pancreatic insufficiency in children · pancreatic insufficiency in children a special ... should...

PRACTICAL GASTROENTEROLOGY • OCTOBER 200338

INTRODUCTION

I n s u fficiency of the exocrine pancreas should beconsidered in the work-up of any pediatric patientwho presents with features of malabsorption such as

failure to thrive, chronic diarrhea, hypoalbuminemia,anemia, or symptoms of trace vitamin and mineral

deficiencies. Testing for pancreatic insufficiency canbe cumbersome due to the time commitment involvedin many of the non-invasive testing techniques and theinvasive nature of some of the more accurate tests.A d d i t i o n a l l y, the health care provider must have a sig-nificant understanding of testing to allow for interpre-tation of results. The purpose of this review article is todiscuss causes and treatment of pancreatic insuff i-ciency in children as well as to discuss in detail currenttesting techniques for pancreatic exocrine disease.

The exocrine function of the pancreas involvesexcretion of digestive enzymes and bicarbonate into theduodenal lumen after meal stimulation. The ability of

Pancreatic Insufficiency in Children

A SPECIAL ARTICLE

John F. Pohl, M.D., Director, Pediatric Cystic FibrosisClinic and David J. Easley, M.D., Section of PediatricGastroenterology, Department of Pediatrics, Scottand White Memorial Hospital and Clinic, Scott, Sher-wood and Brindley Foundation, The Texas A&M Uni-versity System Health Science Center College ofMedicine, Temple, Texas.

Pancreatic exocrine insufficiency is a relatively rare condition in pediatric patients butshould be considered in any child with failure to thrive, steatorrhea, and symptoms ofmalabsorption. The most common cause of pancreatic insufficiency in children is cys-tic fibrosis, but other syndromic causes as well as isolated pancreatic enzyme deficien-cies exist. Pancreatic function testing can be difficult and time consuming, and thesweat test to rule out cystic fibrosis and 72-hour fecal fat test to quantify fat losses areimportant to consider in the face of possible exocrine dysfunction. More invasive test-ing such as pancreatic stimulation with secretin and cholecystokinin can be performedand should be considered in certain clinical scenarios. Treatment consists of pancreaticenzyme replacement, use of acid suppression to prevent enzyme degradation, replace-ment of fat-soluble vitamins, and nutritional support.

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John F. Pohl David J. Easley


the pancreas to maintain exocrine function despiteinjury is impressive and as much as 98% of pancreaticenzyme production may be lost before steatorrheaoccurs. Steatorrhea is defined as fat excretion exceeding7% of fat intake. Symptoms of steatorrhea in childrencan be difficult to determine but should be considered inany child with failure to thrive, chronic diarrhea, symp-toms consistent with bacterial overgrowth, hypoalbu-minemia, edema (due to impaired protein hydrolysis),and trace element or mineral deficiency (1).

DIFFERENTIAL DIAGNOSISThere are a large number of diseases to consider whenevaluating a child for possible exocrine pancreaticinsufficiency (Table 1). Although the differential diag-nosis is quite large and includes many rather uncom-mon diseases, a physician should realize that themajority of children with pancreatic insufficiency haveone of two possible diseases, namely cystic fibrosis orShwachman-Diamond syndrome (2). Cystic fibrosis(CF) is an autosomal recessive disease that affects 1 in2000 white births, and it is the most common cause ofpancreatic insufficiency in children (3). The underly-ing gene defect is on chromosome 7, which leads todysfunction of the CF transmembrane conductanceregulatory protein (CFTR) causing decreased chlorideand water secretion (4). The most common mutationinvolves the loss of phenylalanine at position 508

(ΔF508) of the CFTR protein (1). As a result, inspis-sated pancreatic secretions lead to acinar destructionand pancreatic fibrosis (Figure 1). A positive sweattest is diagnostic of this disease. The second mostcommon cause of pancreatic insufficiency is Shwach-man-Diamond syndrome which is a phenotypicdescription of pancreatic exocrine disease, bone mar-row abnormalities, metaphyseal dystosis, growth retar-dation, and immunodeficiency with recurrent infec-tions as well as other physical abnormalities (Figure2A and B) (5).

O b v i o u s l y, chronic pancreatitis can cause exocrinei n s u fficiency due to the gradual loss of pancreatic func-tion, but this entity occurs less commonly in the pedi-atric population than in adults. Underlying causes ofchronic pancreatitis in children include anatomicalabnormalities such as pancreas divisum, hereditarypancreatitis, α-1-antitrypsin deficiency, toxin exposure,and viral or bacterial processes. Other extremely rarecauses of pediatric pancreatic insufficiency should beconsidered in certain clinical scenarios. Johanson-Bliz-zard syndrome presents in an autosomal recessive pat-tern with steatorrhea from pancreatic exocrine dysfunc-tion as well as other phenotypic features including fail-ure to thrive, deafness, hypothyroidism, microcephaly,abnormal hair pattern, nasal cartilage hypoplasia, andsmall or absent permanent teeth. Pearson’s bone mar-row syndrome presents with pancreatic insuff i c i e n c y,sideroblastic anemia, and bone marrow precursor

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Figure 1. Abdominal ultrasound of a 12-year-old boy withcystic fibrosis reveals fatty infiltration of the pancreas due toprogressive acinar destruction. Pancreatic exocrine insuffi-ciency is present. (continued on page 42)

Table 1 Causes of Pancreatic Insufficiency in Children

• Cystic fibrosis (most common cause of pancreaticinsufficiency)

• Shwachman-Diamond syndrome (second most com-mon cause of pancreatic insufficiency)

• Chronic pancreatitis (anatomical obstruction, heredi-tary pancreatitis, α-1-antitrypsin deficiency, etc.)

• Johanson-Blizzard syndrome• Pearson’s bone marrow syndrome• Congenital rubella syndrome• Pancreatic isolated enzyme defects• Pancreas agenesis/hypoplasia


vacoulization. Various selected enzyme deficiencies(lipase, colipase, trypsin, amylase, enterokinase), con-genital rubella syndrome, and congenital pancreaticagenesis have been described but are extremely rareand outside the scope of this review (1–3, 5).

EXOCRINE PANCREAS TESTING

Sweat Test and Other Cystic Fibrosis Testing The sweat test is the first order of priority in any pedi-atric patient suspected of having pancreatic insuffi-ciency due to the relatively common prevalence ofcystic fibrosis. Standard testing requires a quantitativecollection of sweat in which sodium and chloride con-centrations are measured by pilocarpine iontophoresis.A chloride concentration greater than 60 mmol/L isconsistent with cystic fibrosis, and approximately 98%of cystic fibrosis patients will have this abnormalvalue. False positives can occur in diseases that causean increased chloride elevation (glycogen storage dis-ease type I, familial cholestasis, hypothyroidism,eczema, etc.). False negative testing can occur if thepatient is edematous, if an inadequate amount of sweatis collected, or if a methodological testing error occurs(6). Sweat testing can be difficult to perform in infants,and alternative testing may be necessary. More than500 CFTR gene mutations have been described, andgenetic analysis can be performed at some referral lab-oratories. Measurement of nasal potential differencequantifies the electrical potential inherent to nasalmucosa. If performed accurately, this technique is aneffective measurement technique for testing childrenas young as the first day of life. Unfortunately, this testrequires much expertise and should be only performedin experienced centers (6,7).

Stool Smear for Fat/72-Hour Fecal Fat The presence of steatorrhea makes microscopic exami-nation of stool fat losses an easy screening test for pan-creatic insuff i c i e n c y. A simple qualitative technique formeasuring fat malabsorption utilizes the Sudan stain inwhich neutral fat globules are visualized under themicroscope (“fecal fat smear”). This technique is not,

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B

Figure 2. Chest X-ray of a 15-month-old boy with shortstature, chronic diarrhea, and recurrence of unusual infec-tions reveals shortened ribs with thoracic dystrophy (A). Anosseous survey reveals delayed ossification of the femoralepiphyseal centers with irregular proximal femoral metaphy-ses, and tibial shortening (B). The patient was eventuallydiagnosed with Shwachman-Diamond syndrome.

A


h o w e v e r, an accurate assess-ment of total fat losses. Forexample, petroleum jellylubricants used during a rectalexam can cause false-positiveresults. On the other hand, the72-hour fecal fat collection isan effective technique for fatloss quantification. This test isgenerally reserved for infantsgreater than 6 months of age asyounger children can havefecal fat output greater than7% due to immaturity of pan-creatic secretion. Adequate fatintake (i.e., greater than 100grams fat/day in adults or 3grams fat/kg/day in children)is required for the test to bevalid. All stools must be col-lected over a 72-hour period for determination of thefractional excretion of fecal fat. Important limitationsof this test should be considered. Stool collected from atoilet bowl can be lost in toilet water, so samples mustbe collected in an appropriate container system. At ourinstitution, we have noted that absorbent infant diapersalso lead to a similar mechanism of unrecoverable fatloss, and we recommend that diapers be reversed toallow for accurate collection. All stool samples must berefrigerated to prevent bacterial degradation of fat.Constipation can cause a false-negative result, and thecollection time may have to be extended to 5 days insuch clinical scenarios. Once the specimen is collected,it is important to consider what processing technique isutilized. For example, the van de Kamer method doesnot detect medium-chain triglycerides, and it is not auseful test for patients already consuming a diet con-sisting of this fat source (1,4).

Steatocrit Another simple technique for evaluating fat malab-sorption is stool centrifugation in hematocrit tubing tomeasure the amount of separated lipid stool. This tech-nique (“steatocrit”) is only a crude technique todemonstrate the presence of fat malabsorption. It pro-

vides a very imprecise measurement and does not cor-relate well with 72-hour fecal fat testing (4,8).

Trypsin/Chymotrypsin Both trypsin and chymotrypsin are exclusively createdin the pancreas, and their quantitative measurement canbe used to indicate pancreatic function. Both enzymes,especially trypsin, are susceptible to bacterial degrada-tion. A significant amount of chymotrypsin is trapped ininsoluble stool residue and can appear artificially low onmeasurement. Testing by the photometric method hasbeen shown to be fairly accurate, and pancreatic stimu-lation with cholecystekinin (CCK) may improve testingsensitivity (1). Serum trypsinogen measurement byradioimmunoassay also has potential to determine pan-creatic function over time. Patients with cystic fibrosishave trypsinogen levels well below normal by 7 years ofage, and the test has been validated in this disease (3,9).

Breath Testing The breath test has been utilized as a measurement ofpancreatic exocrine function; however, its usefulness inchildren is limited due to obvious physical coordinationd i fficulties of younger children. The loss of antibacterial

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Figure 3. The photograph on the left shows a duodenal lumen near the ampulla prior tointravenous cholecystokinin (CCK) administration for collection of pancreatic secretions.The photograph on the right shows a large pool of pancreatic secretions present five min-utes after CCK administration. The fluid is collected in suction tubing extended from theoperating channel of the endoscope.


activities inherent to pancreatic enzymes as well asimpaired small bowel peristalsis may lead to bacterialo v e rgrowth in patients with impaired exocrine function.Therefore, the hydrogen breath test with glucose admin-istration has been used to demonstrate bacterial over-growth and pancreatic exocrine insufficiency in adultpatients with chronic pancreatitis (10). Other breath testtechniques such as the 13C-mixed triglyceride CO2 e x h a-lation test have been attempted, but there is no clear dif-ferentiation between normal and pathologic values (11 ) .

Secretin/Cholecystokinin The “gold standard” for pancreatic exocrine insuff i-ciency testing is intravenous stimulation and duodenalintubation for collection of pancreatic secretions.Secretin (SecreFlo™, RepliGen Corporation, Wa l t h a m ,Massachusetts), cholecystokinin (Sincalide™, BraccoDiagnostics, Princeton, New Jersey), or a combinationof the agents are administered, and duodenal fluid iscollected within 10 minutes using collection tubingpassed through the operating channel of an endoscope(Figure 3). Fluid is then analyzed for pancreaticenzyme concentrations (12–14). Decreased fluid col-lection has been reported if collection is performedafter 10 minutes of intravenous administration of eitheragent. It is necessary to check specimen pH for gastricacid contamination, and fluid with a pH less than 7 willhave artificially low enzyme levels (12). Drawbacks forthis technique include its inherent invasiveness,extreme care needed to prevent duodenal fluid contam-ination, and lack of standard testing techniques.

Fecal Elastase A new technique that holds significant promise in thediagnosis of pancreatic exocrine function is measure-ment of fecal elastase. Fecal pancreatic elastase 1 isexcreted in stool, can be directly measured from stoolsamples, and is not affected by bacterial degradation orpancreatic enzyme supplementation. Steatorrhea is con-sidered present if the fecal elastase concentration is lessthan 200 µg/g. This test has excellent sensitivity butdecreased specificity when evaluating for exocrine pan-creatic insufficiency in children. In particular, it is a use-ful measurement of pancreatic function in cystic fibrosis,but low fecal elastase levels can occur in children with

short gut syndrome (perhaps due to stool dilution) aswell as patients with Shwachman-Diamond syndromewho otherwise have normal pancreatic function (15,16).

TREATMENTThe cornerstone of effective treatment for pancreaticexocrine deficiency in childhood is enzyme replace-ment. Therapy for all children with pancreatic insuffi-ciency generally follows guidelines that exist for cys-tic fibrosis patients. Infants should receive 2000–4000U lipase for every 120mL of formula (17). Patientsgreater than 1 year of age with CF should receiveenzymes at a dosage of 500 U lipase/kg/meal and 250U lipase/kg/snack. Dosing can be increased as neededto 2500 U lipase/kg/meal or up to 10,000 Ulipase/kg/day. Adequate enzyme replacement can bemeasured by monitoring for steatorrhea, followingweight gain, and performing appropriate pancreatictesting (3,18). Infants will require formulas high inmedium-chain triglycerides due to impaired lipolysis,and fat-soluble vitamin supplementation is recom-mended in all cases of pancreatic dysfunction.

Care must be given to patients with cystic fibrosiswho undergo enzyme replacement therapy as suprather-apeutic dosing can lead to colonic wall thickening andnarrowing. The entity, described as fibrosing colonopa-t h y, presents with progressive symptoms of bowelobstruction, abdominal pain, emesis, constipation, andinflammatory colitis. Often, this disorder can mimic dis-tal intestinal obstruction syndrome (DIOS). Diagnosisrequires a full-thickness colonic biopsy, which revealsfibrosis in the lamina propria. Pediatric patients have anincreased risk of fibrosing colonopathy, and enzymereplacement greater than 6000 U lipase/kg/meal for atleast 6 months is a significant risk factor (4,18,19).

Patients with CF have a low post-prandial duode-nal pH and acid suppression via H2-antagonists or pro-ton pump inhibitors can be helpful in maximizingenzyme efficacy (4,18). Enteric-coated enzyme prepa-rations and acid-resistant microspheres are also helpfulin preventing untoward effects of gastric acid (2,3).

In summary, the primary care provider should beaware of the causes of pancreatic exocrine insuffi-ciency in children. Cystic fibrosis always must be ini-

A SPECIAL ARTICLE





tially considered, and sweat testing is mandatory inany child who presents with failure to thrive, respira-tory difficulty, or possible steatorrhea. We recommendperforming 72-hour fecal fat collection for diagnosisof exocrine pancreatic insufficiency although pancre-atic stimulation with secretin or cholecystokinin andmeasurement of fecal elastase may be necessary ifmore extensive testing is required. ■

References1. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis,

Management. Wyllie R and Hyams JS, editors, 1993; W.B. Saun-ders Company, Philadelphia, PA.

2. Lerner A, Branski D, Lebenthal E. Pancreatic diseases in chil-dren. Pediatr Clin North Am, 1996; 43: 125-156.

3. Roberts IM. Disorders of the pancreas in children. GastroenterolClin North Am, 1990; 19: 963-973.

4. Pediatric Gastrointestinal Disease:Pathophysiology, Diagnosis, Man-agement. Walker W, editor, 1996;Mosby, St. Louis, MO.

5. Durie PR. Pancreatic aspects of cys-tic fibrosis and other inherited causesof pancreatic dysfunction. Med ClinNorth Am, 2000; 84: 609-620.

6. Rosenstein BJ, Cutting GR. Thediagnosis of cystic fibrosis: a con-sensus statement. Cystic FibrosisFoundation Consensus Panel. J Pedi -atr, 1998; 132: 589-595.

7. LeGrys VA. Sweat testing for thediagnosis of cystic fibrosis: practicalconsiderations. J Pediatr, 1996; 129:892-897.

8. Wagner MH, Bowser EK, ShermanJM, et al. Comparison of steatocritand fat absorption in patients withcystic fibrosis. J Pediatr Gastroen -terol Nutr, 2002; 35: 202-205.

9. Couper RT, Corey M, Durie PR, etal. Longitudinal evaluation of serumtrypsinogen measurement in pancre-atic-insufficient and pancreatic-suffi-cient patients with cystic fibrosis. JPediatr, 1995; 127: 408-413.

10. Casellas F, Guarner L, Vaquero E, etal. Hydrogen breath test with glucosein exocrine pancreatic insufficiency.Pancreas, 1998; 16: 481-486.

11. Adamek RJ, Bodeker C, SzymanskiC, et al. 13C-mixed triglyceride CO2exhalation test. Investigation with anisotope selective, non-dispersiveinfrared spectrophotometer of indi-rect function of the exocrine pan-creas. Dtsch Med Wochenschr, 1999;124: 103-108.

1 2 . Del Rosario MA, Fitzgerald JF, GuptaSK, Croffie JM. Direct measurementof pancreatic enzymes after stimula-tion with secretin versus secretin pluscholecystokinin. J Pediatr Gastroen -terol Nutr, 2000; 31: 28-32.

13. Conwell DL, Zuccaro G, Morrow JB, et al. Cholecystokinin-stimulated peak lipase concentration in duodenal drainage fluid:a new pancreatic function test. Am J Gastroenterol, 2002; 97:1392-1397.

14. Ochi K, Harada H, Mizushima T, et al. Intraductal secretin test isas useful as duodenal secretin test in assessing exocrine pancre-atic function. Dig Dis Sci, 1997; 42: 492-496.

15. Walkowiak J, Herzig KH, Strzykala K, et al. Fecal elastase-1 issuperior to fecal chymotrypsin in the assessment of pancreaticinvolvement in cystic fibrosis. Pediatrics, 2002; 110: e7.

16. Beharry S, Ellis L, Corey M, et al. How useful is fecal pancreaticelastase 1 as a marker of exocrine pancreatic disease? J Pediatr,2002; 141: 84-90.

17. Clinical Practice Guidelines for Cystic Fibrosis. Cystic FibrosisFoundation, 1997.

18. Feranchak AP, Sontag MK, Wagener JS, et al. Prospective, long-term study of fat-soluble vitamin status in children with cysticfibrosis identified by newborn screen. J Pediatr, 1999; 135: 601-610.

19. Cystic Fibrosis, 2nd Edition. Hodson ME and Geddes DM, edi-tors, 2000; Arnold Publishers, London, England.

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