pei mangement guidelines final 160310

8/13/2019 PEI Mangement Guidelines FINAL 160310

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CONTENTS

Page

Chapter 1 – Introduction 3

Chapter 2 – Pancreatic exocrine insufficiency 5

Chapter 3 – Pancreatic enzyme replacement therapy 11

Chapter 4 – Dietary management 17

Chapter 5 – Pancreatitis: Acute pancreatitis in adults 23

Chapter 6 – Pancreatitis: Chronic pancreatitis in adults 28

Chapter 7 – Pancreatitis: Childhood pancreatitis 38

Chapter 8 – Post surgery: Bowel resections 43

Chapter 9 – Post surgery: Gastrectomy 47

Chapter 10 – Post surgery: Parenchymal reduction 53

Chapter 11 – Pancreatic exocrine insufficiency in cystic fibrosis 58

Chapter 12 – Unresectable pancreatic cancer 73

Chapter 13 – Coeliac disease 77

Chapter 14 – Diabetes mellitus 80

Chapter 15 – Human immunodeficiency virus 83

Chapter 16 – Irritable bowel syndrome 86

Chapter 17 – Conclusion 88


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Table 1. Levels of evidence

Level of evidence

a Systematic review of randomised controlled trials1

b Individual randomised controlled trial

a Systematic review of cohort studies

b Individual cohort study or low-quality randomised controlled trial

2

c Outcomes research

a Systematic review of case-control studies3

b Individual case-control study

4 Case series or poor-quality cohort or case-control studies

5 Expert opinion

Reference

1. Sackett DL et al. Evidence-based medicine: How to practice and teach EBM . 2nd ed:Churchill Livingstone.


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Chapter 2

Pancreatic exocrine insufficiency

Introduction The pancreas is a glandular organ located in the upper abdomen behind the stomach(Figure 1). Its head is connected to the duodenum by the main pancreatic duct and theaccessory pancreatic duct (Figure 2). The pancreas serves two major functions. It is anendocrine organ producing insulin and glucagon to regulate blood sugar levels. In addition,it is a digestive organ that secretes digestive enzymes and bicarbonate into the duodenumvia a ductal system.

Pancreatic exocrine excretion Pancreatic enzymes, particularly lipase, amylase, trypsin and chymotrypsin, play a critical

role in macronutrient digestion. Pancreatic enzyme secretion is predominately stimulated byexposure of the duodenal mucosa to nutrients, in particular lipids.

After ingesting a meal, pancreatic enzyme secretion can be divided into three phases (Table1).1 During the first phase, enzyme delivery into the duodenum increases rapidly andreaches maximal levels within 30 to 60 minutes. In the second phase, enzyme secretiondecreases to a slightly lower level and then remains stable for 2 to 3 hours. At the end of thedigestive period, enzyme secretion returns to baseline levels, usually 3 to 4 hourspostprandially. The extent and duration of pancreatic enzyme secretion depends on thecaloric content, nutritional composition and physical properties of the meal.

Table 1. Pancreatic enzyme secretion into the duodenum1

Phase Imaximal secretion

Phase IIstable secretion

Phase IIIbaseline secretion

Lipase (U/min) 3000-6000 2000-4000 1000

Amylase (U/min) 500-1000 500 50-250

Trypsin (U/min) 200-1000 150-500 50-100


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Figure 1. The pancreas and nearby organs

Reproduced from the National Cancer Institute.

Figure 2. The pancreas anatomy

Reproduced from the National Cancer Institute.


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Pancreatic exocrine insufficiencyPancreatic exocrine insufficiency occurs when amounts of enzymes secreted into theduodenum in response to a meal are not sufficient to maintain normal digestive processes.There are three main reasons why sufficient pancreatic enzymes may not be available:1

1. Insufficient capacity of the pancreas to synthesise enzymes due to loss of or injury to thepancreatic parenchyma

2. Reduced stimulation of enzyme production due to postcibal asynchrony3. Impaired delivery of enzymes to the duodenum due to obstruction of the pancreatic duct

Due to the high reserve capacity of the pancreas and compensatory mechanisms that partlysubstitute for the loss of pancreatic enzymes, clinical symptoms of pancreatic exocrineinsufficiency do not usually manifest until duodenal lipase levels fall below 5-10% of normalpostprandial levels.1,2

The main clinical consequence of pancreatic exocrine insufficiency is fat maldigestion andmalabsorption resulting in steatorrhoea. Steatorrhoea is characterised by frothy, foul

smelling and buoyant stools due to their high fat content. Other symptoms may also includeabdominal pain, flatulence and weight loss in adults or lack of weight gain in children. If leftuntreated, fat maldigestion may lead to low circulating levels of micronutrients, fat-solublevitamins and lipoproteins, which have been related to high morbidity due to increased risk ofmalnutrition-related complications and cardiovascular events.3,4

Diagnosis of pancreatic exocrine insufficiencyPancreatic exocrine function is difficult to assess because the organ and its secretions arerelatively inaccessible. However, it is important to be able to differentiatemalabsorption/maldigestion due to pancreatic causes from other causes and to assess theefficacy of treatment. Pancreatic exocrine function can either be tested directly or indirectly.

Direct tests involve collecting pancreatic secretions via duodenal intubation with the pancreas stimulated with exogenous hormones or intestinal nutrients. Although direct testsare the most sensitive and specific methods to assess pancreatic exocrine function, theircost and invasive nature limit their routine use in clinical practice.

Indirect tests are cheaper and easier to administer, but are less sensitive and less specificbecause they are designed to detect abnormalities secondary to loss of pancreatic function.Indirect tests can be divided into 4 categories – faecal tests, breath tests, urinary tests andblood tests.


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Faecal testsThe 3-day faecal fat test is considered the gold standard for diagnosing and quantifyingsteatorrhoea, although it does not distinguish between pancreatic and nonpancreaticcauses. The method most commonly used is the Van de Kramer method.5 Adults consumea diet containing 100 g of fat for 3-5 days.6 Children meticulously weigh their food andmaintain careful dietary records in order to calculate the mean daily fat intake. Stools arecollected over 72 to 96 hours and pooled for analysis. Steatorrhoea is present if more than7% of ingested fat is excreted in patients over 6 months of age or more than 15% in patientsunder 6 months of age.6,7 The odious nature of this test for both patients and laboratorytechnicians makes it an unpopular choice.

Determination of steatocrit can be used to measure faecal fat. Homogenised faeces arecentrifuged at 15,000 rpm for 15 minutes causing the lipid and aqueous phases to separatefrom each other and from the stool residue.8 A lipid phase representing less than 10% ofvolume is considered normal in patients older than 6 months of age. Perchloric acid can beadded to the faecal homogenate to improve sensitivity of the test.9,10 The acid steatocritmethod correlates closely with the 3-day faecal fat test.11,12

Faecal chymotrypsin is measured photometrically after solubilising chymotrypsin with adetergent.13 It is convenient, reproducible and sensitive, and can reliably differentiatebetween pancreatic-sufficient and pancreatic-insufficient patients. Faecal chymotrypsin hasbeen validated by showing good correlation with direct secretion tests following hormonalstimulation with CCK-secretin.14,15

Faecal elastase-1 is measured using an ELISA assay, and has been found to be both moresensitive and specific than faecal chymotrypsin in detecting pancreatic insufficiency.16-18 Assuch, the use of this test is becoming more prevalent in clinical practice. A faecal elastaselevel less than 200 mcg/g stool is indicative of mild pancreatic exocrine insufficiency, andless than 100 mcg/g stool of severe pancreatic exocrine insufficiency.

Microscopic examination of stool for fat globules may be used as a crude screening test formalabsorption. A simple qualitative technique utilises the Sudan III stain in which neutral fatglobules are visualised under the microscope. If fat globules are present, then it may beprudent to perform additional tests.

Breath testsRadiolabelled breath tests take advantage of the fact that ingested lipids are predominantlyhydrolysed by pancreatic lipases in the small intestine, absorbed as free fatty acids andmonoglycerides, and transported to the liver, where oxidative metabolism liberates carbondioxide. Three different trigylcerides have commonly been used – trioctanoin, tripalmitateand triolein. Triolein breath tests appear to be more specific than the others.19 However,

triolein breath tests have not been fully validated against the 3-day faecal fat test forconfirming the presence of fat malabsorption.20,21 In addition, they do not differentiatebetween pancreatic and nonpancreatic causes of fat malabsorption. The clinical use ofradiolabelled breath tests for the diagnosis of pancreatic exocrine insufficiency is still limiteddue to expensive substrates and long test periods with many samples.

Urine testsUrine tests use nonabsorbable substrates that are specifically cleaved by pancreaticenzymes. This results in the release of a rapidly absorbable marker that is conjugated in theliver and excreted in urine. Two substrates have been used – bentiromide and fluoresceindilaurate.22-24 Following substrate ingestion, urine is collected over a specified time period.The test is then repeated on a second day to correct for urinary recovery. Urine tests havebeen superseded by simpler blood tests with better specificity and sensitivity.


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Blood testsTrypsin is exclusively synthesised by the pancreas and small amounts are released into theblood as the proenzyme trypsinogen. Measurement of serum immunoreactive trypsinogen isa sensitive and relatively non-invasive method of screening for pancreatic insufficiency inolder children. It has been validated in children with cystic fibrosis and pancreatic exocrineinsufficiency due to other causes.25,26 Serum trypsinogen levels below 20 ng/mL arereasonably specific for pancreatic insufficiency in patients over 7 years of age.

Serum immunoreactive trypsinogen is also used as a diagnostic screening test for cysticfibrosis in infants less than 1 year of age.27 Individuals with cystic fibrosis have elevatedserum immunoreactive trypsinogen levels during the first year of life. The levels fall tosubnormal levels by 6 years of age in those cystic fibrosis patients who are pancreaticinsufficient.

ConclusionsThe pancreas plays an important role in macronutrient digestion through the secretion of

digestive enzymes into the duodenum. Pancreatic enzyme secretion reaches maximallevels within 1 hour following meal ingestion and remains at a lower, but stable level for anadditional 2 to 3 hours before returning to baseline levels. The extent and duration ofpancreatic stimulation depends on the caloric content, nutrient composition and physicalproperties of the meal.

Pancreatic exocrine insufficiency occurs when pancreatic enzyme secretion is no longersufficient to support normal digestive processes. Steatorrhoea is the main clinicalconsequence that if left untreated can result in significant morbidity.

A number of different tests have been developed to diagnose pancreatic exocrineinsufficiency. Direct function tests are the most specific and sensitive tests, but are too

expensive, cumbersome and invasive for routine use in clinical practice. Three-day faecalfat is the “gold standard” for diagnosing steatorrhoea but is unpopular with patients and labtechnicians. Of the remaining indirect function tests, faecal elastase-1 and serumtrypsinogen are most commonly used.

In clinical practice, the diagnosis of pancreatic exocrine insufficiency is usually based on anassessment of the patient’s clinical state, a self-report of bowel movements and weight lossin adults or failure to thrive in children. Pancreatic enzyme replacement therapy can betrialled, and symptom improvement would support a diagnosis of pancreatic exocrineinsufficiency.


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References

1. Keller J and Layer P. Gut 2005; 54(Suppl VI): vi1-vi28.

2. DiMagno EP et al. N Engl J Med 1973; 288: 813-15.

3. Domínguez-Muñoz JE. Curr Gastroenterol Rep 1007; 9: 116-22.

4. Montalto G et al. Pancreas 1994; 9: 137-38.

5. Van de Kramer JK et al. J Biol Chem 1949; 177: 347-55.

6. Thompson JB et al. J Lab Clin Med 1969; 73: 521-30.

7. Fomon SJ et al. Am J Clin Nutr 1970; 23: 1299-313.

8. Colombo C et al. J Pediatr Gastroenterol Nutr 1987; 6: 926-30.

9. Van den Neucker AM et al. Acta Paediatr 2001; 90: 873-75.

10. Wagner MH et al. J Pediatr Gastroenterol Nutr 2002; 35: 202-05.

11. Van den Neucker et al. Clin Biochem 2002; 35: 29-33.

12. Amann ST et al. Am J Gastroenterol 1997; 92: 2280-84.

13. Kaspar P et al. Clin Chem 1984; 30: 1753-57.

14. Bonin A et al. J Pediatr 1973; 83: 594-600.

15. Brown GA et al. Arch Dis Child 1988; 63: 785-89.

16. Walkowiak J et al. Pediatrics 2002; 110(1 Pt 1):e7.

17. Loser C et al. Gut 1996; 39: 580-86.

18. Glasbrenner B et al. Eur J Gastreneterol Hepatol 1996; 8: 1117-20.

19. Newcomer AD et al. Gastroenterology 1979; 76: 6-13.

20. Pedersen NT et al. Scand J Clin Lab Invest 1991; 51: 699-703.

21. Dumasy V et al. Am J Gastroenterol 2004; 99: 1350-54.

22. Scharpe S and Iliano L. Clin Chem 1987; 33: 5-12.

23. Toakes PP. Gastroenterology 1983; 85: 565-69.

24. Mitchell CJ et al. Scan J Gastrenterol 1979; 14: 737-41.

25. Durie PR et al. Pediatr Res 1986; 20: 209-13.

26. Moore DJ et al. Gut 1986; 27: 1362-68.

27. Couper RT et al. J Pediatr 1995; 127: 408-13.


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Chapter 3

Pancreatic enzyme replacement therapy

IntroductionThe primary treatment goal for pancreatic exocrine insufficiency is to eliminatemaldigestion/malabsorption and maintain adequate nutrition. Ideally, treatment wouldperfectly mimic the exocrine secretory response of a healthy pancreas in terms of thequantity, composition and timing of luminal enzymatic activity.

Pancreatic enzyme replacement therapy is the mainstay of treatment for pancreaticexocrine insufficiency. The objective is to deliver sufficient enzymatic activity into theduodenal lumen simultaneously with the meal in order to restore nutrient digestion and aidabsorption. There are two pancreatic enzyme replacement agents available in Australia –Creon® and Panzytrat®.

Creon® is a porcine pancreatic enzyme extract encapsulated in minimicrospheres with apH-sensitive coating. The minimicrospheres are similar in size to food particles to enablethem to mix homogenously with the chyme (0.7-1.6 mm diameter). Creon is available in fourdifferent strength capsules (Table 1).

Table 1. Minimum enzyme activities in each Creon capsule

Creon 5,000 Creon 10,000 Creon 25,000 Creon 40,000

Lipase (BP units) 5,000 10,000 25,000 40,000

Amylase (BP units) 4,000 8,000 18,000 25,000Protease (Ph Eur Units) 300 600 1,000 1,600

Panzytrat® 25000 is a porcine pancreatic enzyme preparation of encapsulated enteric-coated microtablets. The microtablets are uniform in size and shaped for maximum contactsurface area (2 mm diameter convex spheres of thickness 1.90-2.10 mm) Each capsulecontains no less than lipase 25,000 BP units, amylase 22,500 BP units and protease 1,250Ph Eur Units.

Both preparations contain a pH-sensitive coating to allow the enzymes to mix with thechyme while being protected from inactivation by gastric acid. The intact enzymes then

pass into the alkaline pH of the duodenum where the enteric coating rapidly dissolves andthe enzymes are released.

Several factors influence the effectiveness of pancreatic enzyme replacement therapy:• Variations in enzyme content• Size of the enzyme particles• Dissolution properties of the enteric coating

These factors need to be taken into consideration when reviewing the literature and makingrecommendations for appropriate dosing regimens. They can also influence thebioequivalence of different formulations.


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Enzyme contentUnits of measurement for pancreatic enzyme content and activity vary internationally. Theconversion factors for units of enzyme activity are shown in Table 2. The quality and contentof a product or formulation must conform to the description laid out in the relevantpharmacopoeia. Since enzymes are sensitive proteins, their activity is degraded with time.Measured enzyme activities are generally higher than the declared activities to ensure therequired minimum activity at the end of shelf life.

Table 2. Conversion factors for units of enzyme activity1

EuropeanPharmacopoeia

FederationInternationale

Pharmaceutique

BritishPharmacopoeia

United StatesPharmacopoeia

Lipase 1 1 1 1

Amylase 1 1 1 4.15

Protease 1 1 1* 62.5

*Only free protease for pancreatin; total protease for pancreatic extract (pancrelipase).

Particle sizeTheoretically, enzyme particles that are too large may not empty from the stomach asquickly as smaller food particles. The dissociation of duodenal passage of nutrients andenzymes could prevent their ability to aid digestion. Two studies have investigated theeffects of enzyme particle size on gastric transit time. Another two studies compared theeffectiveness of microspheres and minimicrospheres on fat excretion.

A study in 26 healthy subjects was conducted to identify the size of spheres that wouldempty from the stomach with food and to determine whether different meals altered the

size.2 This study showed that sphere size was a more important determinant of sphereemptying than meal size. Gastric transit time was inversely related to sphere diameter. One-millimetre spheres emptied consistently faster than 2.4 or 3.2 mm spheres when ingestedtogether with either 420 g or 100 g meals. The ideal sphere size was 1.4 +/- 0.3 mm indiameter to empty at the same rate as the test meal of chicken liver.

Another study compared the gastric transit time of 2 mm microspheres with 1.2 mmminimicrospheres in pancreatic-insufficient subjects with cystic fibrosis.3 Patients consumed20 g of free oil in spaghetti meals or 20 g of oil emulsified in a milk meal. This study did notshow a difference in gastric transit time between the two preparations.

The effect of microspheres (1-2 mm diameter) and smaller minimicrospheres (0.7-1.25 mmdiameter) on fat excretion and fat intake was evaluated in a double-blind, randomised,multicentre, crossover study.4 Twenty-three patients with chronic pancreatitis and faecal fatexcretion of greater than 7.5 g/day during a placebo period were randomly assigned toreceive the two treatments in random order. The results showed that the minimicrosphereswere equally effective as microspheres in improving the coefficient of fat absorption.

Similar results were obtained in a study of 24 cystic fibrosis patients.5 Patients tookmicrospheres for 14 days and were then randomised to 28 days of microspheres followedby 28 days of minimicrospheres or vice versa. Stool fat (g/day) and coefficient of fatabsorption were measured at the end of each treatment period, and both products werefound to be therapeutically equivalent.

Taken together, these results suggest that spheres with a diameter of 2 mm or less aremixed intragastrically with the meal and emptied intact into the duodenum within the chyme.


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However, a further decrease in sphere size may not be associated with greater clinicalbenefit.

Dissolution properties of the enteric coating All digestive enzymes are susceptible to acid degradation, especially lipase. Modernpreparations protect enzymes from denaturation with a pH-sensitive enteric coating. Thepolymer coatings of these preparations are designed to release the enzymes when exposedto the higher pH environment of the duodenum. If enzyme release takes too long afterexposure to the intestinal milieu, then the digestive action may be delayed. Therefore, thephysicochemical properties of the enteric coating are crucial for the efficacy of enzymetherapy.

Duodenal pH is normally between 6 and 7, but after a meal, it drops to around 5.5. In vitrostudies show that the coating of most preparations dissolves over a variable period of timeat a pH 5.0-6.0.6-8 Most preparations show more than 90% dissolution within 30 minutes atpH greater than 6.0.

These results suggest that even if enzyme preparations have equivalent enzyme content,they may not be equivalent with respect to their release of enzymatic activity.

Adjunct therapy for acid suppressionThe pH of the duodenum in patients with pancreatic disease may be even lower thannormal due to bicarbonate deficiency.9 It has been shown that duodenal pH declines to lessthan 4 after 100 minutes postprandially in some patients with pancreatic exocrineinsufficiency due to chronic pancreatitis.10 This lower pH may impair the release of enteric-coated pancreatic enzymes and reduce their effectiveness. In theory, acid suppression mayimprove fat absorption by providing a duodenal environment more conducive to efficient

enzyme function.

Several different classes of agents have been used to evaluate the role of acid suppressionin the treatment of pancreatic exocrine insufficiency (Table 3). In general, the results havebeen mixed, and there is limited evidence that these agents improve fat absorption inpatients with pancreatic exocrine insufficiency on enzyme therapy. However, they may beuseful in patients who continue to experience symptoms of pancreatic exocrineinsufficiency, particularly steatorrhoea, despite enzyme therapy.


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Table 3. Acid-suppressing agents evaluated for pancreatic exocrine insufficiency

Class Agent

Antacids BicarbonateHydroxides

H2-receptor antagonists CimetidineMetiamideFamotidineRanitidine

Proton pump inhibitors OmeprazoleLansoprazole

Prostaglandin analogues EnprostilMisoprostol

A 6-week, double-blind, placebo-controlled crossover trial evaluated the efficacy ofmisoprostol (100 µg, 4 times daily) in improving fat absorption in 17 children with cysticfibrosis already on pancreatic enzyme therapy.11 Misoprostol did not further improve fatabsorption in those patients who had >90% absorption on enzyme therapy alone. However,a significant improvement with misoprostol was observed in those with 10% while on enzyme therapy.12 This double-blind, placebo-controlledcrossover study evaluated the effect of gastric acid inhibition by 20 mg omeprazole. Adjuncttherapy with omeprazole resulted in a significant reduction in faecal fat excretion.

The efficacy of omeprazole was also evaluated in another randomised, crossover studyinvolving 15 patients with cystic fibrosis who had residual steatorrhoea despite high-dosepancreatic enzyme supplements (!10,000 lipase/kg/day).13 In this study, omeprazolesignificantly improved fat digestion and absorption. Median faecal fat loss decreased from13 g/day to 5.5 g/day with a similar improvement noted when fat absorption was calculated.The coefficient of fat absorption was 87% without omeprazole versus 94% with omeprazole.

Recommended dosesIn healthy individuals, the amount of digestive enzymes released postprandially far exceedsthe amount required for normal digestive function. In pancreatic exocrine insufficiency,

between 5% and 10% of normal cumulative enzyme outputs may be enough to aid digestionand improve clinical symptoms.

The relationship between dose of pancreatic enzymes required and the presence ofmalabsorption and maldigestion is not linear. Therefore, doses need to be individuallytitrated to the lowest effective dose.

In adults, the initial dose recommended is 25,000 to 40,000 units lipase with each meal. 1,14 The dose can then be titrated up to a maximum of 75,000 to 80,000 units lipase per meal.

In children, 500 to 4,000 units lipase per gram of dietary fat may be given.15 Alternatively,the amount of enzymes may be calculated based on bodyweight; using this method,children under the age of 4 years may be given 1,000 units lipase per kilogram bodyweight


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per meal. Children greater than 4 years of age may be given 500 units lipase per kilogramper meal. The enzyme doses should be halved for snacks.16

In infants, 500 to 1,000 units lipase per gram of dietary fat is recommended. 15 Alternatively,infants may be given 2,000 to 4,000 units lipase per breastfeed or 120 mL of infantformula.16

In infants and children, the maximum dose recommendation is 10,000 units of lipase perkilogram per day.16

The efficacy of pancreatic enzyme replacement therapy for specific conditions is describedin subsequent chapters.

SummaryPancreatic enzyme replacement therapy is the main pharmacological treatment forpancreatic exocrine insufficiency. Modern preparations contain pancreatic extract

encapsulated in microtablets or (mini)microspheres with pH-sensitive enteric coating. Theenzymes mix intragastrically with the chyme while being protected from acid degradation bythe enteric coating. The enzymes are then emptied from the stomach simultaneously withthe chyme. The higher pH in the duodenum dissolves the enteric coating, releasing theenzymes at the appropriate site for digestion and absorption. Not all pancreatic enzymereplacement agents are equivalent, although the therapeutic implications of the differencesare not yet clear.

Patients with pancreatic exocrine insufficiency should be commenced on the lowestrecommended dose of pancreatic enzymes and then increased and titrated to the lowesteffective dose. In adults, the maximum recommended dose is 75,000 to 80,000 units lipaseper meal. In infants and children, the maximum recommended dose is 10,000 units lipase

per kilogram per day. Acid-suppressing agents may be trialled in those patients whocontinue to experience symptoms of pancreatic exocrine insufficiency despite high-doseenzyme therapy.


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References

1. Layer P et al. Curr Gastroenterol Rep 2001; 3: 101-08.

2. Meyer JH et al. Gastroenterology 1988; 94(6): 1315-25.

3. Meyer JH and Lake R. Pancreas 1997 15(3): 226-35.

4. Halm U et al. Aliment Pharmacol Ther 1999; 13(7): 951-57.

5. Patchell CJ et al. J Cyst Fibros 2002; 1(4): 287-91.

6. Gan KH et al. Aliment Pharmacol Ther 1996; 10(5): 771-75.

7. Case CL et al. Pancreas 2005; 30(2): 180-83.

8. Littlewood JM et al. J Pediatr Gastroenterol Nutr 1988; 7(Suppl 1): S22-29.

9. Keller J and Layer P. Gut 2005; 54: 1-28.

10. DiMagno EP et al. N Engl J Med 1977; 296: 1318-22.

11. Robinson P and Sly PD. J Pediatr Gastroenterol Nutr 1990; 11: 37-40.

12. Heijerman HG et al. Dig Dis Sci 1993; 38: 1-6.

13. Proesmans M and De Boeck K. Eur J Pediatr 2003; 162: 760-63.

14. Dominguez-Munoz JE. Curr Gastroenterol Rep 2007; 9: 116-22.

15. Anthony H et al. J Paediatr Child Health 1999; 35(2): 125-29.

16. Baker SS. Ther Clin Risk Manag 2008; 4(5): 1079-84.


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Chapter 4

Dietary management

IntroductionThe management of patients with pancreatic exocrine insufficiency (PEI) is a complex issue.Patients need to be assessed to determine if enzyme therapy is required, what dosage toprescribe and be constantly monitored for compliance. A nutritional assessment of patientswith PEI is essential due to the weight loss in adults or lack of weight gain in childrenassociated with malabsorption, and the potential nutritional deficiencies that can occur.

The involvement of a dietician to oversee dietary management is critical. The role of thedietician is to make an initial assessment of the nutritional adequacy of the patient’s diet.Dietary advice can then be specifically tailored to improve energy and protein intake, andensure the diet is nutritionally adequate in vitamins and minerals. The dietician can also play

a role in ongoing patient management by monitoring dietary compliance, nutritionaldeficiencies and enzyme therapy compliance.

Nutritional assessment

Aetiology of PEIIt is important to understand the underlying aetiology of PEI so that nutritional managementcan address both the PEI and also any specific needs associated with the disease state.Nutritional management differs according to different aetiologies, particularly in themonitoring of nutritional parameters, the recommendations for meal size and frequency andthe potential need for nutritional supplementation.

Detailed diet history A detailed diet history is essential to establish the patient’s baseline diet. This enables anestimation of the patient’s total energy, fat and protein intake. Some important questionsneed to be answered so that the dietician can formulate dietary goals and strategies toaddress problem areas.• Is the patient following a low, normal or high fat diet?• Is the patient’s protein and total energy intake adequate to facilitate weight gain or

prevent weight loss?• Does the patient consume three large meals per day or smaller meals with snacks in

between?

Weight assessmentWeight loss in adults or lack of weight gain in children is common in PEI due tomalabsorption and the patient’s fear of eating. Weight loss is usually gradual in chronicpancreatitis and occurs in the early stages of the disease before steatorrhoea develops. Incontrast, weight loss is rapid in pancreatic cancer. Up to 90% of patients with pancreaticcancer present with weight loss and malabsorption at the time of diagnosis.1

In children with cystic fibrosis (CF), malnutrition continues to be a major clinical problemwith stunted growth evident in most patient populations. Data from the Australasian CF DataRegistry from 2002 indicate that 12% of children and adolescents were below the 5 th percentile for height and 10% were below the 5th percentile for weight.2 Underweightremains prevalent in CF into adulthood, with 8% of adults having a body mass index (BMI)

less than 18 kg/m2, and a further 23% with a BMI between 18 and 20 kg/m2.


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Ensuring adequate growth in children and preventing weight loss in adults are paramount toany dietary management. In adults, BMI is a common method of assessing the weightstatus of populations and also individuals. BMI can have its limitations in individuals due tovariations in lean body mass, skeletal mass and frame, and hence should always be usedwith some caution. Assessing the weight history of the patient when they have been well,together with BMI will allow a logical target weight to be set for an individual. For children,locally available growth charts are used as targets until 18 years of age.

Monitoring body composition may be a better indicator of nutritional status and enabledeteriorations in nutritional status to be detected earlier. In adults, a more direct assessmentof muscle mass and protein status is mid arm muscle circumference (MAMC). MAMCrequires an upper arm girth measurement and tricep fat fold. The muscle circumference isthen estimated using an equation and the result is compared using a centile chart. MAMC isvery useful in conditions where body weight is not a good indicator of nutritional status, suchas in liver disease if significant ascites is present, and hence weight is not an accuratemeasurement. MAMC has been used as a nutritional assessment tool in PEI in adults. In atrial of post-pancreaticojejunostomy patients who took enzyme therapy for PEI, 9 out of 11

patients weighed < 90% of their ideal weight for height.3

However, only 2 patients hadMAMC outside the normal range, and hence weight loss was reflected by a decrease inbody fat not muscle mass. This is very useful information to the dietician to determine whatweight is being lost – fat mass or lean mass, as preservation of lean body mass is the moreimportant issue. Whilst MAMC is a good indicator of protein status and lean muscle mass, itdoes require an experienced and trained person to take the necessary measurementsaccurately.

Similarly, various skin fold measurements on the body may provide information as tochanging fat mass in adults. In children, skin folds for detecting changes in bodycomposition over time are unreliable because their fat free mass is constantly changing.Dual-energy X-ray absorptiometry (DXA) is a superior method to measure body

composition, but is more expensive and more invasive.

Nutritional testingFat malabsorption due to PEI can result in deficiencies in fat-soluble vitamins (A, D, E andK). It is recommended that fat-soluble vitamins be measured at the time of diagnosis andmonitored annually in patients with PEI. Vitamins should be supplemented in those patientswith levels below the reference range.

Vitamin B-12 deficiency may be observed, particularly post-gastrectomy as intrinsic factor inthe stomach facilitates vitamin B-12 absorption in the terminal ileum. Hence any surgerythat reduces intrinsic factor and gastric acidity will reduce vitamin B-12 absorption.

Iron deficiency may occur, particularly in surgical procedures where the duodenum hasbeen bypassed, the primary site for iron absorption. Reduced gastric acidity also impairsconversion of ferric iron to the more absorbable ferrous form, so again, any gastric reductionsurgery or proton pump inhibitor use will affect the ability of iron to be absorbed.


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Dietary recommendations for PEI

Dietary fat intakeHistorically, dietary fat intake has been restricted in patients with PEI to minimise fatmalabsorption and reduce steatorrhoea. Diets containing as low as 20 g of fat per day havebeen prescribed.4 However, low fat diets are lower in total energy, and restricting fat intakealso reduces intake of fat-soluble vitamins, which are already malabsorbed in PEI.Furthermore, it appears lipase activity during small intestinal transit requires the presence ofdietary triglycerides.5,6 In an experimental model of PEI in dogs, fat digestion and absorptionwere higher when enzyme supplements were taken with a high fat diet compared with a lowfat diet.7

Studies in humans have successfully used high fat diets with adequate pancreatic enzymereplacement therapy (PERT) with good results. A randomised, double-blind, placebo-controlled trial showed that lipase-deficient chronic pancreatitis patients do not require a fatrestricted diet when adequate enzyme therapy is prescribed.8 In this study, patientsconsumed at least 100 g of dietary fat per day. Another randomised, placebo-controlled trial

evaluated the effects of PERT in combination with dietary counselling in patients withunresectable pancreatic cancer.9 Patients were encouraged to consume as much fat as theycould tolerate, and to divide energy intake across 6 eating occasions. Patients receivingenzyme therapy consumed 8.42 MJ per day compared with 6.66 MJ per day in placebopatients.

Today, fat restriction is no longer recommended in the dietary management of patients withPEI. Once dietary fat intake is established, the dietician can counsel patients to consume atleast a normal fat intake (e.g. 30% energy from fat). A higher fat intake may berecommended for some patients such as those having difficulty gaining or maintainingweight. Adequate fat intake will increase total energy intake and fat-soluble vitamin intake.

PERT should be taken with all meals since they are likely, and should be encouraged, tocontain at least some fat content. However, enzymes do not need to be taken with fat freesnacks such as fruit, jelly, lollies, juices, cordial etc.

MCTThe use of medium chain triglycerides (MCT) in the dietary management of PEI patients hasbeen controversial. MCTs have two important features that can theoretically make themuseful for managing PEI. First, they do not require pancreatic enzymes or bile forabsorption. Second, they do not stimulate pancreatic exocrine secretion. Few humanstudies have evaluated the therapeutic efficacy of MCTs in clinical practice.

A cross-over study evaluated the absorption of MCTs with and without PERT in 6 patients

with severe PEI due to chronic pancreatitis.10 The patients consumed a low-fat diet to whichbutter or MCT oil was added, with and without PERT. Each diet was consumed for a periodof 5 days. In the absence of PERT, steatorrhoea was substantial with both diets, althoughless with MCT oil compared with butter. However in the presence of PERT, steatorrhoeawas the same with both diets. These results are supported by other studies showing PERTimproved the absorption of MCTs in children with cystic fibrosis and in a patient on anelemental diet after total pancreatectomy.11,12

MCTs do not provide any clear nutritional advantage over the usual long-chain triglycerideswhen PERT is used to manage PEI. They are poorly tolerated in many patients and caninduce side effects such as abdominal pain, nausea and diarrhoea. In addition, MCT oil isheat sensitive, and therefore cannot be used for frying, baking or roasting. They are bestused when added to salads, or used as a spread or as an addition to foods already cooked.


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Tips for increasing energy intake

• Use full fat dairy products rather than reduced fat products

• Use spreadable fats (eg. butter, margarine, peanut butter, cream cheese, mayonnaise)wherever possible on crackers, on vegetables, in mashed potato, in sandwiches. Mono orpolyunsaturated fats are preferred due to cardiovascular benefits over saturated fats

• Fry meat, chicken, fish and vegetables in plenty of mono or polyunsaturated oil or margarine

• Enjoy high fat snacks such as nuts, seeds, cheese & crackers, dips, chips, cake and biscuits

• Have high fat desserts after meals (eg. cheesecake, puddings, ice cream, custard)

• Make sure main meals include a generous portion of protein (eg. meat, fish, chicken, eggs,tofu/vegetable protein)

•

Enjoy nutritious low fat foods (fruit, dried fruit, vegetables, bread) but try to consume withadditional fats such as margarine, nuts, cream or butter

• Make up fortified milk (add skim milk powder to fresh milk) to increase protein and energy,and use on cereal, in tea and coffee, to make custards and desserts, etc

• Use commercially available supplements if still struggling to gain weight

Recommendations for the dietary management of PEI Recommendations Level ofevidence

Patients with PEI should be referred to a dietician for nutrition counselling 5

Patients with PEI should abstain from alcohol 3a

Patients should be counselled to consume at least a normal fat intake (e.g. atleast 30% energy from fat)

5

Patients should be encouraged to consume smaller and more frequent meals 5

Oral PERT should be taken with or immediately after meals 2b

Medium chain triglycerides can be trialed in patients who fail to gain or tomaintain adequate body weight in order to increase energy intake

5

Fat-soluble vitamins should be measured at the time of diagnosis, andannually thereafter, and supplemented as required

5


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References

1. Smith RC et al. Int J Pancreatol 1991; 8: 253-62.

2. Cystic Fibrosis Australia, Cystic fibrosis in Australia and New Zealand 2002: AnnualReport from the Australasian Cystic Fibrosis Data Registry. 2004, Cystic Fibrosis

Australia: Sydney.

3. Van Hoozen CM et al. Pancreas 1997; 14: 174-80.

4. Domínguez-Muñoz JE. Curr Gastroenterol Rep 2007; 9: 116-22.

5. Holtmann G et al. Am J Physiol 1997; 273: G553-58.

6. Thiruvengadam R and DiMagno EP. Am J Physiol 2988; 255: G476-81.

7. Suzuki A et al. Gastroenterology 1999; 116: 431-37.

8. Safdi M et al. Pancreas 2006; 33: 156-62.

9. Bruno MJ et al. Gut 1998; 42: 92-96.

10. Caliari S et al. Scand J Gastroenterol 1996; 31(1): 90-94.

11. Durie PR et al. J Pediatr 1980; 96: 862-64.

12. Caliari S et al. Scand J Gastroenterol 1993; 28: 749-52.

13. Begley CG and Roberts-Thomson IC. Dig Dis Sci 1985; 30(12): 1117-20.

14. Garcia-Puges AM et al. Gastroenterology 1986: 91(1): 17-24.

15. Gullo L et al. Gastroenterology 1988; 95(4): 1063-68.

16. Nagata A et al. Digestion 1986; 33(3): 135-45.

17. Domínguez-Muñoz JE et al. Aliment Pharmacol Ther 2005; 21: 993-1000.


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Chapter 5

Pancreatitis: Acute pancreatitis in adults

Introduction Acute pancreatitis is a common inflammatory disease of the pancreas triggered by theunregulated activation of trypsin within pancreatic acinar cells. Many aetiologies for acutepancreatitis exist, the most common being gallstones and alcohol abuse.1 In approximately10% of cases, no cause is identifiable.2-7

The incidence in Australia has not yet been reported, but overseas estimates range from 5.4to 79.8 per 100,000 adults.1 Most episodes of acute pancreatitis are mild and withoutcomplications. Approximately 15-20% of patients develop severe disease with local and/orsystemic complications. Overall, the mortality in acute pancreatitis is approximately 5%, butis higher in severe cases involving pancreatic necrosis, especially if infected, andmultisystem organ failure.8

Pancreatic exocrine functionThe impact of an episode of acute pancreatitis on pancreatic exocrine function is a subjectof debate. The data are difficult to interpret with studies involving patients with acutepancreatitis of varying severity and underlying aetiology. Furthermore, the studies employeddifferent techniques to test for pancreatic exocrine function and measurements wereundertaken at different stages of recovery.

When taken together, the data support the fact that some patients have pancreatic exocrinedysfunction for a period of time after acute pancreatitis. Pancreatic exocrine insufficiency

occurs more frequently in patients with alcohol as the aetiological factor, and in thoserecovering from severe episodes versus mild episodes, and in those who developednecrosis or pseudocyst.9,10

Early phaseLimited data are available on exocrine pancreatic function in the early phase of acutepancreatitis. The interdigestive pancreatic secretion was studied by a duodenal intubationperfusion technique in eight patients with acute pancreatitis within 72 hours of symptomonset.11 The results showed that exocrine pancreatic secretion in the early phase of mild-to-moderate acute pancreatitis remained within the normal range.

In a more recent study of 75 patients with their first episode of acute pancreatitis, faecal

elastase-1 was determined on the day of refeeding, which was on average 11.2 days afterthe attack.12 Abnormal faecal elastase values were found in 9 out of the 75 patients. Theresults were not significantly related to severity.

Convalescent phaseImpaired exocrine pancreatic function has been noted in the convalescent period after acutepancreatitis. Exocrine pancreatic function was analysed in 53 patients who had recoveredfrom their first attack of necrotising pancreatitis.13 After 4 weeks, 74% had mild-to-moderateinsufficiency, while 26% suffered from severe impairment. After 12 to 18 months, 80-85%had pancreatic insufficiency, with severe insufficiency measured in 5-10%.


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In a study of 30 patients with acute pancreatitis, pancreatic function was abnormal in allpatients at various time intervals in the convalescent period.14 Two to 6 months after theattack, 4 out of 6 patients still had abnormal results. Results were improved or normal in 12of 15 patients who were retested after 1 year.

A recent study of 54 patients with alcoholic acute pancreatitis found that exocrinedysfunction was present in 39% of patients early after their first episode.15 After 2 years,only 9% still had pancreatic exocrine dysfunction.

In another study, 18 patients surviving at least 1 month after necrosectomy for acutenecrotising pancreatitis were followed up.16 At the time of discharge from hospital, 13patients had pancreatic exocrine insufficiency. After 6 weeks, 9 of these patients still hadexocrine insufficiency that continued for 6 months. By 18 months, 7 of these 9 patients hadresolution of symptoms, but steatorrhoea persisted in 2 patients.

The pancreatic exocrine function of 75 patients who had a single attack of acute pancreatitiswas studied.10 Among the 36 patients with alcoholic pancreatitis, 29 had impaired

pancreatic function between 4 and 18 months after the episode. Of the 39 patients withbiliary pancreatitis, only 9 had pancreatic insufficiency. When the tests were repeated 1 yearlater 18 out of 23 patients with alcoholic pancreatitis continued to have pancreaticinsufficiency, whereas only 4 out of 26 patients with biliary pancreatitis showed insufficiency.

A prospective cohort study in 39 patients with severe acute biliary pancreatitis evaluated theinfluence of necrosectomy on pancreatic exocrine function after 12 months.17 Most of thepatients with necrosectomy had an abnormal exocrine pancreatic function, withsteatorrhoea in 25%. By comparison, exocrine function was abnormal in only 13.3% ofpatients without surgery, with no cases of steatorrhoea.

Another prospective study assessed pancreatic exocrine function in 23 patients recovering

from a first attack of acute pancreatitis and evaluated its relationship to severity of attackand extent of pancreatic necrosis.9 Pancreatic exocrine insufficiency occurred in 6 out of 7patients recovering from severe attacks compared with 2 out of 16 patients recovering frommild attacks. All 5 patients who developed pancreatic necrosis or pseudocyst developedpancreatic exocrine insufficiency whereas only 3 out of 18 patients who did not developnecrosis or pseudocyst had exocrine insufficiency. The development of pancreatic exocrineinsufficiency was strongly correlated with the extent of pancreatic necrosis.

In contrast to the above studies, a study of 63 patients with acute biliary pancreatitis foundno deficiency in pancreatic exocrine function at 1, 6 or 12 months after the episode.18

Long-term follow up

Pancreatic exocrine function gradually improves following an episode of acute pancreatitis.The length of time for the recovery appears to depend on the severity of the episode, withthe more severe cases having the longest recovery phase.

The late outcome of acute alcoholic pancreatitis was studied in 47 patients with moderateclinical course.19 Pancreatic exocrine function was impaired in nearly two-thirds of patients 4to 7 years after the acute episode. Similar results were observed in 34 patients who hadrecovered from biliary or post-ERCP acute pancreatitis after an average of 4.6 years follow-up.20 In a retrospective study, 35 patients with severe acute pancreatitis were followed upfor a median time of 7 years.21 Nine patients had signs of severe exocrine dysfunction. Inanother study of 30 patients who had completed at least 6 months of recovery, 12 hadabnormal faecal fat excretion.22 There was a higher frequency of pancreatic exocrineinsufficiency in the first year after recovery, and incidence decreased as duration of follow-up increased.


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A long-term follow up of 27 patients treated with conservative surgery of necrohaemorrhagicpancreatitis showed that an almost complete recovery of the exocrine function is achievedwithin 4 years.23 Similar results were reported in 28 patients with infected pancreaticnecrosis treated with necrosectomy.24 During a follow up 2 to 8 years after discharge,median stool elastase-1 concentrations were in the normal range.

In contrast, a study of 63 patients who underwent pancreatic necrosectomy found that one-quarter developed exocrine insufficiency during a median follow up of 28.9 months.25 Similarly, a long-term study evaluating the outcomes after operative treatment of necrotisingpancreatitis found that one-quarter developed clinical pancreatic exocrine insufficiencyduring the mean follow up of 5 years.26 Normal pancreatic function was associated with 27%parynchymal necrosis suggesting that pancreatic insufficiency varies with the extent ofnecrosis.

Another study found that 2 of 21 patients who underwent necrosectomy for severenecrotising pancreatitis developed pancreatic exocrine insufficiency as a late complication.27

A follow-up study of nine patients with infected pancreatic necrosis treated with catheterdrainage and necrosectomy evaluated pancreatic exocrine function after 30 months.28 Mild-to-moderate exocrine dysfunction was found in 5 patients, severe restriction of exocrinepancreatic function in 2 patients and normal function in 1 patient.

Pancreatic enzyme replacement therapyThere has only been one clinical trial investigating pancreatic enzyme supplementation inacute pancreatitis.29 The study was a double-blind, prospectively randomised, placebo-controlled trial including 23 patients with proven acute pancreatitis. Patients were given 3capsules 4 times per day, providing a daily total of 7,800 units of protease, 96,000 units oflipase, and 108,000 units of amylase. The patients took the enzymes for a minimum of 5

days. Those predicted to have a severe attack or those who developed complicationsreceived enzymes for 10 days. There were no significant differences in pain scores,analgesic requirements, length of hospital stay or incidence of complications compared withplacebo. Based on these results, there is no evidence to support the use of pancreaticenzyme supplements in the initial stages of acute pancreatitis.

However, pancreatic exocrine function seems to be impaired at least during the first 6 to 18months after acute pancreatitis, if not longer in the more severe cases. Most studiesreported dysfunction based on biochemical analysis, so the incidence of clinically-relevantinsufficiency is not clear. Therefore, it is recommended that all patients recovering fromacute pancreatitis should be monitored for pancreatic exocrine insufficiency. Those whohave suffered from an acute necrotising attack should be given potent oral pancreatic

enzymes and then an evaluation be made later in the recovery period whether or not thepatient has pancreatic steatorrhoea.


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Conclusion Acute pancreatitis is an inflammatory disease associated with significant morbidity andmortality. While there is no evidence to support the use of pancreatic enzyme replacementtherapy during the initial stages of acute pancreatitis, the data do support the fact that somepatients have pancreatic exocrine dysfunction for a period of time after acute pancreatitis.Therefore patients should be monitored for pancreatic exocrine insufficiency for at least 6 to18 months and treated with oral pancreatic enzymes as indicated. Since the length of timefor the recovery of exocrine function appears to depend on the severity of the episode, itmay be prudent to supplement those recovering from an acute necrotising attack with oralpancreatic enzymes and then evaluate exocrine function later in the recovery period.

Recommendations for pancreatic enzyme replacement therapy in acute pancreatitis

Recommendations Level ofevidence

There is no evidence to support the use of pancreatic enzyme replacementtherapy in the initial stages of acute pancreatitis

1b

Patients recovering from an episode of acute pancreatitis should bemonitored for pancreatic exocrine insufficiency for at least 6 to 18 months

2b

Patients recovering from an acute necrotising attack should besupplemented with oral pancreatic enzymes and then their exocrinefunction evaluated later in the recovery period

5

References

1. Lankisch PG. Epidemiology of acute pancreatitis. In: Buchler MW, Uhl W, Friess H,

Malfertheiner P, eds. Acute Pancreatitis: Novel Concepts in Biology and Therapy .London: Blackwell Science Ltd, 1999; 145-53.

2. Lankisch PG et al. Int J Pancreatol 1997; 22: 235-36.

3. Maes B et al. Eur J Gastroenterol Hepatol 1999; 11: 891-96.

4. Bank S and Indaram A. Gastroenterol Clin North Am 1999; 28: 571-89.

5. Halvorsen FA and Ritland S. Scand J Gastroenterol 1996; 31: 411-14.

6. Grendell JH. Gastroenterol Clin North Am 1990; 19: 843-48.

7. Tarnasky PR and Hawes RH. Gastrointest Endosc Clin North Am 1998; 8: 13-37.

8. Banks PA et al. Am J Gastroenterol 2006; 101: 2379-400.

9. Boreham B and Ammori BJ. Pancreatology 2003; 3: 303-08.

10. Migliori M et al. Pancreas 2004; 28: 359-63.

11. Dominguez-Munoz JE et al. Scand J Gastroenterol 1995; 30(2): 186-91.

12. Pezzilli R et al. Hepatobiliary Pancreat Dis Int 2009; 8: 316-19.

13. Bozhurt T et al. Hepatogastroenterology 1995; 42: 55-58.

14. Mitchell CJ et al. Scand J Gastroenterol 1983; 18: 5-8.


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15. Pelli H et al. Pancreatology 2009; 9: 245-51.

16. Bavare C et al. Indian J Gastroenterol 2004; 23: 203-05.

17. Sabater L et al. Pancreas 2004; 28: 65-68.

18. Pareja E et al. Pancreatology 2002; 2: 478-83.

19. Malecka-Panas E et al. Mater Med Pol 1996; 28: 64-68.

20. Symersky T et al. JOP 2006; 7: 447-53.

21. Appelros S et al. Eur J Surg 2001; 167: 281-86.

22. Gupta R et al. J Gastrointest Surg 2009; 13: 1328-36.

23. Angelini G et al. Digestion 1984; 30: 131-37.

24. Reszetow J et al. Pancreas 2007; 35: 267-72.

25. Connor S et al. Surgery 2005; 137: 499-505.

26. Tsiotos GG et al. Br J Surg 1998; 85: 1650-53.

27. Tzovaras G et al. Dig Surg 2004; 21(1): 41-46.

28. Endlicher E et al. Hepatogastroenterology 2003; 50: 2225-28.

29. Patankar RV et al. HPB Surgery 1995; 8: 159-62.


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Chapter 6

Pancreatitis: Chronic pancreatitis in adults

Introduction

Chronic pancreatitis is the persistent damage of pancreatic tissue and function due tovarious aetiologies. It is characterised by progressive and irreversible damage to both theexocrine and endocrine components of the pancreas.1 Its reported incidence inindustrialised countries ranges from 3.5 to 10 per 100,000 people.2, 3

Aetiology Alcohol is considered the primary cause of chronic pancreatitis, and accounts for 60-70% ofall cases.2, 4 However, its aetiology varies with geographical location. There is a body ofevidence suggesting that alcoholic pancreatitis may begin as acute pancreatitis, withrecurrent episodes of acute necroinflammation leading to irreversible loss of pancreaticstructure and function (the “necrosis-fibrosis hypothesis”).2

Other aetiological factors may include hyperlipidaemia, hereditary factors, autoimmunedisease, congenital pancreatic anomalies (eg. pancreatic divisum, cystic fibrosis) andhyperparathyroidism.1-3, 5 In about 10-30% of chronic pancreatitis, no identifiable cause canbe found and a diagnosis of idiopathic chronic pancreatitis is made.3, 4 However, recentresearch indicates that a significant percentage of these patients may have an identifiablecause for their condition.

PathologyPancreatic fibrosis, acinar atrophy, chronic inflammation, distorted and blocked pancreaticducts are key pathological features of chronic pancreatitis.3 Histological changes fromnormal pancreatic architecture include irregular fibrosis, acinar cell loss, islet cell loss andinflammatory cell infiltrates.6

At the early stage, there are scattered foci of fat necrosis, lobular and periductal fibrosis,protein plugs within side branches of the main pancreatic duct and formation of calculi. Inthe advanced stage, stricturing and dilatation of pancreatic ducts may occur. In the latestage, the pancreatic endocrine tissue is involved, leading to loss of endocrine cells.5

Symptoms

This progressive loss of pancreatic parenchyma eventually leads to impairment of exocrineand endocrine functions, and subsequent malabsorption.4 The three key clinical features ofchronic pancreatitis are pain, maldigestion and diabetes.3

Abdominal pain is usually, but not always, the initial manifestation of chronic pancreatitis.Typically, the pain is epigastric or periumbilical in location and may radiate to the back andinto the chest or flanks. Although recurrent or continuous pain is considered an importantsymptom of chronic pancreatitis, a subgroup of patients may have no pain at all, presentinginstead with symptoms of pancreatic insufficiency.

Maldigestion is a relatively late manifestation of chronic pancreatitis. It does not becomeclinically evident until digestive enzyme output is reduced to less than 10% of normal

secretion.7

In general, maldigestion of fat occurs earlier than that of carbohydrate or proteinsbecause secretion of lipase decreases more rapidly than that of amylase or proteases.8 As


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such, steatorrhoea is the predominant manifestation of maldigestion, with overt casesoccurring in about 30% of patients with chronic pancreatitis.9 Marked steatorrhoea may beassociated with weight loss.

DiagnosisThe diagnosis of chronic pancreatitis relies on relevant symptoms, imaging of pancreaticstructure and assessment of pancreatic function. In general, advanced stages of chronicpancreatitis may be easily diagnosed by imaging procedures whereas diagnosis of earlydisease presents a considerable challenge. Histology could be considered the goldstandard for pathological diagnosis of chronic pancreatitis, but it is difficult to justify biopsiesto obtain pancreatic tissue in clinical practice. The next best diagnostic methods todemonstrate changes consistent with chronic pancreatitis are endoscopic ultrasound (EUS)or magnetic resonance cholangiopancreatography (MRCP). The advantage of endoscopicultrasound is that tissue can be obtained for histological evaluation; however, it is aninvasive procedure and the results are highly operator dependent. Computed axialtomography (CT) scan or endoscopic retrograde cholangiopancreatography (ERCP) can

also be used.

The biochemical, structural and functional parameters used to assist in the diagnosis ofchronic pancreatitis are outlined in Table 1.


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Table 1: Patient assessment for chronic pancreatitis

Parameter Interpretation

Surgical biopsy The diagnostic gold standard of early stage disease, but rarelyavailable

Serum levels of lipase oramylase

Used to identify an acute episode of the disease in patients withpainLevels may be low in pancreatic insufficiency and may not beraised with acute flares of the diseaseCannot be used in isolation to diagnose chronic pancreatitis dueto low sensitivity

Analysis of fat in stools Used for the diagnosis of steatorrhoea Alleviation of steatorrhoea with pancreatic enzymes wouldsuggest a pancreatic causeMost useful parameter for determining the efficacy of treatmentof maldigestion

Abdominal x-ray Calcification on abdominal x-ray and associated steatorrhoeawould make chronic pancreatitis likely

Transabdominal ultrasound First procedure usually performed in patients with suspectedchronic pancreatitisOperator dependentMore sensitive than abdominal x-ray for calcificationClarity of images often confounded by bowel gas

Abdominal CT Widely usedUseful for outlining pancreatic and surrounding anatomySensitive in the detection of pancreatic calcificationCan detect ductular abnormalities although ERCP and MRCPare more sensitiveUseful for detecting/excluding pancreatic neoplasms and cysticlesions

Magnetic resonancecholangiopancreaticography(MRCP)

May eventually supersede ERCP as a noninvasive alternativeUseful in patients at high risk of developing post-ERCPpancreatitis or where the pancreatic duct is inaccessible as aresult of surgeryCan outline ductal and parenchymal changesCan be combined with secretagogues to provide structural aswell as functional data

Endoscopic ultrasonography(EUS)

Possibly most sensitive procedure to detect chronic pancreatitisalthough analysis of accuracy is ongoingUnclear diagnostic role in early stage disease

Endoscopic retrogradecholangiopancreatography(ERCP)

Used for identification of ductular structural abnormalitiesMost common imaging modality for planning intervention(endoscopic or surgical)

All patients with painful established chronic pancreatitis should undergo an uppergastrointestinal endoscopy, abdominal CT scan and ERCP/MRCP in order to detect apotentially reversible cause of pain, such as peptic ulcer, pseudocyst or common bile ductstricture.

Classification Chronic pancreatitis may be separated into 4 different stages based on diseasepresentation (Table 2). It is important to note that patients may not experience every stageof illness.


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Table 2: Classification of chronic pancreatitis3

Stage Symptoms

I A pre-clinical stage with absent or uncharacteristic symptoms

IIRecurrent acute episodes of pancreatitis without definite signs of chronic pancreatitison imaging

IIIFurther recurrent episodes with intermittent or constant pain in between and signs ofchronic pancreatitis on imaging

IVFinal stage mostly without acute flares and absence or decreased frequency of pain,possibly associated with evidence of endocrine and exocrine insufficiency

Associated morbidity and mortalityUp to 70% of patients with calcific pancreatitis develop diabetes.2 Diabetes develops late inthe disease course of chronic pancreatitis and therefore denotes advanced disease.

Chronic pancreatitis patients have an increased incidence of pancreatic cancer. The risk ofdeveloping pancreatic cancer is 16.5-fold higher in chronic pancreatitis patients than age-matched healthy controls.10 Those with hereditary pancreatitis have an even higher risk ofpancreatic cancer. The estimated cumulative risk of pancreatic cancer to age 70 years inpatients with hereditary pancreatitis is as high as 40%.11 There is also a five-fold increase inrelative risk of developing pancreatic cancer in those with tropical pancreatitis.12

Mortality in chronic pancreatitis, particularly alcoholic pancreatitis, is reported to beapproximately 30% higher than that in the age- and sex-matched general population.13 One-fifth of this excess mortality can be directly attributed to pancreatitis itself. The majority aresecondary to the effects of alcohol and/or smoking on the liver, the respiratory and thedigestive systems.

Pancreatic exocrine insufficiencyPancreatic exocrine insufficiency (PEI) due to chronic pancreatitis is a consequence ofvarious factors which regulate digestion and absorption of nutrients.14 Although pancreaticfunction has been extensively studied, some aspects of secretion and gastrointestinal

adaptation are not well understood. However, it is known that a progressive loss ofpancreatic acinar cell function in chronic pancreatitis does lead to deficiencies in thesecretion of digestive enzymes from the pancreas. This results in maldigestion of nutrients.

PEI after disease onset depends on the type of pancreatitis.3 PEI develops earlier inalcoholic, tropical and late-onset idiopathic pancreatitis than early-onset idiopathicpancreatitis. Those with alcoholic pancreatitis generally develop PEI within 5-6 years ofdisease onset. Pancreatic exocrine and endocrine insufficiency is usually present at thetime of presentation in 70% of patients with tropical pancreatitis.

The main clinical manifestations of PEI are fat malabsorption (commonly manifesting assteatorrhea), weight loss, abdominal discomfort and distention.


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Overt steatorrhoea occurs in about one-third of patients with chronic pancreatitis.9 Fatmalabsorption also results in a deficit of fat-soluble vitamins (A, D, E and K) withconsequent clinical manifestations.

Evidence clearly shows that malabsorption does occur in patients with chronic pancreatitis.Further, natural history studies indicate that the clinical diagnoses of steatorrhoea andexocrine insufficiency are usually not evident until relatively late in the course of thedisease.15 Untreated malabsorption is related to many long-term harmful effects includingweight loss,4 malnutrition and osteoporosis.15 This suggests that malabsorption, even if it isnot yet clinically evident, merits therapy.

Management of PEI in chronic pancreatitisThe general principles for the management of chronic pancreatitis are mainly to controlsymptoms, improve nutrition and treat complications.5 These principles should be kept in mindwhen managing associated PEI.

Pancreatic enzyme replacement therapy (PERT)The cornerstone of therapy for PEI is replacement of pancreatic enzymes to allow forefficient digestion and nutrient absorption. PERT has been shown to improve fat absorption,but steatorrhoea may persist.16-18 It is important to note that the efficacy of PERT may beinfluenced by a number of factors including type of preparation, enzyme concentration,dosage schedule and the use of adjuvant therapy to improve bioavailability of enzymes.

A small study with 29 chronic pancreatitis patients was conducted using enteric-coated,gastric acid resistant minimicrospheres.16 All patients were on a fat-balanced diet across thethree study phases:•

Phase 1: 7-day baseline to assess malabsorption• Phase 2: 7-day run-in on PERT• Phase 3: 14-day randomised parallel-group treatment phase of PERT vs placebo

This study showed no statistically significant differences in most PEI symptoms betweentreatment arms, but a trend towards improvement in stool frequency and consistency wasobserved in PERT-treated patients.16

In a multicentre, randomised, placebo-controlled trial involving 27 patients with chronicpancreatitis, PERT-treated patients had significantly less steatorrhoea and had animprovement in stool consistency. Patients on PERT also had a decrease in stoolfrequency.17

PERT in painful chronic pancreatitisThe exogenous replacement of pancreatic proteases for pain is based on the concept offeedback inhibition of pancreatic exocrine secretion.19 As patients with chronic pancreatitishave decreased protease activity, perpetual pancreatic stimulation may occur.

It has been proposed that PERT can also stimulate receptors in the proximal small intestineand trigger a negative feedback loop which suppresses baseline pancreatic secretion,decreasing ductal pressures and therefore decreasing pain.20, 21 Nevertheless, there areother pathophysiological mechanisms for pain including perineural inflammation and

fibrosis, uninhibited cholinergic stimulation of pancreas secretion and colonic hypermotility.


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Of these, only colonic hypermotility due to steatorrhoea and malabsorption would potentiallyrespond to PERT.22

A meta-analysis in 1997 analysed the available studies and concluded that there was nosignificant benefit of pancreatic enzymes for pain relief in painful chronic pancreatitis.23 Since then, a prospective, multicentre, follow-up study of patients with chronic pancreatitiswas conducted to assess quality of life before and after PERT.24 PERT therapy reduced theextent of steatorrhoea and pain and was associated with a significant improvement inquality of life.

Therefore, the role of PERT in reducing pain in chronic pancreatitis remains unclear. 25 The American Gastroenterological Association recommends a trial of high-dose pancreaticenzymes coupled with acid suppression therapy before proceeding with continuous use ofnarcotics or invasive treatment.26

Dosage and administration

The relationship between the dose of pancreatic enzymes required and symptoms ofmaldigestion is not linear. For efficient digestion, it is essential that the concentration ofenzymes delivered exogenously to the gut represents at least 5% of normal digestiveenzyme output.1 In general, the dose of lipase required with each meal is of the order of25,000 to 50,000 units.27 Dosing should be with, or immediately following each meal.28

In case of an inadequate response to therapy, compliance should be checked bymeasurement of faecal chymotrypsin, although this is not a standardised procedure.29 In thecompliant patient, doses may be doubled or tripled.

Unprotected digestive enzymes are rapidly destroyed by gastric acid. Acid degradation is a

major factor influencing the bioavailability of PERT.

30

Several commercial pancreaticenzyme preparations are available as enteric-coated tablets, capsules or microspheres. Theuse of concurrent acid suppression therapy may be a useful adjunct therapy and isrecommended, especially if severe steatorrhoea continues with adequate dosing ofpancreatic enzyme.31

The use of high-strength preparations can reduce pill burden. High doses of PERT havebeen associated with the development of fibrosing colonopathy and colonic strictures inpatients with cystic fibrosis.32-34 There is evidence to suggest that these adverse effectswere due to the presence of the methacrylic acid copolymer in the enteric coating ratherthan the dose of lipase.35

If compliant patients remain unresponsive to therapy, the diagnosis of PEI needs to bereviewed. Coeliac disease, (concomitant) bacterial overgrowth, and blind loop syndrome, aswell as giardiasis, need to be excluded or otherwise be treated specifically.29

A treatment algorithm for PERT in patients with PEI associated with chronic pancreatitis isproposed in Figure 1.


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Figure 1: Recommendations for pancreatic enzyme therapy in patients withpancreatic exocrine insufficiency due to chronic pancreatitis

Adapted from Domínguez-Muñoz. 2007.30


[25,000–50,000 USP U of lipase/meal]

Inadequate response

Check compliance (faecal chymotrypsin) Increaseenzyme dose (2 to 3 times)

Adequate response

Inadequate response Adequate response

Additional gastric suppression

Inadequate response Adequate response

Check diagnosisBacterial overgrowth, giardiasis, coeliac disease?

Trial low-fat diet or

substitute dietary fatfor medium-chaintriglycerides

Specific therapy

NOYES


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SummaryOne of the most common causes of PEI is chronic pancreatitis. Alcohol is considered theprimary cause. The progressive loss of pancreatic parenchyma leads to impaired exocrinefunction. Malabsorption occurs in the majority of patients with chronic pancreatitis. However,the clinical diagnoses of steatorrhoea and exocrine insufficiency are usually not evident untilrelatively late in the course of the disease. Therefore, early treatment of PEI is warranted.

The efficacy of PERT may be influenced by a number of factors including type ofpreparation, enzyme concentration, dosage schedule and the use of adjuvant therapy toimprove bioavailability of enzymes. For the treatment of PEI, 25,000 to 50,000 units oflipase are required with each meal. PERT should be taken with or immediately followingmeals.

In cases of an inadequate response to therapy, doses may be increased two- to three-fold.If severe steatorrhoea continues with adequate dosing of pancreatic enzyme, adjunctiveacid suppression therapy is recommended. If patients remain unresponsive to therapy,other possible causes (e.g. bacterial overgrowth) should be considered.

General dietary and nutritional considerations for patients with PEI due to other causes canbe applicable to patients with chronic pancreatitis. Abstinence from alcohol cannot beoveremphasised for patients with chronic pancreatitis.

Dietary counselling, coupled with PERT, in patients with chronic pancreatitis not onlyreduced the extent of steatorrhea and pain, but also significantly improved patients’ qualityof life.

Recommendations for pancreatic enzyme replacement therapy in chronicpancreatitis


PEI occurs in almost all patients with chronic pancreatitis, even thoughPEI symptoms often do not manifest until the later stages of the disease.

3a

PERT for chronic pancreatitis patients can improve the symptoms of PEI. 3a

PERT for chronic pancreatitis patients can improve quality of life. 4

Generally, the required amount of lipase with each meal 25,000 to 50,000units.

5

For severe, persisting steatorrhoea, consider the use of adjunct acidsuppressant therapy.

4/5

Patients with chronic pancreatitis should abstain from alcohol. 3a


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References

1. DiMagno EP et al. Chronic pancreatitis. In: Go VLW, DiMagno EP, Gardner JD,Lebenthal L, Reber HA and Scheele GA, [Editors]. The pancreas: biology, pathobiologyand disease. New York: Plenum Press, 1993: 665–706.

2. Tandon RK et al. J Gastroenterol Hepatol 2002; 17(4): 508-18.

3. Witt H et al. Gastroenterology 2007; 132(4): 1557-73.

4. Dumasy V et al. Am J Gastroenterol 2004; 99(7): 1350-54.

5. Pancreas Study Group (Chinese Society of Gastroenterology). Chin J Dig Dis 2005;6(4): 198-201.

6. Etemad B and Whitcomb DC. Gastroenterology 2001; 120(3): 682-707.

7. DiMagno EP et al. N Engl J Med 1973; 288(16): 813-15.

8. DiMagno EP et al. Ann N Y Acad Sci 1975; 252(200-07.

9. Lankisch PG et al. Lancet 1996; 347(9015): 1620-21.

10. Lowenfels AB et al. N Engl J Med 1993; 328(20): 1433-37.

11. Lowenfels AB et al. J Natl Cancer Inst 1997; 89(6): 442-46.

12. Chari ST et al. Pancreas 1994; 9(1): 62-66.

13. Levy P et al. Gastroenterology 1989; 96(4): 1165-72.

14. Pezzilli R. World J Gastroenterol 2009; 15(14): 1673-76.

15. Forsmark CE. Am J Gastroenterol 2004; 99(7): 1355-57.

16. O'Keefe SJ et al. J Clin Gastroenterol 2001; 32(4): 319-23.

17. Safdi M et al. Pancreas 2006; 33(2): 156-62.

18. Stern RC et al. Am J Gastroenterol 2000; 95(8): 1932-38.

19. Gupta V and Toskes PP. Postgrad Med J 2005; 81(958): 491-97.

20. Slaff J et al. Gastroenterology 1984; 87(1): 44-52.

21. Ihse I et al. Scand J Gastroenterol 1979; 14(7): 873-80.

22. Winstead NS and Wilcox CM. Pancreatology 2009; 9(4): 344-50.

23. Brown A et al. Am J Gastroenterol 1997; 92(11); 2032-35.

24. Czako L et al. Can J Gastroenterol 2003; 17(10): 597-603.

25. AGA Technical Review: treatment of pain in chronic pancreatitis. Gastroenterology1998; 115(3): 765-76.

26. American Gastroenterological Association Medical Position Statement: tratment of painin chronic pancreatitis. Gastroenterology 1998; 115(3): 763-64.

27. Ferrone M et al. Pharmacotherapy 2007; 27(6): 910-20.

28. Dominguez-Munoz JE et al. Aliment Pharmacol Ther 2005; 21(8): 993-1000.


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29. Keller J and Layer P. Curr Treat Options Gastroenterol 2003; 6(5): 369-74.

30. Dominguez-Munoz JE. Curr Gastroenterol Rep 2007; 9(2): 116-22.

31. Marotta F et al. Dig Dis Sci 1989; 34(3): 456-61.

32. Smyth RL et al. Lancet 1994; 343(8889): 85-86.

33. Stevens JC et al. J Pediatr Gastroenterol Nutr 1998; 26(1): 80-84.

34. Pawel BR et al. Hum Pathol 1997; 28(4): 395-99.

35. Prescott P and Bakowski MT. Pharmacoepidemiol Drug Saf 1999; 8(6): 377-84.


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Chapter 7

Pancreatitis: Childhood pancreatitis

Introduction Acute and chronic pancreatitis in childhood causes occasional death and significantmorbidity globally.1

The incidence of acute pancreatitis in children and adolescence has increased over the past10 to 15 years,2-6 although it is still less than in adults.7 In contrast with adults, in whomalcohol or gall stones are the usual causes of acute pancreatitis, the aetiology in children isdiverse (Table 1).1 Most cases of acute pancreatitis in children have a mild course, andsymptoms settle if food and drink are withheld for 3 to 5 days.1

Approximately 13-20% of cases of acute pancreatitis in children have a prolonged course

with persistent symptoms or associated complications.8-10 A protracted course is morecommon in children with systemic disease as the underlying cause of the pancreatitis.

Up to 10% of children have recurrent episodes of acute pancreatitis. Recurrence is morecommon in children with idiopathic, structural or familial causes.8,11,12

Chronic pancreatitisChronic pancreatitis is an inflammatory disorder that results in anatomical changes thatinclude chronic inflammatory cell infiltration and gland fibrosis, with loss of exocrine andendocrine function.1 The more common childhood causes are outlined in Table 2.

Chronic pancreatitis can occur as a result of repeated episodes of acute pancreatitis orfollowing a sentinel acute pancreatitis event of sufficient severity.1 Diagnosis is based on acombination of clinical features and functional and imaging studies.1 In addition toabdominal pain, patients may present with steatorrhoea and weight loss resulting fromdiminished pancreatic exocrine function. Diabetes mellitus may also occur as insulin andglucagon producing cells are destroyed in chronic pancreatitis. Paediatric data on theprevalence and incidence of exocrine and endocrine failure are limited. In adults, exocrineinsufficiency ultimately occurs in 50-80% of patients and diabetes in 40-70% of patients.13,14

Patients with chronic pancreatitis require long-term follow up with emphasis on monitoringfor pancreatic exocrine insufficiency and diabetes mellitus.1


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Table 1. Aetiology of acute pancreatitis in children1

Acute pancreatitis

Drugs Salicylates

Paracetamol

Cytotoxic drugs (ie. L-asparaginase)

CorticosteroidsImmunosuppresives (particularly azathioprine and 6-MP)

Thiazides

Sodium valproate

Tetracycline (particularly if aged)

Erythromycin

Periampullary obstruction Gallstones

Choledochal cysts

Pancreatic duct obstruction

Congenital anomalies of pancreas (especially pancreas divisum)

Enteric duplication cysts

Epstein-Barr virus

MumpsMeasles

Cytomegalovirus

Influenza A

Mycoplasma

Leptospirosis

Malaria

Rubella

Ascariasis

Cryptosporidium

Trauma Blunt injury (handle bar, child abuse, etc)

ERCP

Metabolic α-1 antitrypsin deficiency

Hyperlipidaemia

Hypercalcemia

Toxin Scorpion, Gila monster, tropical marine snakes

Miscellaneous Refeeding pancreatitis

Inflammatory/systemic Haemolytic-uremic syndrome

diseases Reye’s syndrome

Kawasaki disease

Inflammatory bowel disease

Henoch-Schonlein purpura

SLE

ERCP: endoscopic retrograde cholangiopancreatography, 6-MP: 6-mercaptopurine, SLE: systemic

lupus erythematesus.


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Table 2. Aetiology of chronic pancreatitis in children1

Chronic pancreatitis

Chronic pancreatitis in Cystic fibrosis

childhood Fibrosing pancreatitis

Hereditary chronic pancreatitis

Tropical calcific pancreatitisInborn errors of metabolism (particularly branched chain aminoacidemias)

Idiopathic

Chronic hereditary Hyperlipidaemias

pancreatitis diagnosed Partial lipodystrophy

mainly in adult life Wilson’s disease

Haemochromatosis

α-1 antitrypsin deficiency


There is no evidence to support the use of pancreatic enzyme replacement therapy inchildren with acute pancreatitis.1

In children with chronic pancreatitis, pancreatic enzyme replacement therapy may be usedfor two reasons – to treat pancreatic exocrine insufficiency or to aid pain relief. In theory,supplemental pancreatic enzymes decrease pain by suppressing the feedback mechanismthat regulates cholecystokinin release.1 Cholecystokinin release results in acinar drive andpotentially contributes to inflammation. Nine clinical trials have evaluated the use ofpancreatic enzyme replacement therapy for painful chronic pancreatitis with varyingresults.15-23 Of the six randomised controlled trials, only two studies using non-enteric coatedenzyme preparations reported some reduction in pain.15,17 The other five randomisedcontrolled trials using enteric-coated supplements did not report significant benefit for painreduction.16,18-21 There have been two prospective, observational studies both of whichreported reductions in pain. One used an enteric-coated preparation22 whereas the otherone did not specify the supplement used.23 The variable results with the differentpreparations may be explained by the fact that the feedback-sensitive part of the smallbowel is proximally located and that enzymes in enteric-coated preparations are releasedonly distally.1

In children with pancreatic exocrine insufficiency, pancreatic enzyme replacement therapyshould be used to:• Correct macro- and micronutrient maldigestion• Eliminate abdominal symptoms directly attributable to maldigestion•

Establish normal stools and bowel habits• Sustain normal growth and nutritional status24

Guidelines for dosing are based on those used for children with pancreatic exocrineinsufficiency due to cystic fibrosis.24,25 Infants should be given 500 to 1,000 units lipase pergram of dietary fat or 2,000 to 4,000 units lipase per breastfeed or 120 mL of infant formula.In children, 500 to 4,000 units lipase per gram of dietary fat may be given. Alternatively,children under the age of 4 years may be given 1,000 units lipase per kilogram bodyweightper meal, whereas those over 4 years of age may be given 500 units lipase per kilogram permeal. The maximum dose per day should not exceed 10,000 units lipase per kilogram

bodyweight.


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ConclusionsPancreatitis in children often has a different aetiology and natural history than in adults.Most cases of acute pancreatitis in children have a mild course and symptoms resolvewithout incident. In contrast, management of chronic pancreatitis includes aetiologicalinvestigations, adequate pain control and long-term follow up for monitoring and treatingpancreatic exocrine and endocrine insufficiency.

There is no evidence for the use of pancreatic enzyme replacement therapy in the treatmentof acute pancreatitis in children. Supplemental enzymes should be used in patients withchronic pancreatitis and documented pancreatic exocrine insufficiency. In patients withpainful chronic pancreatitis, pancreatic enzyme replacement therapy may be trialled for painrelief even in the absence of documented pancreatic exocrine insufficiency.

Recommendations for pancreatic enzyme replacement therapy in childhoodpancreatitis


There is no evidence to support the use of pancreatic enzymereplacement therapy in acute pancreatitis

5

Pancreatic enzyme replacement therapy may be trialled in children withchronic pancreatitis for pain relief

1b (uncoatedpreparations)

2b (coatedpreparations)

Long-term follow up of children with chronic pancreatitis should includemonitoring for pancreatic exocrine insufficiency

5

Children with chronic pancreatitis and documented pancreatic exocrineinsufficiency should be treated with pancreatic enzyme replacement

therapy

5

Recommended dosesFor infants: 500-1,000 units lipase per gram of dietary fat OR 2,000-4,000 units lipase per breastfeed or 120 mL of infant formula.For children: 500-4,000 units lipase per gram of dietary fat OR 1,000units lipase per kilogram bodyweight per meal (4 years old). Doses could behalved if having a snack instead of a full meal.Maximum dose: 10,000 units per kilogram bodyweight per day

5

References

1. Nydegger A et al. J Gastroenterol Hepatol 2006; 21(3): 499-509.

2. Nydegger A et al. J Gastroenterol Hepatol 2007; 22(8): 1313-16.

3. Lowe ME and Greer JB. Curr Gastroenterol Rep 2008; 10(2): 128-35.

4. Lopez MJ. J Pediatr 2002; 140(5): 622-24.

5. Sánchez-Ramírez CA et al. Acta Paediatr 2007; 96(4): 534-37.

6. Werlin SL et al. J Pediatr Gastroenterol Nutr 2003; 37(5): 591-95.

7. Steinberg W and Tenner S. N Engl J Med 1994; 330(17): 1198-1210.


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8. Benifla M and Weizman Z. J Clin Gastroenterol 2003; 37(2): 169-72.

9. Kandula L and Lowe ME. J Pediatr 2008; 152(1): 106-10.

10. DeBanto JR et al. Am J Gastroenterol 2002; 97(7): 1726-31.

11. Appelros S and Borgström A. Br J Surg 1999; 86(4): 465-70.

12. Jaakkola M and Nordback I. Gut 1993; 34(9): 1255-60.

13. Ammann RW et al. Gastroenterology 1984: 86(5 Part 1): 820-28.

14. Layer P et al. Gastroenterology 1994; 107(5): 148

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