme Therapy on Fat Digestion In this prospective study, 29 patients (mean age, 51 y; range, 27– 85 y; 21 men) previously diagnosed with pancreatic exocrine insufficiency secondary to alcohol-related chronic pancreatitis were included. The coefficient of fat absorption (CFA) was evaluated as the gold standard before and after 2 weeks of oral pancreatic enzyme substitution therapy by near-infrared– based fat quantification in stool samples collected over the last 72 hours of a 5-day period of standardized diet containing 100 g of fat/day.11 The CFA was calculated as follows: CFA ⫽ (fat intake [g/day] ⫺ fecal fat excretion [g/day]) ⫻ 100/fat intake (g/day). Based on the definition of steatorrhea as a daily fecal excretion higher than 7.5 g, a CFA higher than 92.5% was considered normal. A 13C-MTG breath test was performed as previously described10 on the day before starting pancreatic enzyme therapy (basal), and on the last day of the 2-week period of enzyme substitution therapy. For the breath test, 250 mg of mixed 13C-triglyceride (Eurisotop, Cedex, France) was given orally together with a standard solid test meal containing 16 g of fat (2 slices of toasted white bread, 20 g butter, and 200 mL water) after an overnight fast. The substrate was spread on the butter for an optimal mixture. Metoclopramide 10 mg was given orally 30 minutes before the breath test to avoid potential problems related to gastric emptying. Breath samples were collected in Exeteiner (Labco Ltd, High Wycombbe, United Kingdom) tubes before ingestion of the test meal and at 15-minute intervals for 6 hours. The quotient 13CO2/12CO2 was measured in each breath sample by mass spectrometry (BreathMat, Finnigan, Germany) and the global 6-hour cumulative recovery rate (CRR) of 13CO2 was considered as the result of the test. Based on previous studies performed by our group in patients with chronic pancreatitis with and without steatorrhea, a 13CO2-CRR of less than 58% detects fat maldigestion with sensitivity and specificity higher than 90%.10 For therapy, 40,000 Pharmacology units (PhU) lipase in the form of enteric-coated minimicrospheres (4 capsules of Creon 10,000; Solvay Pharmaceuticals, Hannover Germany) were given orally for 2 weeks along with each of the 3 main daily meals (1 capsule just before meals, 2 during the meals, and 1 just after the meals).12 The same enzyme dose also was given orally along with the test meal for the last 13C-MTG breath test. The distribution of data was analyzed by the Kolmogorov– Smirnov test. Based on that, results of fat absorption and the breath test are shown as the mean and SD; results in figures are shown as individual values, mean and 25th–75th percentiles. Oral enzyme-mediated improvement of fat absorption, as measured by fecal fat quantification and the breath test, is shown as the median and 95% confidence interval. Quantitative and qualitative variables were compared statistically by the Student t test for related samples and the Fisher exact test, respectively.
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Use and Clinical Impact of the 13C-Mixed Triglyceride Breath Test to Assess Enzyme Substitution Therapy In this prospective, comparative, paired study, 30 consecutive patients (mean age, 55 y; range, 32–76 y; 23 men) newly diagnosed with steatorrhea secondary to alcohol-related chronic pancreatitis, who did not participate in the previous study, were included. If required, patients were treated initially with pancreatic enzymes in the form of enteric-coated minimicrospheres at a dose that avoided diarrhea and weight loss. Of the 30 patients, 7 with a daily fecal fat excretion of less than 15 g, who did not suffer from diarrhea, and who had a stable body weight did not receive any substitution therapy. Of the remaining 23 patients, 14 were treated with enzymes at a dose of 20,000 PhU lipase per meal, and the remaining 9 were treated with enzymes at a dose of 40,000 PhU lipase per meal. Seven patients had endocrine pancreatic insufficiency requiring insulin therapy and 9 had pancreatic calcifications as shown by abdominal ultrasound. After 1 year of follow-up evaluation, those patients with persistent abnormal nutritional status, as defined by low serum levels of retinol-binding protein (RBP), underwent modification of the therapy to normalize fat digestion as evaluated by the 13C-MTG breath test described previously. With this aim, the enzyme dose was increased gradually in 20,000 PhU lipase/meal measures, starting with 20,000 PhU lipase/meal up to a maximum of 60,000 PhU lipase/meal. Esomeprazole 40 mg (Nexium; AstraZeneca, Mölndal, Sweden) was added as a single daily dose before breakfast in patients with an abnormal breath test result despite enzyme substitution therapy at the dose of 60,000 PhU lipase per meal. The breath test was repeated 1 week after each therapy modification until a normal test result was obtained. The nutritional status was evaluated before and 1 year after optimization of the therapy by quantifying the body weight and serum levels of RBP (normal, ⬎3 mg/dL) and prealbumin (normal, ⬎21 mg/dL). Data are shown as mean and SD; results in figures are shown as individual values, mean and 25th–75th percentiles. A statistical comparison was performed by using the Student t test for related samples.
Ethical Considerations Studies were conducted in accordance with the current guidelines of good clinical practice. The study protocols were approved by the Regional Committee for Ethics and Clinical Research. Patients participated voluntarily in the study after the investigator explained it properly. A written, dated, and signed informed consent was obtained from all subjects before entry into the study.
Results Accuracy of the 13C-Mixed Triglyceride Breath Test for Evaluating the Effect of Enzyme Therapy on Fat Digestion CFA increased significantly from 80.8% ⫾ 11.0% before enzyme substitution therapy to 93.5% ⫾ 3.4% during therapy (P ⬍ .001) (Figure 1). Similarly, 13CO2-CRR in the context of the 13C-MTG breath test increased from 23.3% ⫾ 15.9% before therapy to 61.5% ⫾ 16.7% during therapy (P ⬍ .001) (Figure 1). The absolute improvement of fat digestion obtained by enzyme
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Figure 1. Coefficient of fat absorption (%) and 13CO CRR (%) in the context of the 13C-MTG 2 breath test in patients with pancreatic exocrine insufficiency secondary to chronic pancreatitis. Individual values, mean (horizontal line), and 25th–75th percentiles (box) before (basal) and during enzyme substitution therapy (treatment) are shown. The lower limits of normal are shown as a dotted line.
substitution therapy was 11.0% (1.1%–39.4%) and 32.9% (8.4%– 79.1%), as measured by fecal fat quantification and 13C-MTG, respectively. All patients had abnormal CFA and 13CO2-CRR before therapy (Figure 1). CFA normalized during enzyme substitution therapy in 18 patients (65.5%), whereas the breath test result normalized in 15 patients (51.7%) (P⫽NS) (Figure 1).
Use and Clinical Impact of the 13C-Mixed Triglyceride Breath Test to Assess Enzyme Substitution Therapy Of the 30 consecutive patients with chronic pancreatitis-related maldigestion who were treated with pancreatic enzymes at a median dose of 20,000 PhU lipase (range, 0 – 40,000 PhU lipase) for 1 year to avoid diarrhea and weight loss, 20 had persistent malnutrition defined as an abnormally low serum
Figure 2. 13CO2 CRR (%) in the 13C-MTG breath test in patients with chronic pancreatitis–related pancreatic exocrine insufficiency during therapy with oral pancreatic extracts. Results (individual data; mean, horizontal line; 25th–75th percentiles, box) before and after therapeutic modification are shown. The lower limit of normal is shown as a dotted line.
concentration of RBP. With this therapy all 20 patients had an abnormal breath test result. The breath test result normalized in all patients after increasing the enzyme dose to a median of 40,000 PhU lipase per meal (14 patients required 40,000 PhU lipase/meal and 6 patients required 60,000 PhU lipase/meal) and giving a proton pump inhibitor to 3 of the patients (Figure 2). After 1 year of this treatment, body weight increased significantly from 67.5 ⫾ 12.4 kg to 71.8 ⫾ 12.6 kg (P ⬍ .001) (Figure 3). Similarly, serum RBP levels increased significantly from 2.4 ⫾ 0.6 mg/dL to 3.1 ⫾ 0.6 mg/dL (P ⬍ .001) and reached normal values in 14 patients (70%) (Figure 4A), and serum prealbumin levels increased significantly from 20.7 ⫾ 4.1 mg/dL to 25.2 ⫾ 3.1 mg/dL (P ⬍ .001) and became normal in all 20 patients (Figure 4B).
Figure 3. Body weight (kg) in patients with chronic pancreatitis–related pancreatic exocrine insufficiency during therapy with oral pancreatic extracts. Results (individual data; mean, horizontal line; 25th–75th percentiles, box) before and after therapeutic modification are shown.
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Figure 4. Serum levels of (A) RBP and (B) prealbumin in patients with chronic pancreatitis–related pancreatic exocrine insufficiency during therapy with oral pancreatic extracts. Results (individual data; mean, horizontal line; 25th–75th percentiles, box) before and after therapeutic modification are shown. The lower limits of normal are shown as a dotted line.
Discussion In this study we corroborate previous findings that fat malabsorption of exocrine pancreatic insufficiency can be corrected3,12–17 and that a breath test can be used to assess the response to enzyme therapy.12,17–22 Important findings of our study are that the 13C-MTG breath test is a simple, accurate, alternative method to the quantitative fecal fat test to assess correction of fat malabsorption during therapy, and that 1 year after correction of fat malabsorption nutrition improved, manifested by significant weight gain, and increased serum concentrations of RBP and prealbumin. Pancreatic exocrine insufficiency with maldigestion develops in most patients with chronic pancreatitis over time, which
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leads to a situation of malnutrition that may have important prognostic consequences.1,2 The impact of malnutrition on the prognosis of chronic pancreatitis has been poorly investigated. Nevertheless, and independently of its cause, malnutrition is associated with severe complications and a high risk of death.23 Actually, maldigestion has been shown to be associated with a higher risk of life-threatening cardiovascular events in patients with chronic pancreatitis, which seems to be related to abnormally low plasma levels of high-density lipoprotein C, apolipoprotein A-I, and lipoprotein A.2 Therefore, therapy of pancreatic exocrine insufficiency should normalize digestion and ensure a normal nutritional status, and not just improve symptoms. Enteric-coated minimicrospheres have been developed to facilitate an adequate intragastric mixture of the exogenous enzymes with the meal and simultaneous gastric emptying of the enzymes with the chyme.7,13 With the same objective, the administration schedule of oral pancreatic enzymes should be optimized, and enzyme intake distributed with meals is preferred to intake before meals.12 In addition, inhibition of gastric acid secretion occasionally is required to enhance the effect of orally ingested enzymes, either by avoiding acid-mediated lipase inactivation14 –16 or by facilitating enzyme release from the microspheres within the proximal intestine.17 The efficacy of oral pancreatic enzymes usually is assessed in individual patients by a simple clinical evaluation of steatorrhea-related symptoms.3 In our previous experience, which is confirmed in the present study, about two thirds of patients with maldigestion secondary to chronic pancreatitis have abnormally low nutritional parameters despite adequate clinical control during treatment with oral pancreatic enzyme supplements.8 Therefore, oral pancreatic enzyme substitution therapy cannot be optimized correctly based simply on clinical evaluation (absence of weight loss, diarrhea, and other steatorrhearelated symptoms). From a clinical and therapeutic point of view, fat maldigestion, which appears to develop once pancreatic lipase secretion is less than 10% of normal, is more relevant than protein and carbohydrate maldigestion.24,25 Enzyme substitution therapy in patients with pancreatic exocrine insufficiency thus should be able to normalize fat digestion and absorption. Evaluation of the CFA after fecal fat quantification generally is accepted as the gold standard for fat digestion analysis.9 This method, however, is too cumbersome and unpleasant to be applied widely in clinical practice. Different breath tests thus have been developed to evaluate fat digestion and absorption by using 13Clabeled substrates such as mixed triglycerides,26 hiolein,27 triolein,21 and cholesteryl-octanoate.28 The 13C-labeled mixed triglyceride breath test recently was optimized by our group for the diagnosis of fat maldigestion secondary to chronic pancreatitis.10 This test is simple, easily applicable to clinical routine, and, thus, repeatable as frequently as needed. We and others previously have used different breath tests for monitoring enzyme replacement treatment of pancreatic exocrine insufficiency secondary to chronic pancreatitis,12,17,18 cystic fibrosis in children19,20 and in adults,21 after pancreatic surgery,22 and in pancreatic cancer.29 Although comparative studies between different breath tests in this setting are lacking, the 13C-MTG appears to be superior to cholesteryl 13C-octanoate for the diagnosis of fat maldigestion.30 The present study confirms that the 13C-MTG breath test is highly accurate for
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evaluating the efficacy of oral pancreatic enzyme substitution therapy, and therefore it is ready to substitute fecal fat quantification in clinical routine. In summary, the breath test result is consistently abnormal in patients with malnutrition despite a theoretically adequate enzyme substitution therapy based on clinical response. Modifying the enzyme substitution therapy to normalize the breath test result is associated with normalization of the nutritional status in most patients. In conclusion, therapy for maldigestion in patients with chronic pancreatitis requires normalizing fat digestion and absorption, which may be evaluated easily by the 13C-MTG breath test. This therapeutic approach may lessen morbidity and prolong survival. References 1. Layer P, Yamamoto H, Kalthoff L, et al. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994;107:1481131487. 2. Montalvo G, Zorreéis M, Carroccio A, et al. Lipoproteins and chronic pancreatitis. Pancreas 1994;9:137–138. 3. Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep 2001;3:101–108. 4. Dutta SK, Rubin J, Harvey J. Comparative evaluation of the therapeutic efficacy of a pH-sensitive enteric coated pancreatic enzyme preparation with conventional pancreatic enzyme therapy in the treatment of pancreatic exocrine insufficiency. Gastroenterology 1983;84:476 – 482. 5. Kühnelt P, Mundlos S, Adler G. The size of enteric coated microspheres influences the intraduodenal lipolytic activity. Z Gastroenterol 1991;29:417– 421. 6. Meyer JH, Elashoff J, Porter-Fink V, et al. Human postprandial gastric emptying of 1–3 millimeter spheres. Gastroenterology 1988;94:1315–1325. 7. Domínguez-Muñoz JE, Birkelbach U, et al. Effect of oral pancreatic enzyme administration on digestive function in healthy subjects: comparison between two enzyme preparations. Aliment Pharmacol Ther 1997;11:403– 408. 8. Iglesias-García J, Vilariño-Insua M, Iglesias-Rey M, et al. Oral pancreatic enzyme supplementation in patients with exocrine pancreatic insufficiency: is it enough to evaluate clinical response? Gastroenterology 2003;124(Suppl 1):A-632. 9. Domínguez-Muñoz JE. 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? In: Domínguez-Muñoz JE, ed. Clinical pancreatology for practising gastroenterologists and surgeons. Oxford: Blackwell Publishing, 2005:259 –266. 10. Iglesias-García J, Vilariño M, Iglesias-Rey M, et al. Accuracy of the optimized 13C-mixed triglyceride breath test for the diagnosis of steatorrhea in clinical practice. Gastroenterology 2003;124 (Suppl 1):A-631. 11. Stein J, Purschian B, Bieniek U, et al. Near-infrared reflectance analysis (NIRA): a new dimension in the investigation of malabsorption syndromes. Eur J Gastroenterol Hepatol 1994;6:889 – 894. 12. Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, et al. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther 2005;21:993–1000. 13. Halm U, Loser C, Lohr M, et al. A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency. Aliment Pharmacol Ther 1999;13:951–957.
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14. Regan PT, Malagelada JR, DiMagno EP, et al. Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 1977;297:854 – 858. 15. Durie PR, Bell L, Linton W, et al. Effect of cimetidine and sodium bicarbonate on pancreatic replacement therapy in cystic fibrosis. Gut 1980;21:778 –786. 16. Bruno MJ, Rauws EA, Hoek FJ, et al. Comparative effects of adjuvant cimetidine and omeprazol during pancreatic enzyme replacement therapy. Dig Dis Sci 1994;39:988 –992. 17. Domínguez-Muñoz JE, Iglesias-García J, Iglesias-Rey M, et al. Optimizing the therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor to enteric-coated pancreatic extracts. Gut 2006;55:1056 –1057. 18. Mundlos S, Kuhnelt P, Adler G. Monitoring enzyme replacement treatment in exocrine pancreatic insufficiency using the cholesteryl octanoate breath test. Gut 1990;31:1324 –1328. 19. De Boeck K, Delbeke I, Eggermont E, et al. Lipid digestion in cystic fibrosis: comparison of conventional and high-lipase enzyme therapy using the mixed-triglyceride breath test. J Pediatr Gastroenterol Nutr 1998;26:408 – 411. 20. Braden B, Picard H, Caspary WF, et al. Monitoring pancreatin supplementation in cystic fibrosis patients with the 13C-Hiolein breath test: evidence for normalized fat assimilation with high dose pancreatin therapy. Z Gastroenterol 1997;35:123–129. 21. Ritz MA, Fraser RJ, Di Matteo AC, et al. Evaluation of the 13Ctriolein breath test for fat malabsorption in adult patients with cystic fibrosis. J Gastroenterol Hepatol 2004;19:448 – 453. 22. Bruno MJ, Borm JJ, Hoek FJ, et al. Comparative effects of entericcoated pancreatin microsphere therapy after conventional and pylorus-preserving pancreatoduodenectomy. Br J Surg 1997;84: 952–956. 23. Mason JB. Nutritional assessment and management of the malnourished patient. In: Feldman M, Friedman LS, Brandt LJ, eds. Gastrointestinal and liver disease. 8th ed. Philadelphia: Saunders-Elsevier, 2006:319 –355. 24. 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. 25. Lankisch PG, Lembcke B, Wengen G, et al. Functional reserve capacity of the exocrine pancreas. Digestion 1986;35:175–181. 26. Vantrappen GR, Rutgeerts PJ, Ghoos YF, et al. Mixed triglyceride breath test: a noninvasive test of pancreatic lipase activity in the duodenum. Gastroenterology 1989;96:1126 –1134. 27. Lembcke B, Braden B, Caspary WF. Exocrine pancreatic insufficiency: accuracy and clinical value of the uniformly labelled 13CHiolein breath test. Gut 1996;39:668 – 674. 28. Ventrucci M, Cipolla A, Ubalducci GM, et al. 13C labelled cholesteryl octanoate breath test for assessing pancreatic exocrine insufficiency. Gut 1998;42:81– 87. 29. Perez MM, Newcomer AD, Moertel CG, et al. Assessment of weight loss, food intake, fat metabolism, malabsorption, and treatment of pancreatic insufficiency in pancreatic cancer. Cancer 1983;52:346 –352. 30. Iglesias-García J, Vilariño-Insua M, Lourido MV, et al. Development of a breath test for the diagnosis of steatorrhea. Gastroenterology 2002;122(Suppl 1):A-52.
Address requests for reprints to: Dr J. Enrique Domínguez–Muñoz, Department of Gastroenterology, University Hospital of Santiago de Compostela, C/ Choupana, s/n, 15706-Santiago de Compostela, Spain. e-mail: enriquedominguezmunoz@fienad.com; fax: (34) 981951-365. Supported by a grant from the Health Institute Carlos III, Spanish Ministry of Health (G03/156), and the Foundation for Research in Digestive Diseases.