Diagnosis and management of pancreatic exocrine insufficiency (PEI) in primary care: consensus

guidance of a Canadian expert panel

P Durie1, J-D Baillargeon2, S Bouchard3, F Donnellan4, S Zepeda-Gomez5, C Teshima6*

1. Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

2. Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC,

Canada

3. Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada

4. Vancouver General Hospital, Vancouver, BC, Canada

5. University of Alberta, Edmonton, AB, Canada

6. St. Michael’s Hospital and University of Toronto, Toronto, ON, Canada.

Correspondence should be addressed: Christopher Teshima, Therapeutic Endoscopy, St.

Michael’s Hospital, Toronto, Ontario, M5B 1W8. Email: TeshimaC@smh.ca

Transparency

Declaration of funding

This manuscript was funded by BGP Pharma ULC.

Declaration of financial/other relationships

CT declares grant/research funding from Medtronic, consultant/advisor fees from Boston Scientific,

speakers’ bureau from Cook Endoscopy and other fees from Olympus. All other authors have no

disclosures to report. Peer reviewers on this manuscript have received an honorarium from CMRO for

their review work, and one reviewer declares having acted as an advisor and speaker for Mylan and

Abbott Pharmaceuticals.

Acknowledgments

The authors gratefully acknowledge writing and editorial support from Sarah von Riedemann, MSc and

John Ashkenas, PhD (SCRIPT, Toronto, Canada). Their participation in this project was made possible by

support from BGP Pharma ULC.

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Abstract

Pancreatic exocrine insufficiency (PEI) results in maldigestion due to inadequate activity of pancreatic

enzymes in the small bowel. PEI can arise from a variety of medical conditions that reduce enzyme

synthesis within the pancreatic parenchyma or from secondary factors that may occur despite optimal

parenchymal function, such as pancreatic duct obstruction or reduced or poorly synchronized enzyme

release. The most characteristic symptom of PEI is steatorrhea – voluminous, lipid-rich stools; other

common signs and symptoms include unexplained weight loss and deficiencies of fat-soluble vitamins

and other micronutrients. Pancreatic enzyme replacement therapy (PERT) can relieve symptoms and

long-term sequelae of PEI. Diagnosis of PEI and initiation of PERT are usually the responsibility of

gastroenterology specialists. However, primary care physicians (PCPs) are well positioned to identify

potential cases of PEI and to participate in the collaborative, long-term management of patients already

seen by a specialist. In this document, a panel of Canadian gastroenterologists has conducted a critical

review of the literature on PEI and PERT and has developed practical diagnostic and treatment

recommendations for PCPs. These recommendations provide guidance on identifying patients at risk of

PEI, the triggers for PEI testing and referral, and best practices for co-managing patients with confirmed

PEI.

Keywords: Pancreatic enzymes, pancreatitis, cystic fibrosis, steatorrhea, maldigestion, vitamin

deficiency

Running title: Pancreatic enzyme insufficiency

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Introduction

Pancreatic exocrine insufficiency (PEI) is not a distinct disease entity in its own right; rather, it occurs as

a consequence of a wide variety of medical conditions.1 In all forms of PEI, maldigestion arises because

of inadequate digestive enzyme activity within the small intestine, due to loss of enzyme synthesis

within the exocrine pancreas, failure to enter the small bowel due to pancreatic duct obstruction, lack of

hormone-induced secretion, or inadequate mixing of enzymes with partially digested food1-3. Depending

on the underlying etiology, PEI may present at any time in a patient’s life, from infancy to advanced old

age1.

Maldigestion has both acute and chronic effects. In the absence of normal catabolism, specifically of

dietary fats and protein, the stool is voluminous and abnormally lipid-rich, a condition known as

steatorrhea. Micronutrient deficiencies develop in these patients due to excess excretion of lipid-soluble

vitamins4, 5. At the same time, poor recovery of macronutrients can cause chronic weight loss or, in

children, failure to thrive6. All of these defects and their clinical sequelae can be ameliorated by

providing exogenous pancreatic enzymes (pancreatic enzyme replacement therapy; PERT)3, 7.

Primary care physicians (PCPs) are well positioned to identify patients with possible PEI. Unfortunately,

diagnosis is complicated by the inconsistent association of PEI with the various predisposing medical

conditions and the lack of sensitive and specific diagnostic tests. Careful workup is required to clarify the

patient’s clinical situation, to distinguish individuals with non-specific gastrointestinal (GI) complaints

from those whose symptoms could respond to PERT and from those who require urgent referral to

exclude serious GI diseases8, 9.

A group of Canadian gastroenterologists has conducted a critical review of the literature, in order to

develop practical guidance for PCPs managing patients who are at risk of PEI or who present with

symptoms of PEI. Based on this review, we provide consensus recommendations on testing and

monitoring these patients, on best practice for referral to a GI specialist, and on ongoing, collaborative

management of patients who have already been seen by a specialist for PEI.

Scope and methods

The expert panel was selected based on the guidance of one of the co-chairs (CT), with the goal of

achieving representation from across Canada by gastroenterologists with a special interest in PEI, in

both the pediatric and adult settings.

The consensus guidance in this document is based on a list of key clinical questions developed by one of

the co-Chairs (CT) and revised and approved by the full author panel. These clinical questions, focusing

on practical issues relevant in the primary care setting, formed the basis of focused literature searches

for published findings that could support PCP treatment recommendations. These searches were

conducted on all published literature in English, with no restrictions on year of publication. For each of

the clinical questions, appropriate keywords were selected and used to search the PubMed database;

Web of Science was used to conduct forward and backward searches on key articles, and the reference

lists of review papers and clinical trial reports were examined for additional sources of relevant data.

The literature search was completed in January 2017, and refined in March-April 2017 based on input

from all authors.

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Based on the findings of the literature search, the two co-Chairs (CT and PD) compiled a list of draft

recommendations that were vetted, revised, and approved during a consensus webinar in April 2017.

The clinical statements presented here are classified as “recommendations” in the case of unanimous

agreement (6 of 6 faculty members), and as “suggestions” if unanimity was not reached but 4 or 5 of the

participants agreed.

Findings

1. What is PEI, and who are the patients at risk?

PEI is defined as inadequate activity of the pancreatic enzymes within the lumen of the small intestine,

resulting in impaired digestive function and nutrient malabsorption. PEI can arise through several

mechanisms, including loss of parenchymal function, decreased secretion, and/or altered timing of

secretion, as can occur following gastric bypass6, 8. It is useful to distinguish between primary causes,

related to defects in the exocrine pancreatic parenchyma, and secondary causes, which include failure

to secrete enzymes or damage to or blockage of the main pancreatic duct (Table 1).

The overall population prevalence of PEI is difficult to ascertain, but the condition is associated with

disorders (Table 2) for which PEI incidence and prevalence data may be available. In each case, clinically

significant PEI arises only when residual enzymatic activity is severely reduced, relative to what is

observed in healthy individuals. In patients with cystic fibrosis (CF) or Shwachman-Diamond syndrome,

the threshold for clinical effects may be as low as 2% of normal lipase and 1% of normal colipase

activity10. For patients with chronic pancreatitis (CP), maintaining >10% of normal lipase level may be

sufficient to prevent signs and symptoms of PEI11, 12.

For practical purposes, it is helpful for PCPs to be aware of the association with CF, CP and other

conditions, bearing in mind that PEI may develop over time or not at all. Close monitoring is a necessity

for all at-risk individuals.

2. What symptoms will patients with PEI commonly present with?

The most common symptoms relate to insufficient lipase and colipase secretion, with consequent lipid

malabsorption.13 These include: weight loss with malnutrition and, in children, poor growth; steatorrhea

– fat droplets in the toilet, large-volume stools; and deficiencies in fat-soluble vitamins (A, D, E, K), as

well as sequelae of these deficiencies5, 14. None of these findings is pathognomonic for PEI. For example,

low bodyweight and malnutrition may be unreliable criteria; obese patients with CP can develop PEI15-17.

However, they are meaningful when observed together.

Patients with PEI may show no symptoms or very few symptoms; equally commonly, they may grow

accustomed to their symptoms, thus highlighting the importance of laboratory screening for all patients

with predisposing conditions such as CP2. The underlying cause of CP should be understood to include

patient genetics and environmental (e.g., alcohol abuse) and other risk factors; mutations affecting the

trypsin activation pathway, lipase or duct cell function predispose patients to CP18, 19. Smoking increases

the overall risk of CP; heavy smokers (>1 pack/day) have up to a 4.5 times greater risk of developing

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

pancreatitis than non-smokers20-22, whereas smoking cessation substantially reduces the risk of CP

progression23-25.

In the primary care setting, a possible diagnosis of PEI should be pursued on the basis of a combination

of patient history and presenting symptoms. Symptoms suggestive of PEI are listed in the text box

below. In general, PEI should be considered in patients with unexplained suggestive symptoms, even in

the absence of any known predisposing condition. Conversely, a new diagnosis of pancreatic disease

should raise suspicion of PEI, even in the absence of GI complaints. PEI should be investigated if patients

experiencing these suggestive symptoms have CP, Type 1 diabetes, or unresponsive celiac disease or

HIV/AIDS, or if they are current or former smokers26 or have a longstanding history of alcohol abuse

(defined as ≥5 drinks/day)2, 23. The last two risk categories interact, such that risk of PEI with alcohol

abuse is heightened among current smokers27.

3. What basic tests should a primary care physician consider before making a specialist referral?

When investigating a possible diagnosis of PEI, PCPs should make note of the patient’s clinical history,

including prior chronic or recurrent acute pancreatitis, alcohol abuse, smoking, GI surgery, diabetes and

family history of pancreatitis or GI complaints suggestive of pancreatic insufficiency. Patients’ weight

and body mass index should be determined, and basic laboratory tests should be performed, including

complete blood counts with differential, a comprehensive metabolic panel, international normalized

ratio, HbA1c, and levels of albumin, prealbumin and micronutrients28 (fat-soluble vitamins and

nutritional markers such as magnesium, carotene and retinol-binding protein). Bone mineral density

testing is also appropriate.5, 14, 29

Of these, blood tests for deficiencies in fat-soluble vitamins (Table 3) are particularly important because,

although they can occur for reasons unrelated to malabsorption, deficiencies associated with an

underlying condition (e.g., CP) are highly suggestive of PEI. Conversely, PEI is unlikely if all of these

measures are normal28. For patients with CP, asymptomatic or minimally symptomatic PEI is common,

so regular (e.g., yearly) screening is appropriate.

Stool tests, including fecal Sudan staining and fecal elastase (FE-) 1, should also be done, although not

necessarily on an annual basis30, 31. Because Sudan Red identifies lipids, bright red staining of fat globules

can help corroborate a patient report of steatorrhea. FE-1 is produced by the exocrine pancreas, so low

Suggestive symptoms of PEI

Large-volume stools with malodorous fat droplets like cooking oil in toilet bowl (steatorrhea); micrographs

show evidence of fat droplets in stool

Unexplained weight loss

Specific deficits in fat-soluble vitamins

Clinical sequelae of certain micronutrient deficiencies (see Table 3)

Symptoms of diabetes mellitus secondary to CP

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

levels of this enzyme provide direct evidence of primary or secondary PEI. While FE-1 is a useful test,

interpretation is complicated by the use of different procedures (monoclonal versus polyclonal

antibodies)32, 33 in different locales and confusion over appropriate reference values. The test is also

meaningless if the stool sample is dilute (e.g., if the patient has diarrhea).30

Other investigations that are not ordinarily expected of the PCP might be appropriate if wait time for

specialist care is long. Differential diagnosis of PEI is complex, but some alternative diagnoses, such as

giardiasis or celiac disease, can be investigated at the primary care level. In addition, the PCP may

consider computed tomography (CT) imaging to assess possible CP or pancreatic cancer. A trial of PERT

may also be considered under certain circumstances (see below). Because PERT supplements were

available over the counter until 2015, the patient may have experience with this treatment; any history

of, and response to, pancreatic enzyme supplements should be noted.

Conversely, certain investigations may be safely left for the specialist to pursue, if appropriate. These

include direct tests of pancreatic secretory function34 (e.g., secretin- or cholecystokinin-stimulated

secretion) and morphologic investigations of the exocrine pancreas or ducts.

4. When and how should the primary care physician refer the patient to a gastroenterologist?

Referral should be considered when the patient shows evidence of abnormal tests (e.g., FE-1, plasma

fat-soluble vitamin deficiencies) following screening, and/or when the patient experiences ongoing

symptoms, such as steatorrhea or weight loss. It is particularly important for patients to be referred to a

specialist for further diagnostic workup if PEI is diagnosed in the absence of any previously established

predisposing conditions, as PEI can often be the first clinical manifestation of pancreatic cancer or CP.

For this reason, obtaining a CT scan to exclude pancreatic cancer or CP after diagnosing PEI while

awaiting specialist consultation should be strongly considered.

For patients with symptoms suggestive of PEI, such as steatorrhea or unexplained weight loss, the PCP

should document duration and nature of symptoms, along with any abnormal nutritional parameters

and markers of malnutrition. If a trial of PERT has been attempted, dosing, duration of treatment and

clinical outcomes should be reported in the referral letter.

Given time constraints, a thoroughly documented referral letter will improve the patient’s prospects of

being seen promptly by the gastroenterology specialist. The essential elements of such a letter are

shown in the boxed text below.

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

5. How should the primary care physician manage pancreatic enzyme replacement therapy and

assess response?

General principles of PERT

As noted, PERT is ordinarily initiated by gastroenterology specialists, but PCPs should understand the

therapy in order to monitor treatment and make appropriate adjustments.

PERT provides biologically active porcine enzymes to replace endogenous enzyme activity within the

lumen of the small bowel. Most currently available enzyme preparations are packaged as capsules,

which may contain either powdered enzymes or microspheres, i.e., biodegradable polymer-based

microparticles that allow controlled drug release35. An enteric coating is used on most products to

prevent inactivation by gastric acid, allowing the enzymes to remain active as they enter the duodenum.

Conversely, products without enteric coating should be taken at higher dose, generally with a proton

pump inhibitor (PPI) to minimize gastric acid inactivation36. PCPs should be aware that uncoated

enzymes are sometimes used specifically for pain relief associated with CP37, 38 and that dosing in this

application is distinct from that for PEI.

Table 4 lists the formulations of pancreatic enzyme supplements available to Canadian prescribers.

Dosing of pancreatic enzyme supplements is uncertain because response varies between patients, and

according to body weight in children. No dose-response relationship has been documented for any of

the supplements used in adult or pediatric PEI. Standard dosing is not based on treatment efficacy, but

rather on safety (avoidance of fibrosing colonopathy, specifically in the CF patient population). Therapy

must therefore be tailored to the individual patient, based on severity of symptoms and response to

treatment.

Elements of a complete specialist referral letter for patients with suspected PEI 1) Thorough documentation of duration and severity of symptoms (if any)

Chronic diarrhea Features of steatorrhea Abdominal pain

2) Quantified weight loss or failure to thrive in infants and children 3) Summary of investigations performed:

Biochemical markers of nutritional status Stool tests for fecal fat FE-1 if done

4) Imaging results (if done) 5) Response to PERT (if tried) 6) Alcohol and smoking history 7) History of recurrent acute pancreatitis, CP, or diabetes 8) Family history of CP, pancreatic cancer, or CF 9) List of medical conditions 10) List of medications

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Enzyme supplements are taken with meals and snacks containing fat and/or protein; if several capsules

are required, they should be taken at various times before, during, and after eating. If swallowing

capsules is an issue, powdered formulations can be mixed in with soft, easy-to-swallow food; capsules

can be broken open and the microspheres mixed in with food this way.

Some but not all authorities recommend starting with a small number of capsules (or small amount of

powder) and titrating upward based on response. For adult patients with CP, a typical effective dose is

40-50,000 United States Pharmacopeia (USP) units of lipase/meal, sometimes ranging up to 90K USP

units lipase/meal39. Doses for a snack may be half of that for a meal. Dosing in CF tend to be higher; for

children, dosing are tailored to the patient’s weight and/or fat intake40.

The overall safety profile of pancreatic enzymes is similar across all formulations36, 41-43. The most

common adverse effects are gastrointestinal in nature (e.g., abdominal pain, abdominal distension,

diarrhea, constipation, vomiting, nausea) and generally mild to moderate in severity; some may be

symptoms of the underlying disorder, rather than a treatment effect. Pancreatic enzymes come with a

warning for fibrosing colonopathy, a rare but serious adverse drug reaction whose risk appears to be

directly related to dose, as documented in CF patients40, 44. Allergy and hypersensitivity reactions, mainly

skin rash, have been reported but occur rarely. More commonly, infants and others may experience

perianal irritation, especially early in treatment.

Additional safety considerations apply to particular formulations. Formulations without enteric coating

can cause mucosal irritation if held in the mouth for too long. Patients using powdered formulations

should take care not to inhale the powder, which can cause irritation and asthma-like reactions.36

Evaluation and optimization of pancreatic enzyme therapy

Although specialists may conduct a 72-hour test to quantify a coefficient of fecal lipid (CFA; the gold-

standard efficacy measurement for PEI treatment), success of PERT is usually assessed based on reversal

of PEI signs and symptoms. Patients may experience restored capacity to metabolize ingested fats

(reducing but generally not eliminating steatorrhea) and correction of fat-soluble vitamin deficiencies.

Lack of resolution of symptoms need not indicate complete lack of efficacy – there may be other

beneficial effects (e.g., improved fat absorption) that are not identified symptomatically.

Other expectations following optimization of the PERT regimen include a patient’s improved tolerance

for a normal-fat diet31; objectively documented reversal of weight loss; normalization of clinical markers

of malnutrition, including prealbumin (transthyretin), albumin, and transferrin; and secondary benefits

of restored nutrients, e.g., improved bone mineral density and restoration of normal lymphocyte count.

Conversely, although patients may experience reduced stool volume, meta-analysis suggests no

improvement in stool frequency with PERT45.

For some symptoms, benefits of PERT are detectable within weeks of initiating effective treatment,

reversing rapidly upon discontinuation. In one placebo-controlled study of patients with PEI secondary

to pancreatic surgery, patient-reported symptoms (stool form, flatulence and abdominal pain) differed

significantly between treatment arms over a 1-week double-blind period, with benefits maintained over

a 1-year open-label extension, relative to baseline35. CFA in this study likewise improved significantly, in

parallel with the subjectively defined outcomes. Similarly, a prospective observational study of patients

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

with CP found that quality-of-life improvements related to GI symptoms and pain improved significantly

over 1 year, relative to the pre-treatment period. Another study, working with CF patients using PERT,

showed a significant recurrence of maldigestion and patient-reported GI symptoms within 1 week in

patients randomized to withdrawal of active treatment, relative to those maintaining PERT46.

For patients who do not experience satisfactory response to PERT, it is reasonable to reconsider the

diagnosis and also to query the patient about treatment adherence. The fecal chymotrypsin test47,

available in some locales, can provide objective evidence of PERT use.

If the patient appears to be adhering to the treatment, the PERT regimen may need to be adjusted,

either by changing the dose or schedule of pancreatic enzymes or by adding a PPI. Use of PPIs is

required to maintain the activity of uncoated pancreatic enzyme supplements36. Concomitant use of

PPIs also increases the effectiveness of PERT when coated enzymes are taken, and in some cases can be

sufficient to control maldigestion in patients who failed to respond to pancreatic enzyme supplements

alone48; addition of a PPI is therefore a reasonable initial step in optimizing PERT, typically before

increasing the enzyme dosage.

If possible, modifications of PERT regimen should be overseen by a GI specialist, and the PCP may wish

to write a re-referral to facilitate this.

6. What lifestyle and dietary measures should be recommended to patients?

Given that patients with PEI are at risk of malnourishment, low-fat diets are generally not appropriate4, 9,

49, although they might be considered for individuals who are overweight or obese.

Patients with PEI should be strongly encouraged to quit smoking and to avoid alcohol. Psychological and

other support may be needed for patients attempting to make these behavioral changes50.

Treatment Recommendations and Suggestions

A series of recommendations for management of suspected or known PEI in primary care were

proposed by the Chairs and discussed and vetted by the physician-authors. Final approved wording of

these items is shown in Table 5. In the case of Item 6, a minority (2/6 votes) disagreed with the routine

use of fecal FE-1 testing and fecal Sudan staining in patients lacking clinical signs or symptoms of PEI.

Thus, the regular use of fecal biochemical tests is approved as a treatment suggestion, whereas all of the

other items were agreed to unanimously by 6 of 6 faculty members and are approved as treatment

recommendations.

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

References

1. Toouli J, Biankin AV, Oliver MR, et al. Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. Med J Aust 2010 Oct 18;193:461-7. 2. Muniraj T, Aslanian HR, Farrell J, et al. Chronic pancreatitis, a comprehensive review and update. Part I: epidemiology, etiology, risk factors, genetics, pathophysiology, and clinical features. Dis Mon 2014 Dec;60:530-50. 3. Dominguez-Munoz JE. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency: when is it indicated, what is the goal and how to do it? Adv Med Sci 2011;56:1-5. 4. Duggan S. A Practical Guide to the Nutritional Management of Chronic Pancreatitis. Pract Gastroenterol 2013 June 2013;118:24 - 32. 5. Haaber AB, Rosenfalck AM, Hansen B, et al. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency. Int J Pancreatol 2000 Feb;27:21-7. 6. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut 2005 Jul;54 Suppl 6:vi1-28. 7. Trang T, Chan J, Graham DY. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21(st) century. World J Gastroenterol 2014 Sep 07;20:11467-85. 8. Sugumar A, Pearson, R.K. Pancreatic Exocrine Insufficiency: The Primary Care Perspective. http://www.medscape.org/viewarticle/724507. Accessed May 2017. Medscape 2010. 9. Pongprasobchai S. Maldigestion from pancreatic exocrine insufficiency. Journal of gastroenterology and hepatology 2013 Dec;28 Suppl 4:99-102. 10. Gaskin KJ, Durie PR, Lee L, et al. Colipase and lipase secretion in childhood-onset pancreatic insufficiency. Delineation of patients with steatorrhea secondary to relative colipase deficiency. Gastroenterology 1984 Jan;86:1-7. 11. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973 Apr 19;288:813-5. 12. Lankisch PG, Lembcke B, Wemken G, et al. Functional reserve capacity of the exocrine pancreas. Digestion 1986;35:175-81. 13. Andersen DK. Mechanisms and emerging treatments of the metabolic complications of chronic pancreatitis. Pancreas 2007 Jul;35:1-15. 14. Haas S, Krins S, Knauerhase A, et al. Altered bone metabolism and bone density in patients with chronic pancreatitis and pancreatic exocrine insufficiency. JOP 2015 Jan 31;16:58-62. 15. Ammann RW, Raimondi S, Maisonneuve P, et al. Is obesity an additional risk factor for alcoholic chronic pancreatitis? Pancreatology 2010;10:47-53. 16. Lowenfels AB, Maisonneuve P, Sullivan T. The changing character of acute pancreatitis: epidemiology, etiology, and prognosis. Curr Gastroenterol Rep 2009 Apr;11:97-103. 17. Teichmann J, Riemann JF, Lange U. Prevalence of exocrine pancreatic insufficiency in women with obesity syndrome: assessment by pancreatic fecal elastase 1. ISRN Gastroenterol 2011;2011:951686. 18. Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013 Jun;144:1292-302. 19. Zator Z, Whitcomb DC. Insights into the genetic risk factors for the development of pancreatic disease. Therap Adv Gastroenterol 2017 Mar;10:323-36. 20. Tolstrup JS, Kristiansen L, Becker U, et al. Smoking and risk of acute and chronic pancreatitis among women and men: a population-based cohort study. Arch Intern Med 2009 Mar 23;169:603-9. 21. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med 2009 Jun 08;169:1035-45. 22. Yadav D, Whitcomb DC. The role of alcohol and smoking in pancreatitis. Nat Rev Gastroenterol Hepatol 2010 Mar;7:131-45.

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

23. Law R, Parsi M, Lopez R, et al. Cigarette smoking is independently associated with chronic pancreatitis. Pancreatology 2010;10:54-9. 24. Maisonneuve P, Frulloni L, Mullhaupt B, et al. Impact of smoking on patients with idiopathic chronic pancreatitis. Pancreas 2006 Aug;33:163-8. 25. Talamini G, Bassi C, Falconi M, et al. Smoking cessation at the clinical onset of chronic pancreatitis and risk of pancreatic calcifications. Pancreas 2007 Nov;35:320-6. 26. Rebours V, Vullierme MP, Hentic O, et al. Smoking and the course of recurrent acute and chronic alcoholic pancreatitis: a dose-dependent relationship. Pancreas 2012 Nov;41:1219-24. 27. Lindkvist B, Appelros S, Manjer J, et al. A prospective cohort study of smoking in acute pancreatitis. Pancreatology 2008;8:63-70. 28. Lindkvist B, Dominguez-Munoz JE, Luaces-Regueira M, et al. Serum nutritional markers for prediction of pancreatic exocrine insufficiency in chronic pancreatitis. Pancreatology 2012 Jul-Aug;12:305-10. 29. Ramsey ML, Conwell DL, Hart PA. Complications of Chronic Pancreatitis. Dig Dis Sci 2017 Mar 09. 30. Beharry S, Ellis L, Corey M, et al. How useful is fecal pancreatic elastase 1 as a marker of exocrine pancreatic disease? J Pediatr 2002 Jul;141:84-90. 31. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol 2013 Nov 14;19:7258-66. 32. Pezzilli R, Morselli-Labate AM, Palladoro F, et al. The ELISA fecal elastase-1 polyclonal assay reacts with different antigens than those of the monoclonal assay. Pancreas 2005 Aug;31:200-1. 33. Schneider A, Funk B, Caspary W, et al. Monoclonal versus polyclonal ELISA for assessment of fecal elastase concentration: pitfalls of a new assay. Clin Chem 2005 Jun;51:1052-4. 34. Schibli S, Corey M, Gaskin KJ, et al. Towards the ideal quantitative pancreatic function test: analysis of test variables that influence validity. Clin Gastroenterol Hepatol 2006 Jan;4:90-7. 35. 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 Apr;37:691-702. 36. Viokace Product Monograph. Aptalis Pharma Canada Inc, Mont-Saint-Hilaire, QC. Date of revision: September 30, 2011. 37. D'Haese JG, Ceyhan GO, Demir IE, et al. Pancreatic enzyme replacement therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis: a 1-year disease management study on symptom control and quality of life. Pancreas 2014 Aug;43:834-41. 38. Yaghoobi M, McNabb-Baltar J, Bijarchi R, et al. Pancreatic Enzyme Supplements Are Not Effective for Relieving Abdominal Pain in Patients with Chronic Pancreatitis: Meta-Analysis and Systematic Review of Randomized Controlled Trials. Canadian journal of gastroenterology & hepatology 2016;2016:8541839. 39. Muniraj T, Aslanian HR, Farrell J, et al. Chronic pancreatitis, a comprehensive review and update. Part II: Diagnosis, complications, and management. Dis Mon 2015 Jan;61:5-37. 40. Borowitz DS, Grand RJ, Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr 1995 Nov;127:681-4. 41. Cotazym Product Monograph. Merck Canada Inc, Kirkland, QC. Date of revision: February 13, 2015. 42. Creon Product Monograph. Abbott Laboratories, Limited, St Laurent, QC. Date of revision: August 21, 2015. 43. Pancrease Product Monograph. Janssen Inc, Toronto, ON. Date of revision: January 31, 2014. 44. FitzSimmons SC, Burkhart GA, Borowitz D, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. N Engl J Med 1997 May 01;336:1283-9. 45. de la Iglesia-Garcia D, Huang W, Szatmary P, et al. Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. Gut 2016 Dec 09.

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

46. Trapnell BC, Strausbaugh SD, Woo MS, et al. Efficacy and safety of PANCREAZE(R) for treatment of exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros 2011 Sep;10:350-6. 47. Goldberg DM. Proteases in the evaluation of pancreatic function and pancreatic disease. Clinica chimica acta; international journal of clinical chemistry 2000 Feb 15;291:201-21. 48. Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, et al. Optimising the therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor to enteric coated pancreatic extracts. Gut 2006 Jul;55:1056-7. 49. Pezzilli R, Andriulli A, Bassi C, et al. Exocrine pancreatic insufficiency in adults: a shared position statement of the Italian Association for the Study of the Pancreas. World J Gastroenterol 2013 Nov 28;19:7930-46. 50. Nordback I, Pelli H, Lappalainen-Lehto R, et al. The recurrence of acute alcohol-associated pancreatitis can be reduced: a randomized controlled trial. Gastroenterology 2009 Mar;136:848-55.

Table 1: Primary and secondary forms of pancreatic enzyme insufficiency.

Classification Mechanism Examples

Primary pancreatic insufficiency (defect in pancreatic parenchyma)

Inadequate synthesis and secretion of pancreatic enzymes into the small bowel lumen

Chronic pancreatitis

Cystic fibrosis

Other inherited disorders of the pancreas (e.g., Shwachman-Diamond Syndrome, Johanson-Blizzard Syndrome, pancreatic aplasia)

Tropical pancreatitis

Pancreatic resection

Secondary pancreatic insufficiency (decreased secretion despite intact parenchyma)

Obstruction of pancreatic duct

Ductal stenosis

Papillary tumours

Decreased endogenous stimulation

Enteropathies (e.g., celiac or Crohn’s disease) that reduce cholecystokinin stimulation)

Somatostatinomas

Decreased pancreatic enzyme activity in the small bowel, despite normal secretion

Poor mixing of pancreatic enzymes in the bile (e.g., in dumping syndrome or following portoenterostomy)

Postcibal asynchrony (e.g., gastric resections, short bowel syndrome)

Intraluminal inactivation (e.g., Zollinger-Ellison syndrome, tetrahydrolipistatin, gastrinoma, hypersecretory state)

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Table 2: Pancreatic exocrine insufficiency (PEI) in common predisposing or comorbid conditions.

PEI-predisposing

condition

Canadian incidence or prevalence Rate of PEI within this condition

Chronic pancreatitis (CP)

51

• Estimated prevalence of 14,400; estimated Canadian incidence of 2070 patients annually

• Contrast this with ~15,000 annually for acute pancreatitis, which:

• Can cause transient PEI symptoms • If recurrent, can progress to CP

28,

52, 53

• Not well defined. However, maldigestion leading to vitamin deficiencies can occur early in the disease process

Cystic fibrosis (CF)

54

• Prevalence more than 4100 • 120 new diagnoses in 2014 (mostly infants,

but 18 adults)

• Over 95% of patients with severe CFTR mutations are pancreatic-insufficient in childhood or progress to PEI

• For those with milder alleles, representing ~15% of the CF population, exocrine function may be sufficient in childhood but decline with age, or may remain sufficient over the long term

55

Type 1 diabetes56 • Prevalence: Approximately 250,000 (2.5 million total diabetes cases, of which ~10% are type 1)

• Incidence of Type 1 >17,500

• About 51% (26–74%) of patients with Type 1 diabetes have abnormal pancreatic exocrine function;

57 not

specified how many have clinically relevant PEI

• Type 1 diabetes must be distinguished from pancreatogenic diabetes (T3cDM), a consequence of long-term CP

• T3cDM occurs in up to 51.5% of CP patients after 20 years

58-62

• T3cDM increases with age in patients with CF-associated PEI

63

Pancreatic cancer64

• Annual incidence: 4800; mortality 4600 • The relative risk (RR) of pancreatic cancer

for patients with CP is much higher than for the general population

• 65% of pancreatic cancer patients have fat malabsorption, and 50% have protein malabsorption prior to surgery

49

• Among pancreatic tumours that are unresectable, PEI is common (50-100%) and often progressive

65

• Investigation of clinically evident PEI (weight loss/ steatorrhea) may lead to detection of the cancer

66

HIV/AIDS67

• Prevalence: 71,300 • Incidence: 3175

• According to one report (n=233), 45% of HIV-positive patients whose viremia was successfully controlled with anti-retroviral therapy experienced PEI; additionally, hepatitis C infection and its treatment were associated with further increased risk of PEI in HIV-positive individuals

68

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Post-surgical69

• Major indication for pancreatic surgery is ductal adenocarcinoma; 15-20% of cases are considered resectable at diagnosis; given incidence <5000, number of surgeries annually would be <1000

• Pancreatectomy with islet cell transplantation is becoming increasingly common

70, 71

• Other surgeries on nearby organs (e.g., bowel, stomach) can also precipitate PEI

5

• Will depend on which anatomical

structures are resected, how much tissue

was removed, what degree of PEI was

present prior to surgery, whether surgical

diversion played a role

• Total pancreatectomy requires lifelong

pancreatic enzyme replacement therapy

(PERT)

Celiac disease (CD) and non-responsive CD

72-

74

• Prevalence of CD: 1 in 133 people, based on US data

• In ~7% - 30% of CD patients, symptoms fail to respond to a gluten-free diet

• 4.4% of the overall CD population, based on fecal elastase-1 (FE-1) findings

75

• Up to 30% of patients with non-responsive CD have PEI that contributes to their persistent CD symptoms; some of these cases are primary PEI, due to pancreatic atrophy

76

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Table 3. Consequences of fat-soluble vitamin deficiencies.

Normal range Clinical signs/ symptoms with

deficiency

Comments

Vitamin A Serum retinol

0.30-1.20 mg/L in

adults77

Poor dark adaptation; corneal

opacity, perforation; Bitot (grey)

spots on eyes; dry skin, hair, and

eyes (xerophthalmia); pruritus;

fragile nails78

Rarely clinically deficient with

pancreatic exocrine insufficiency

(PEI), but often biochemically

deficient – symptoms can be very

mild or unnoticed by patient.

Supplement if needed

Vitamin D Serum 25(OH)D

>50 nmol/L79

Osteopenia or osteoporosis;

osteomalacia; muscle pain;

periosteal pain80

Repletion may be

incomplete despite

adequate pancreatic

enzyme replacement

therapy (PERT), particularly

in patients with underlying

cystic fibrosis (CF); poor

diagnostic value, as vitamin

D insufficiency is common in

Canada79

Vitamin E Serum alpha

tocopherol 5.5-17

mg/L81

Hyporeflexia or ataxia; muscle

weakness; limited upward gaze;

visual field restriction; night

blindness81

Vitamin B12 Serum cobalamin

≥148 pmol/L82

Impaired vibration

sense; ataxia; paresthesia; poor

joint position, especially legs,

leading to wide-based gait;

Romberg sign83

Rarely clinically deficient with PEI.84

Supplement only if needed

Vitamin K 0.2-3.2 μg/L85 Coagulopathies, osteoporosis85 Commonly reported as International

Normalized Ratio. May be of limited

value for identification or monitoring

of PEI

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Table 4. Pancreatic enzyme formulations in Canada.

Brand name Manufacturer Formulation Dosage (United States Pharmacopeia [USP]

units)

Lipase Amylase Protease

Cotazym®41 Merck Capsules; enteric

coated (ECS) and

non-coated versions

available

Non-coated: 10,000 40,000 35,000

ECS 8: 10,800 42,000 45,000

ECS 20: 25,000 100,000 100,000

Creon®42 Mylan Minimicrospheres, as

granules or capsules

Granules: 5,000 21,165 20,000

6: 6,000 30,000 19,000

10: 10,000 46,480 45,625

25: 25,000 105,825 100,000

Pancrease®43 Janssen Delayed-release

capsules

4: 4,200 17,500 10,000

10: 10,500 43,750 25,000

16: 16,800 70,000 40,000

Viokace®37 Aptalis Tablet (non-coated) 10 tablet: 10,440 56,400 57,100

20 tablet: 20,880 113,400 112,500

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Table 5. Approved treatment recommendations and suggestions for management of suspected or

confirmed pancreatic enzyme insufficiency (PEI) in primary care

Recommendation 1

As PEI is a clinical diagnosis, patients should never be assumed to have PEI based on isolated laboratory findings (e.g., fecal elastase-1) or the presence of a predisposing condition such as chronic pancreatitis (CP) or cystic fibrosis (CF).

Recommendation 2

Pancreatic-sufficient patients with predisposing conditions require ongoing monitoring for emergence of PEI signs and symptoms.

Recommendation 3

PEI should always be considered in individuals with a newly diagnosed pancreatic disease predisposing to PEI, including CP, CF and type 1 diabetes.

Recommendation 4

PEI should be investigated if suggestive signs and symptoms develop in a patient with a known pancreatic disease or in patients with a predisposing condition (e.g., type 1 diabetes or unresponsive celiac disease). The following signs and symptoms should be considered suggestive of PEI:

a. Large-volume malodorous stools b. Steatorrhea; fat droplets like cooking oil in toilet bowl; microscopic

evidence of fat droplets in stool; abnormal 72-hour fecal fat c. Unexplained weight loss d. Unexplained deficits in fat-soluble vitamins e. Clinical sequelae of certain micronutrient deficiencies (see Table 3) f. Diabetes mellitus secondary to chronic pancreatitis

Recommendation 5

PEI may also be considered in patients with unexplained suggestive signs or symptoms but no known predisposing condition.

What should primary care physicians (PCPs) do to investigate patients at risk of developing PEI?

Recommendation 6

For patients with a condition predisposing to PEI, regular screening should include:

a. Weight and body mass index

b. Fat-soluble vitamins and other nutritional markers

c. HbA1c

d. Bone mineral density scan

Suggestion 6a In addition to the recommended screening tests (above), fecal biochemical tests such as fecal elastase (FE-1) or Sudan staining should be carried out regularly.

Recommendation 7

For patients with signs or symptoms suggestive of PEI, thorough investigation by the PCP should include the following considerations:

a. Duration and nature of symptoms (e.g., steatorrhea)

b. Documented unexplained weight loss

c. Other basic laboratory values, including complete blood counts with differential; comprehensive metabolic panel; international normalized ratio; serum albumin and prealbumin levels

d. Patient’s clinical history, including prior chronic or recurrent acute pancreatitis; alcohol abuse; smoking; and GI surgery

e. Any family history of a pancreatic disease.

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/

Recommendation 8

Certain considerations that are not ordinarily expected of the PCP might be appropriate, particularly if wait time for specialist care is long. While waiting for specialist evaluation, the PCP may consider:

a. Trial use of pancreatic enzyme replacement therapy (PERT), with specific dosing, duration of treatment, and clinical outcomes reported in a referral letter

b. Computed tomography (CT) imaging to assess possible pancreatic cancer or complications of pancreatic disease in patients with CP or CF

When and how should the PCP refer to a specialist?

Recommendation 9

GI referral should be considered when the patient shows evidence of abnormal tests (e.g., FE-1 or fat-soluble vitamin deficiencies) following screening, and/or ongoing symptoms suggestive of PEI.

Recommendation 10

Given specialist wait times, a thoroughly documented referral letter will improve the patient’s prospects of being seen promptly by the specialist.

How should the PCP manage PERT treatment and assess response?

Recommendation 11

Patients with PEI who have an inadequate response to PERT should be referred or re-referred to a specialist. If there is a suspicion of pancreatic cancer or another serious diagnosis, referral should be urgent.

Recommendation 12

If specialist access is limited or wait time is long, the PCP may: a. Assess current dosing schedule and reinforce importance of daily

dosing with all meals and snacks b. Query the patient on PERT adherence; order fecal chymotrypsin test if

available c. Investigate alternate diagnoses, such as:

i. Giardia (stool test) ii. Pancreatic cancer (pancreatic imaging)

iii. Gluten sensitivity/celiac disease d. Initiate trial of concomitant PPIs e. Initiate trial of higher-dose PERT within accepted guidelines

What other measures should PCPs recommend for their patients with PEI?

Recommendation 13

PCPs should recommend alcohol and smoking cessation for pancreatic-sufficient and -insufficient patients with CP; consider pharmacologic or psychological support for treating alcohol abuse and smoking.

Recommendation 14

Most individuals with PEI should not be counselled to reduce or avoid dietary fat, although obese patients constitute a likely exception to this.

Dow

nloa

ded

by [

Shan

ghai

Jia

oton

g U

nive

rsity

] at

22:

22 0

8 O

ctob

er 2

017

http://guide.medlive.cn/