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doi:10.1111/jgh.12406
N U T R I T I O N A L FA C T O R S I N PA N C R E AT O B I L I A R Y D I S O R D E R S
Maldigestion from pancreatic exocrine insufficiency Supot Pongprasobchai Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
Key words chronic pancreatitis, exocrine insufficiency, maldigestion, pancreatic enzyme. Accepted for publication 24 September 2013. Correspondence Dr Supot Pongprasobchai, Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. Email: [email protected] Conflicts of interest: None.
Abstract Pancreatic exocrine insufficiency (PEI) is one of the long-term consequences of chronic pancreatitis (CP). Majority of patients with PEI were undiagnosed or undertreated. Inadequately treated or subclinical severe PEI causes malnutrition and may pose the patients at risk of premature atherosclerosis and cardiovascular events. Indication of pancreatic enzyme replacement therapy (PERT) is patients with severe PEI, as indicated by the presence of steatorrhea, diarrhea, weight loss, fecal fat > 7 g/day, 13C-mixed triglyceride breath test < 29%, fecal elastase < 100 ug/g stool, imaging or endoscopic findings of pancreatic ductal dilatation or calculi, and eight endosonographic criteria of CP. The mainstay treatment of PEI is PERT. Dietary fat restriction is unnecessary. PERT with lipase > 40 000 U per meal is recommended. Enteric-coating may be preferred to conventional enzymes because of the availability of high-dose preparations and no need of acid suppression co-therapy. Administration of enzymes with meals is proven to be the most effective regimen. Response to PERT should be measured by the improvement of patients’ symptoms, nutritional status, and, in selected cases, by fecal fat or 13C-mixed triglyceride breath test. Patients unresponsive to PERT should be checked for compliance, increase the dose of lipase to 90 000 units/meal or co-therapy with proton pump inhibitor. In patient with previous gastrointestinal surgery that may interfere enzyme-food mixing, opening the capsules and administering the enzyme granules with meals. Finally, search for small intestinal bacterial overgrowth syndrome and other causes of small bowel malabsorption.
Introduction Pancreatic exocrine insufficiency (PEI) is one of the long-term consequences of various pancreatic disorders, e.g. chronic pancreatitis (CP), cystic fibrosis and after pancreatic surgeries. In clinical practice, PEI from CP is the most common cause. The consequences of untreated severe PEI are obvious, i.e. fat maldigestion, malnutrition, weight loss, diarrhea and steatorrhea but those of inadequately-treated or subclinical (asymptomatic) severe PEI are less clear. Nevertheless, there are some recent evidences demonstrated significant depletions of vitamins and micronutrients, for example retinol binding protein, transferrin and prealbumin,1,2 and lipoproteins (apoproteins A1 and lipoprotein A) in CP patients with inadequately-treated PEI.3 Some investigators postulated that these micronutrients and lipoprotein abnormalities might link and pose CP patients to the development of premature atherosclerosis and cardiovascular (CV) events.3 Case-control studies demonstrated that CP patients had more CV lesions (33%) compared with control (9%)4 and more commonly had aortic calcifications (60%) than smoker controls (30%) and nonsmoker controls (0%).5 Finally, CV disease is the number one cause of death of CP patients according to the International Pancreatitis Study Group.6 Thus, the adequacy of the treatment of PEI is now probably much more important than what we have thought.
Despite of this importance, a recent large-scale study from Netherland showed that majority of CP patients with PEI were undertreated (50% were underdosage, and 75% remained having steatorrhea).7 The exact reason is unknown but might attribute either to the patients or the physicians ourselves. This review will summarize current understanding, indications of treatment, diagnostic methods, and the appropriate treatment strategy of PEI in patients with CP.
Important principle of PEI PEI is the condition that exocrine pancreas secretes pancreatic enzymes, that is, lipase, amylase, or proteases lower than normal levels. Insufficiencies of amylase and proteases are not clinically important because the other nonpancreatic sources of enzymes (i.e. salivary, gastric, and small intestinal enzymes) are usually able to compensate the deficiencies. In contrast, pancreatic lipase insufficiency is the most important because it occurs earliest,8 lipase is fragile and most easily destroyed by gastric acid and luminal proteases,9 and the only source of compensation is gastric lipase. Although gastric lipase can increase threefold to fourfold in patients with CP,10,11 it is unpredictable and varies among patients. For these reasons, the mostly concerned PEI is lipase insufficiency.
Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4): 99–102 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Table 1
S Pongprasobchai
Concept of subclinical and symptomatic severe PEI and effects to patients
Lipase secretion (% of normal) Fecal fat > 7 g/day Overt steatorrhea Maldigestion, weight loss or diarrhea Malnutrition Vitamin, micronutrient, lipoprotein deficiency Effect to patient’s health Benefit of PERT
Subclinical severe PEI
Symptomatic severe PEI
< 10% Yes No No Yes (subclinical) Yes Possibly increase cardiovascular risk Probable
< 10% Yes Yes Yes Yes (clinical) Yes Malnutrition and impaired quality of life Definite
PEI, pancreatic exocrine insufficiency; PERT, pancreatic enzyme replacement therapy.
In general, fat maldigestion and steatorrhea occur when the amount of lipase is below 10% of normal secretion.12 This degree of PEI is pathological because fat maldigestion has occurred even though the patient may or may not have symptoms. This level of deficiency is usually labeled as “severe PEI” and needed to be recognized and treated properly. The concept of subclinical and symptomatic severe PEI is shown in Table 1.
Indications of the treatment of PEI Currently, the most widely accepted indications of the treatment of PEI by pancreatic enzyme replacement therapy (PERT) are symptomatic severe PEI or fecal fat > 15 g/day. These indications are endorsed by the Australian Pancreatic Club recommendations13 and the Italian Consensus Guidelines for CP.14 In these groups of patients, PERT has been proven to improve patients’ fat digestion,15–17 symptoms and quality of life.18 In subclinical severe PEI, the benefit of treatment is debatable. However, study by Dominguez-Munoz and Iglesias-Garcia et al. demonstrated that all patients with asymptomatic steatorrhea (fecal fat 7–15 g/day) had depletion of retinol-binding protein, transferrin, and prealbumin, indicating subclinical malabsorption, and PERT was shown to normalize these micronutrient deficiencies.2 Therefore, it is the author’s belief that this group of patients should logically be treated with PERT to correct subclinical malnutrition and, hopefully, might reduce the long-term CV events, although this benefit has yet to be proven. In summary, the current indication of PERT should include both symptomatic and subclinical severe PEI in order to abolish steatorrhea and normalize any level of fat maldigestion.
Diagnosis of severe PEI Severe PEI can be diagnosed by many ways and was summarized in Table 2. Symptomatic severe PEI can be easily diagnosed by the presence of overt steatorrhea, weight loss, or diarrhea, although these features usually indicate a very severe PEI (fecal fat is usually > 15 g/day). Therefore, in order to detect subclinical severe PEI, one of the following laboratory investigations should be tested (if possible), for example quantitative fecal fat > 7 g/ day12 (or in other words, coefficient of fat absorption [CFA] < 93%), positive qualitative fecal fat staining by Sudan III,19 13Cmixed triglyceride breath test < 29%1 or fecal elastase < 100 μg/g of stool.20 100
Table 2
Methods to diagnose severe pancreatic exocrine insufficiency
Clinical† Steatorrhea Unexplained diarrhea Unexplained weight loss Imaging or endoscopic findings Pancreatic ductal dilatation Main pancreatic duct calculi Eight endosonographic criteria of chronic pancreatitis Laboratory findings Quantitative fecal fat > 7 g/day Positive qualitative fecal fat (Sudan III) staining Fecal elastase-1 < 100 μg/g of stool 13 C-mixed triglyceride breath test < 29% †
Usually indicates very severe PEI.
Some imaging or endoscopic findings can also indicate high likelihoods of severe PEI. They include main pancreatic duct dilatation (by computed tomography [CT],21 endoscopic retrograde cholangiopancreatography [ERCP],21 or endoscopic ultrasonography [EUS]22), main pancreatic duct stone (by CT,21 ERCP,21 or EUS22), or the presence of eight EUS criteria of CP.22 Patients with such findings have > 80% likelihood for the presence of severe PEI;21 thus, it may be reasonable to start a trial of PERT in these patients without the need of pancreatic function testing.
Treatment of severe PEI Dietary modification. Currently, dietary fat restriction is no longer recommended because study has shown that if the dosage of prescribed PERT is adequate, fat absorption will be highest in the presence of high-fat diet, not fat restriction.23 Therefore, normal-to-high-fat diet should be advised together with the adequate prescription of PERT.24 PERT Dose. The dosage of lipase is the key to the success of PERT. The minimal dosage of lipase should be 90 000 U (Ph Eur or USP) per meal. This dosage is equivalent to 10% of normal lipase secretion, which is likely enough to normalize fat digestion.12 However, the exact amounts of lipase in most pancreatic enzyme preparations are usually higher than the labeled amounts for twofolds.25 Thus,
Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4): 99–102 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Pancreatic exocrine insufficiency
physicians may prescribe only half of the number of pancreatic enzyme calculated. In other words, we may calculate the number of capsule or tablet to achieve the lipase amount of > 40 000– 45 000 U per meal. This dosage of 40 000 U per meal is what being recommended by the Australian Pancreatic Club recommendations,13 the Italian Consensus Guidelines for CP,13,14 and some experts.26,27 However, it should be kept in mind that this dosage is the minimum one. One study has shown that with this dosage of lipase, fat digestion could be normalized in only 60% of cases.28 Two recent studies that prescribed the dosage of lipase 75 000 U29 or 80 000 U30 per meal demonstrated an increase of CFA to only 78% and 86%, respectively, which remained abnormal. Thus, increasing the dosage of lipase to 90 000 U per meal or higher may be required in some patients.31 Considerably, this dosage of PERT, the amount of amylase and proteases that the patients receive are always more than enough and need not be concerned.24 Preparations. Enteric-coating enzymes are now preferred to conventional enzymes because of the availability of preparations that contain large dose of lipase, and the presence of entericcoating will preclude the need of co-therapy with proton pump inhibitor (PPI) as being required in the case of conventional pancreatic enzymes. Some enteric-coated preparations also have microspheric forms that may more effectively mix with food than those in the tablet forms. Administration regimen. Past study by DiMagno et al.32 and recent study by Dominguez-Munoz et al.33 confirmed that the best regimen for administrating PERT is to take the enzymes with meals. Try to distribute the enzyme throughout the meal, for example one capsule after the first few bites of food, two more capsules in the middle of the meal, and last capsule after finishing the meal (1-2-1 regimen in case of requiring four capsules per meal or 2-2-2 regimen if requiring six capsules per meal).24 Evaluation of response. Response to PERT should mainly be measured by the improvement of patients’ symptoms, weight gain, and nutritional parameters.13,14 In selected cases, particularly the patients who start with subclinical severe PEI, follow up with quantitative fecal fat measurement or 13C-mixed triglyceride breath test1 may be required to assure normalization of fat digestion because some patients may remain having subclinical malnutrition measured by low prealbumin, transferring, and retinolbinding protein.1 Increasing the dosage of PERT can normalize this subclinical malnutrition.1 Nonresponders. Patients who are not well responded to adequate PERT should be asked for the compliance. Fecal chymotrypsin can be used to check for the compliance. Then, increase the dose of lipase to 90 000 or 1000 U of lipase/kg/meal should be tried. In case the patient had previous upper gastrointestinal surgery or anastomosis that may interfere the mixing between pancreatic enzyme and the food, opening the capsules and administering the enzyme granules directly with meals may solve the problem. If none of the earlier factors is found, co-therapy of PPI with enteric-coating enzymes has been shown to improve steator-
Figure 1 Algorithm of the management of pancreatic enzyme nonresponders. PERT, pancreatic enzyme replacement therapy; PPI, proton pump inhibitor; SIBO, small intestinal bacterial overgrowth syndrome.
rhea in this group of patients.28 The mechanism is to improve micelle formation, which is often impaired due to bile acid precipitation from the low duodenal pH in CP patients.34 Finally, search for small intestinal bacterial overgrowth (SIBO) syndrome and other causes of small bowel malabsorption. SIBO can occur in 25–70% of CP patients35–37 and can be diagnosed by hydrogen breath test or culture of the jejunal fluid aspirate. A 2-week trial of antibiotics, for example metronidazole is also reasonable if the tests for SIBO are unavailable. Parasitic and protozoan infections such as giadiasis38 should be sought, particularly in patient who has hypoalbuminemia. Algorithm of the management of PERT nonresponders is shown in Figure 1.
Conclusion Every CP patient should be sought for the presence of severe PEI. Diagnosis can be done mainly by clinical ground, with special work-ups in some cases. Treatment comprises of normal-to-highfat diet with adequate PERT containing lipase 40 000–90 000 U per meal with meals. In nonresponders, check the compliance, increase the dosage of PERT, add PPI, and finally, look for SIBO or small bowel causes of malabsorption.
References 1 Dominguez-Munoz JE, Iglesias-Garcia J, Vilarino-Insua M, Iglesias-Rey M. 13C-mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis. Clin. Gastroenterol. Hepatol. 2007; 5: 484–8. 2 Dominguez-Munoz JE, Iglesias-Garcia J. Oral pancreatic enzyme substitution therapy in chronic pancreatitis: is clinical response an appropriate marker for evaluation of therapeutic efficacy? JOP 2010; 11: 158–62.
Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4): 99–102 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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3 Montalto G, Soresi M, Carroccio A et al. Lipoproteins and chronic pancreatitis. Pancreas 1994; 9: 137–8. 4 Gullo L, Stella A, Labriola E, Costa PL, Descovich G, Labo G. Cardiovascular lesions in chronic pancreatitis: a prospective study. Dig. Dis. Sci. 1982; 27: 716–22. 5 Gullo L, Tassoni U, Mazzoni G, Stefanini F. Increased prevalence of aortic calcification in chronic pancreatitis. Am. J. Gastroenterol. 1996; 91: 759–61. 6 Lowenfels AB, Maisonneuve P, Cavallini G et al. Prognosis of chronic pancreatitis: an international multicenter study. International Pancreatitis Study Group. Am. J. Gastroenterol. 1994; 89: 1467–71. 7 Sikkens EC, Cahen DL, van Eijck C, Kuipers EJ, Bruno MJ. Patients with exocrine insufficiency due to chronic pancreatitis are undertreated: a Dutch national survey. Pancreatology 2012; 12: 71–3. 8 DiMagno EP, Malagelada JR, Go VL. Relationship between alcoholism and pancreatic insufficiency. Ann. N. Y. Acad. Sci. 1975; 252: 200–7. 9 Layer P, Go VL, DiMagno EP. Fate of pancreatic enzymes during small intestinal aboral transit in humans. Am. J. Physiol. 1986; 251: G475–80. 10 Carriere F, Grandval P, Renou C et al. Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis. Clin. Gastroenterol. Hepatol. 2005; 3: 28–38. 11 Carriere F, Grandval P, Gregory PC et al. Does the pancreas really produce much more lipase than required for fat digestion? JOP 2005; 6: 206–15. 12 DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N. Engl. J. Med. 1973; 288: 813–15. 13 Toouli J, Biankin AV, Oliver MR, Pearce CB, Wilson JS, Wray NH. Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. Med. J. Aust. 2010; 193: 461–7. 14 Frulloni L, Falconi M, Gabbrielli A et al. Italian consensus guidelines for chronic pancreatitis. Dig. Liver Dis. 2010; 42 (Suppl. 6): S381–406. 15 Waljee AK, Dimagno MJ, Wu BU, Schoenfeld PS, Conwell DL. Systematic review: pancreatic enzyme treatment of malabsorption associated with chronic pancreatitis. Aliment. Pharmacol. Ther. 2009; 29: 235–46. 16 Taylor JR, Gardner TB, Waljee AK, Dimagno MJ, Schoenfeld PS. Systematic review: efficacy and safety of pancreatic enzyme supplements for exocrine pancreatic insufficiency. Aliment. Pharmacol. Ther. 2010; 31: 57–72. 17 Shafiq N, Rana S, Bhasin D et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst. Rev. 2009; (4): CD006302. 18 Czako L, Takacs T, Hegyi P et al. Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis. Can. J. Gastroenterol. 2003; 17: 597–603. 19 Drummey GD, Benson JA Jr, Jones CM. Microscopical examination of the stool for steatorrhea. N. Engl. J. Med. 1961; 264: 85–7. 20 Loser C, Mollgaard A, Folsch UR. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut 1996; 39: 580–6. 21 Malfertheiner P, Buchler M, Stanescu A, Ditschuneit H. Exocrine pancreatic function in correlation to ductal and parenchymal morphology in chronic pancreatitis. Hepatogastroenterology 1986; 33: 110–14.
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22 Dominguez-Munoz JE, Alvarez-Castro A, Larino-Noia J, Nieto L, Iglesias-Garcia J. Endoscopic ultrasonography of the pancreas as an indirect method to predict pancreatic exocrine insufficiency in patients with chronic pancreatitis. Pancreas 2012; 41: 724–8. 23 Suzuki A, Mizumoto A, Sarr MG, DiMagno EP. Bacterial lipase and high-fat diets in canine exocrine pancreatic insufficiency: a new therapy of steatorrhea? Gastroenterology 1997; 112: 2048–55. 24 Pongprasobchai S, DiMagno EP. Treatment of exocrine pancreatic insufficiency. In: Forsmark CE, ed. Pancreatitis and Its Complications. Totowa, NJ: Humana press, 2005; 295–312. 25 Egberts JH, DiMagno EP. What is the dose of lipolytic activity that corrects human pancreatic steatorrhea? Gastroenterology 2000; 118: A420. 26 Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr. Gastroenterol. Rep. 2007; 9: 116–22. 27 Dominguez-Munoz JE. Chronic pancreatitis and persistent steatorrhea: what is the correct dose of enzymes? Clin. Gastroenterol. Hepatol. 2011; 9: 541–6. 28 Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, Vilarino-Insua M. Optimising the therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor to enteric coated pancreatic extracts. Gut 2006; 55: 1056–7. 29 Seiler CM, Izbicki J, Varga-Szabo L et al. Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension. Aliment. Pharmacol. Ther. 2013; 37: 691–702. 30 Thorat V, Reddy N, Bhatia S et al. Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis—a double-blind, placebo-controlled study. Aliment. Pharmacol. Ther. 2012; 36: 426–36. 31 DiMagno MJ, DiMagno EP. Chronic pancreatitis. Curr. Opin. Gastroenterol. 2012; 28: 523–31. 32 DiMagno EP, Malagelada JR, Go VL, Moertel CG. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N. Engl. J. Med. 1977; 296: 1318–22. 33 Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, Figueiras A, Vilarino-Insua M. 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. 34 Regan PT, Malagelada JR, Dimagno EP, Go VL. Reduced intraluminal bile acid concentrations and fat maldigestion in pancreatic insufficiency: correction by treatment. Gastroenterology 1979; 77: 285–9. 35 Lembcke B, Kraus B, Lankisch PG. Small intestinal function in chronic relapsing pancreatitis. Hepatogastroenterology 1985; 32: 149–51. 36 Trespi E, Ferrieri A. Intestinal bacterial overgrowth during chronic pancreatitis. Curr. Med. Res. Opin. 1999; 15: 47–52. 37 Pongprasobchai S, DiMagno EP. Are small intestinal bacterial overgrowth and pancreatic diseases associated? Pancreatology 2002; 2: 217–361. 38 Sheehy TW, Holley HP Jr. Giardia-induced malabsorption in pancreatitis. JAMA 1975; 233: 1373–5.
Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4): 99–102 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
doi:10.1111/jgh.12406
N U T R I T I O N A L FA C T O R S I N PA N C R E AT O B I L I A R Y D I S O R D E R S
Maldigestion from pancreatic exocrine insufficiency Supot Pongprasobchai Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
Key words chronic pancreatitis, exocrine insufficiency, maldigestion, pancreatic enzyme. Accepted for publication 24 September 2013. Correspondence Dr Supot Pongprasobchai, Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. Email: [email protected] Conflicts of interest: None.
Abstract Pancreatic exocrine insufficiency (PEI) is one of the long-term consequences of chronic pancreatitis (CP). Majority of patients with PEI were undiagnosed or undertreated. Inadequately treated or subclinical severe PEI causes malnutrition and may pose the patients at risk of premature atherosclerosis and cardiovascular events. Indication of pancreatic enzyme replacement therapy (PERT) is patients with severe PEI, as indicated by the presence of steatorrhea, diarrhea, weight loss, fecal fat > 7 g/day, 13C-mixed triglyceride breath test < 29%, fecal elastase < 100 ug/g stool, imaging or endoscopic findings of pancreatic ductal dilatation or calculi, and eight endosonographic criteria of CP. The mainstay treatment of PEI is PERT. Dietary fat restriction is unnecessary. PERT with lipase > 40 000 U per meal is recommended. Enteric-coating may be preferred to conventional enzymes because of the availability of high-dose preparations and no need of acid suppression co-therapy. Administration of enzymes with meals is proven to be the most effective regimen. Response to PERT should be measured by the improvement of patients’ symptoms, nutritional status, and, in selected cases, by fecal fat or 13C-mixed triglyceride breath test. Patients unresponsive to PERT should be checked for compliance, increase the dose of lipase to 90 000 units/meal or co-therapy with proton pump inhibitor. In patient with previous gastrointestinal surgery that may interfere enzyme-food mixing, opening the capsules and administering the enzyme granules with meals. Finally, search for small intestinal bacterial overgrowth syndrome and other causes of small bowel malabsorption.
Introduction Pancreatic exocrine insufficiency (PEI) is one of the long-term consequences of various pancreatic disorders, e.g. chronic pancreatitis (CP), cystic fibrosis and after pancreatic surgeries. In clinical practice, PEI from CP is the most common cause. The consequences of untreated severe PEI are obvious, i.e. fat maldigestion, malnutrition, weight loss, diarrhea and steatorrhea but those of inadequately-treated or subclinical (asymptomatic) severe PEI are less clear. Nevertheless, there are some recent evidences demonstrated significant depletions of vitamins and micronutrients, for example retinol binding protein, transferrin and prealbumin,1,2 and lipoproteins (apoproteins A1 and lipoprotein A) in CP patients with inadequately-treated PEI.3 Some investigators postulated that these micronutrients and lipoprotein abnormalities might link and pose CP patients to the development of premature atherosclerosis and cardiovascular (CV) events.3 Case-control studies demonstrated that CP patients had more CV lesions (33%) compared with control (9%)4 and more commonly had aortic calcifications (60%) than smoker controls (30%) and nonsmoker controls (0%).5 Finally, CV disease is the number one cause of death of CP patients according to the International Pancreatitis Study Group.6 Thus, the adequacy of the treatment of PEI is now probably much more important than what we have thought.
Despite of this importance, a recent large-scale study from Netherland showed that majority of CP patients with PEI were undertreated (50% were underdosage, and 75% remained having steatorrhea).7 The exact reason is unknown but might attribute either to the patients or the physicians ourselves. This review will summarize current understanding, indications of treatment, diagnostic methods, and the appropriate treatment strategy of PEI in patients with CP.
Important principle of PEI PEI is the condition that exocrine pancreas secretes pancreatic enzymes, that is, lipase, amylase, or proteases lower than normal levels. Insufficiencies of amylase and proteases are not clinically important because the other nonpancreatic sources of enzymes (i.e. salivary, gastric, and small intestinal enzymes) are usually able to compensate the deficiencies. In contrast, pancreatic lipase insufficiency is the most important because it occurs earliest,8 lipase is fragile and most easily destroyed by gastric acid and luminal proteases,9 and the only source of compensation is gastric lipase. Although gastric lipase can increase threefold to fourfold in patients with CP,10,11 it is unpredictable and varies among patients. For these reasons, the mostly concerned PEI is lipase insufficiency.
Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4): 99–102 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
99
Pancreatic exocrine insufficiency
Table 1
S Pongprasobchai
Concept of subclinical and symptomatic severe PEI and effects to patients
Lipase secretion (% of normal) Fecal fat > 7 g/day Overt steatorrhea Maldigestion, weight loss or diarrhea Malnutrition Vitamin, micronutrient, lipoprotein deficiency Effect to patient’s health Benefit of PERT
Subclinical severe PEI
Symptomatic severe PEI
< 10% Yes No No Yes (subclinical) Yes Possibly increase cardiovascular risk Probable
< 10% Yes Yes Yes Yes (clinical) Yes Malnutrition and impaired quality of life Definite
PEI, pancreatic exocrine insufficiency; PERT, pancreatic enzyme replacement therapy.
In general, fat maldigestion and steatorrhea occur when the amount of lipase is below 10% of normal secretion.12 This degree of PEI is pathological because fat maldigestion has occurred even though the patient may or may not have symptoms. This level of deficiency is usually labeled as “severe PEI” and needed to be recognized and treated properly. The concept of subclinical and symptomatic severe PEI is shown in Table 1.
Indications of the treatment of PEI Currently, the most widely accepted indications of the treatment of PEI by pancreatic enzyme replacement therapy (PERT) are symptomatic severe PEI or fecal fat > 15 g/day. These indications are endorsed by the Australian Pancreatic Club recommendations13 and the Italian Consensus Guidelines for CP.14 In these groups of patients, PERT has been proven to improve patients’ fat digestion,15–17 symptoms and quality of life.18 In subclinical severe PEI, the benefit of treatment is debatable. However, study by Dominguez-Munoz and Iglesias-Garcia et al. demonstrated that all patients with asymptomatic steatorrhea (fecal fat 7–15 g/day) had depletion of retinol-binding protein, transferrin, and prealbumin, indicating subclinical malabsorption, and PERT was shown to normalize these micronutrient deficiencies.2 Therefore, it is the author’s belief that this group of patients should logically be treated with PERT to correct subclinical malnutrition and, hopefully, might reduce the long-term CV events, although this benefit has yet to be proven. In summary, the current indication of PERT should include both symptomatic and subclinical severe PEI in order to abolish steatorrhea and normalize any level of fat maldigestion.
Diagnosis of severe PEI Severe PEI can be diagnosed by many ways and was summarized in Table 2. Symptomatic severe PEI can be easily diagnosed by the presence of overt steatorrhea, weight loss, or diarrhea, although these features usually indicate a very severe PEI (fecal fat is usually > 15 g/day). Therefore, in order to detect subclinical severe PEI, one of the following laboratory investigations should be tested (if possible), for example quantitative fecal fat > 7 g/ day12 (or in other words, coefficient of fat absorption [CFA] < 93%), positive qualitative fecal fat staining by Sudan III,19 13Cmixed triglyceride breath test < 29%1 or fecal elastase < 100 μg/g of stool.20 100
Table 2
Methods to diagnose severe pancreatic exocrine insufficiency
Clinical† Steatorrhea Unexplained diarrhea Unexplained weight loss Imaging or endoscopic findings Pancreatic ductal dilatation Main pancreatic duct calculi Eight endosonographic criteria of chronic pancreatitis Laboratory findings Quantitative fecal fat > 7 g/day Positive qualitative fecal fat (Sudan III) staining Fecal elastase-1 < 100 μg/g of stool 13 C-mixed triglyceride breath test < 29% †
Usually indicates very severe PEI.
Some imaging or endoscopic findings can also indicate high likelihoods of severe PEI. They include main pancreatic duct dilatation (by computed tomography [CT],21 endoscopic retrograde cholangiopancreatography [ERCP],21 or endoscopic ultrasonography [EUS]22), main pancreatic duct stone (by CT,21 ERCP,21 or EUS22), or the presence of eight EUS criteria of CP.22 Patients with such findings have > 80% likelihood for the presence of severe PEI;21 thus, it may be reasonable to start a trial of PERT in these patients without the need of pancreatic function testing.
Treatment of severe PEI Dietary modification. Currently, dietary fat restriction is no longer recommended because study has shown that if the dosage of prescribed PERT is adequate, fat absorption will be highest in the presence of high-fat diet, not fat restriction.23 Therefore, normal-to-high-fat diet should be advised together with the adequate prescription of PERT.24 PERT Dose. The dosage of lipase is the key to the success of PERT. The minimal dosage of lipase should be 90 000 U (Ph Eur or USP) per meal. This dosage is equivalent to 10% of normal lipase secretion, which is likely enough to normalize fat digestion.12 However, the exact amounts of lipase in most pancreatic enzyme preparations are usually higher than the labeled amounts for twofolds.25 Thus,
Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4): 99–102 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Pancreatic exocrine insufficiency
physicians may prescribe only half of the number of pancreatic enzyme calculated. In other words, we may calculate the number of capsule or tablet to achieve the lipase amount of > 40 000– 45 000 U per meal. This dosage of 40 000 U per meal is what being recommended by the Australian Pancreatic Club recommendations,13 the Italian Consensus Guidelines for CP,13,14 and some experts.26,27 However, it should be kept in mind that this dosage is the minimum one. One study has shown that with this dosage of lipase, fat digestion could be normalized in only 60% of cases.28 Two recent studies that prescribed the dosage of lipase 75 000 U29 or 80 000 U30 per meal demonstrated an increase of CFA to only 78% and 86%, respectively, which remained abnormal. Thus, increasing the dosage of lipase to 90 000 U per meal or higher may be required in some patients.31 Considerably, this dosage of PERT, the amount of amylase and proteases that the patients receive are always more than enough and need not be concerned.24 Preparations. Enteric-coating enzymes are now preferred to conventional enzymes because of the availability of preparations that contain large dose of lipase, and the presence of entericcoating will preclude the need of co-therapy with proton pump inhibitor (PPI) as being required in the case of conventional pancreatic enzymes. Some enteric-coated preparations also have microspheric forms that may more effectively mix with food than those in the tablet forms. Administration regimen. Past study by DiMagno et al.32 and recent study by Dominguez-Munoz et al.33 confirmed that the best regimen for administrating PERT is to take the enzymes with meals. Try to distribute the enzyme throughout the meal, for example one capsule after the first few bites of food, two more capsules in the middle of the meal, and last capsule after finishing the meal (1-2-1 regimen in case of requiring four capsules per meal or 2-2-2 regimen if requiring six capsules per meal).24 Evaluation of response. Response to PERT should mainly be measured by the improvement of patients’ symptoms, weight gain, and nutritional parameters.13,14 In selected cases, particularly the patients who start with subclinical severe PEI, follow up with quantitative fecal fat measurement or 13C-mixed triglyceride breath test1 may be required to assure normalization of fat digestion because some patients may remain having subclinical malnutrition measured by low prealbumin, transferring, and retinolbinding protein.1 Increasing the dosage of PERT can normalize this subclinical malnutrition.1 Nonresponders. Patients who are not well responded to adequate PERT should be asked for the compliance. Fecal chymotrypsin can be used to check for the compliance. Then, increase the dose of lipase to 90 000 or 1000 U of lipase/kg/meal should be tried. In case the patient had previous upper gastrointestinal surgery or anastomosis that may interfere the mixing between pancreatic enzyme and the food, opening the capsules and administering the enzyme granules directly with meals may solve the problem. If none of the earlier factors is found, co-therapy of PPI with enteric-coating enzymes has been shown to improve steator-
Figure 1 Algorithm of the management of pancreatic enzyme nonresponders. PERT, pancreatic enzyme replacement therapy; PPI, proton pump inhibitor; SIBO, small intestinal bacterial overgrowth syndrome.
rhea in this group of patients.28 The mechanism is to improve micelle formation, which is often impaired due to bile acid precipitation from the low duodenal pH in CP patients.34 Finally, search for small intestinal bacterial overgrowth (SIBO) syndrome and other causes of small bowel malabsorption. SIBO can occur in 25–70% of CP patients35–37 and can be diagnosed by hydrogen breath test or culture of the jejunal fluid aspirate. A 2-week trial of antibiotics, for example metronidazole is also reasonable if the tests for SIBO are unavailable. Parasitic and protozoan infections such as giadiasis38 should be sought, particularly in patient who has hypoalbuminemia. Algorithm of the management of PERT nonresponders is shown in Figure 1.
Conclusion Every CP patient should be sought for the presence of severe PEI. Diagnosis can be done mainly by clinical ground, with special work-ups in some cases. Treatment comprises of normal-to-highfat diet with adequate PERT containing lipase 40 000–90 000 U per meal with meals. In nonresponders, check the compliance, increase the dosage of PERT, add PPI, and finally, look for SIBO or small bowel causes of malabsorption.
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