Serum Immunoreactive Pancreatic Lipase and Cationic Trypsinogen for the Assessment of Exocrine Pancreatic Function in Older Patients With Cystic Fibrosis

(1)

Serum

Immunoreactive

Pancreatic

Lipase

and

Cationic Trypsinogen

for the Assessment

of

Exocrine

Pancreatic

Function

in Older

Patients

With Cystic

Fibrosis

Geoffrey

Cleghorn,

MBBS,

FRACP,

Lynne

Benjamin,

BSc,

Mary

Corey,

MSc,

Gordon

Forstner,

MD, FRCP(C),

Francesco

Dati,

PhD,

and

Peter

Dune,

MD, FRCP(C)

From the Division of Qastroenterology, Departments of Pediatrics, and the Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada, and Behringwerke AG, Marburg, FederalRepublic of Germany

ABSTRACT.

Indirect and qualitative tests of pancreatic

function are commonly used to screen patients with cystic

fibrosis for pancreatic insufficiency. In an attempt to

develop a more quantitative assessment, we compared

the usefulness of measuring serum pancreatic lipase using

a newly developed enzyme-linked immunosorbent

im-munoassay with that of cationic trypsinogen using a

radioimmunoassay in the assessment of exocrine

pan-creatic function in patients with cystic fibrosis.

Previ-ously, we have shown neither lipase nor trypsinogen to

be of use in assessing pancreatic function prior to 5 years of age because the majority ofpatients with cystic fibrosis in early infancy have elevated serum levels regardless of

pancreatic function. Therefore, we studied 77 patients

with cystic fibrosis older than 5 years of age, 41 with steatorrhea and 36 without steatorrhea. In addition, 28 of 77 patients consented to undergo a quantitative pan-creatic stimulation test. There was a significant differ-ence between the steatorrheic and nonsteatorrheic pa-tients with the steatorrheic group having lower lipase and

trypsinogen values than the nonsteatorrheic group (P <

.001). Sensitivities and specificities in detecting

steator-rhea were 95% and 86%, respectively, for lipase and 93% and 92%, respectively, for trypsinogen. No correlations were found between the serum levels of lipase and

tryp-sinogen and their respective duodenal concentrations because of abnormally high serum levels of both enzymes

found in some nonsteatorrheic patients. We conclude from this study that both serum lipase and trypsinogen

levels accurately detect steatorrhea in patients with cystic

fibrosis who are older than 5 years but are imprecise

Received for publication Jan 8, 1985; accepted May 2, 1985. Presented, in part, at the combined American Pediatric Society/ Society for Pediatric Research meeting in San Francisco, May

1983.

Reprint requests to (P.R.D.) Division of Gastroenterology, The Hospital for Sick Children, 555 University Aye, Toronto, On-tario, Canada, M5G 1X8.

American Academy of Pediatrics.

indicators of specific pancreatic exocrine function above

the level needed for normal fat absorption. Pediatrics

1986;77:301-306; pancreatic lipase, cationic trypsinogen, pancreas function, cystic fibrosis, steatorrhea.

Quantitative pancreatic function tests in patients

with cystic fibrosis have shown that approximately 10% to 15% of patients with cystic fibrosis possess

variable, but sufficient, exocrine pancreatic

func-tion to have normal fat absorption.’ Also, we have

shown that, as a group, those patients with cystic fibrosis who do not have steatorrhea maintain bet-ter pulmonary function and seemingly have a better prognosis than their counterparts with fat malab-sorption.2 Thus, routine pancreatic enzyme replace-ment may not be required in all patients with cystic fibrosis, and because therapy is both unnecessary and may have potential complications, patients

with normal fat absorption should be identified. At present, the quantitative pancreatic stimula-tion test is the most specific and accurate method for estimating exocrine pancreatic function. How-ever, this invasive, direct pancreatic function test is time consuming, expensive, and often beyond the scope of many nonspecialized hospital units. As an alternative to pancreatic stimulation testing, mdi-rect tests ofpancreatic function, such as fat balance studies, the bentiromide test, and 14C02 breath tests, are used to screen for pancreatic

insuffi-ciency.3

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test of pancreatic function. In recent years, it has become possible to detect, using different assay techniques, a variety of pancreatic enzymes, such

as immunoreactive trypsinogen, lipase, and

isoam-ylase

in plasma or serum of both normal individuals

and patients with a variety of conditions affecting

the exocrine pancreas. With the ability to quanti-tate the levels of these circulating enzymes, our

group and others4#{176} have been investigating the

usefulness of their measurement in the assessment

of exocrine pancreatic function in patients with cystic fibrosis.

In a separate study7 of infants and children

younger than 10 years of age with cystic fibrosis,

with and

without steatorrhea, we have shown that

both

serum lipase and trypsinogen values are

sig-nificantly elevated in infants younger than 1 year and decline throughout the first few years of life. Prior to 5 to

7

years of age, there was no correlation between either serum enzyme and the presence or absence of steatorrhea, but in a small number of patients older than 5 years, there was a suggestion

that both lipase and trypsinogen

values were of use

in distinguishing cystic fibrosis children with pan-creatic insufficiency from cystic fibrosis children

with

normal fat absorption. The purpose of the present study, therefore, was to examine and com-pare the usefulness of serum lipase with immuno-reactive trypsinogen for the assessment of exocrine pancreatic function in a larger number of patients older than 5 years, both with and without steator-rhea, who were known to have cystic fibrosis.

METHODS

We studied

77 patients

(mean

age 17.7 years,

range 5 to 41; 37 males and 40 females), older than

5 years,

who

were known to have cystic .fibrosis

based upon typical clinical features and at least two elevated sweat chloride determinations (>60 mEciJ L). All patients included in this study were being treated at the cystic fibrosis clinic, the Hospital for Sick Children, Toronto. This study was ap-proved by the Ethics and Human Experimentation Committee of the Hospital for Sick Children.

Assessment

of Pancreatic

Function

Fecal fat output was estimated in three-day stool collections by the method of van der Kamer et a!.8

In any patient receiving medium chain triglyceride

supplements, fecal fat output was estimated using the methods of Jeejeebhoy et al.9 Fecal fat output was expressed as a percentage of fat intake as

determined by dietary recording and weighing and

with reference to standard food content tables.

Pa-tients with cystic fibrosis were considered to have

pancreatic insufficiency if they had fecal fat outputs

>7%

of intake on previous fat balance studies.

Cystic fibrosis patients with fecal fat outputs

s7%

of intake were

considered

to have pancreatic suffi-ciency. The term pancreatic sufficiency has been

coined

for cystic fibrosis patients with probable

pancreatic pathology and variable loss of function but who have sufficient residual pancreatic activity for normal fat absorption.’#{176} Thirty-six patients (mean age 19.0 ± 1.5 years, range 6.5 to 36.7 years) were considered to have pancreatic sufficiency by these criteria and 41 patients (mean age 15.9 ± 1.5 years, range 5 to 41 years) were considered to have pancreatic insufficiency.

Pancreatic

Stimulation

Test

Twenty-eight of the

77

patients with cystic

fibro-sis included in the study consented to undergo a

simultaneous, quantitative pancreatic stimulation

test. This involved intubation of the duodenum

with

a double-lumen tube so that one lumen opened

proximally near the ampulla of Vater and the other,

which

contained several ports, was positioned

dis-tally at the ligament of Treitz. A nonabsorbable

marker

solution

was infused through the proximal

opening at a constant rate, and pancreatic juice

mixed with marker solution was aspirated through the distal port during an initial collection period of 20 minutes without stimulation and then during 1

hour with continuous intravenous infusion of

secre-tin and pancreozymin. Gastric juice was aspirated

through

a separate nasogastric tube to prevent

con-tamination of duodenal contents. Duodenal

aspi-rates were

analyzed

for colipase, total lipase, and

trypsin content by titermetric techniques.11”2 En-zyme output was corrected for distal losses and expressed in units per kilogram of body weight per

hour. All individuals with fat malabsorption had

extremely low enzyme output values consistent with data previously reported from our laboratory. The range of enzyme output in the patients with

cystic fibrosis

without

steatorrhea

was extremely

wide

from values marginally above the threshold for developing steatorrhea to outputs well within the normal control range.”

On the basis of the stimulation test and previous experience from our laboratory,4”13”4 the 28 pa-tients with cystic fibrosis were divided into two groups: low and adequate enzyme output groups. These groups represented the range of pancreatic function seen in cystic fibrosis, with the low enzyme output group corresponding to patients at or below the threshold for developing steatorrhea and the adequate output group corresponding to patients

without

steatorrhea

but with pancreatic

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160

140

120

100

80

60

40

20

0 :‘ #{149}. #{149}#{149}.

:,

‘. .: , . . , . J .

5 9 13 17 21 25 29 31 33 37

AGE YEARS

Fig 1.

Serum trypsinogen plotted against age in patients with cystic fibrosis older than 5 years. 0, Patients with pancreatic sufficiency;

#{149},

patients with pancreatic insuf-ficiency; horizontal interrupted line, 97.5th percentile of standard error of estimate for cystic fibrosis patients with pancreatic insufficiency. No correlation existed between

serum trypsinogen and age for either pancreatic

insuffi-cient (r = .1) or sufficient (r = .12) patients.

SERUM LIPASE g/L

2201 0

180

160

140

120

100#{149}

80

60

40

20 #{176}#{176}#{176}

_

_o___o

A .4.:’#{149}

#{149}

#{149}. #{149}#{149}.#{149}#{149} #{149} . #{149}

j

#{149} - S

AGE YEARS

Fig 2.

Serum pancreatic lipase plotted against age in patients with cystic fibrosis older than 5 years. 0,

Pa-tients with pancreatic sufficiency;

#{149},

patients with

pan-creatic insufficiency; horizontal interrupted line, 97.5th percentile of standard error of estimate for cystic fibrosis

patients with pancreatic insufficiency. No correlation

existed between serum lipase and age for either pan-creatic insufficient (r = .17) or sufficient (r = .01) pa-tients.

for noncystic fibrosis controls.4”3”4 Thus, serum trypsinogen was compared with pancreatic trypsin output: low trypsin output (50 U/kg/h, n = 6),

adequate trypsin output (>50 U/kg/h, n = 22), and serum lipase was compared with total pancreatic

lipase

output: low lipase output (250 U/kg/h, n =

8) and adequate

lipase

output (>250 U/kg/h, n =

20). Although the duodenal output of pancreatic trypsin and lipase was highly correlated (r =

.73,

P

< .01), some individual patients exhibited a degree of nonparallel loss for trypsin and lipase output

and, thus, the patient groups were not identical.

Assay

of Serum

Pancreatic

Enzymes

A random blood sample was obtained from each patient, centrifuged, and the serum stored at -70#{176}C until analyzed. Serum lipase was measured using

an enzyme-linked immunosorbent immunoassay

(ELISA) double-antibody sandwich technique as

described by Grenner

et al.’5 In brief, the method-ology entailed the addition of serum (200 tL) to

plastic tubes coated

with specific antibodies to

li-pase raised in sheep. After incubation (two hours at

25#{176}C),

the test tubes were washed and

peroxi-dase-conjugated

antibodies

to

human lipase added.

After further incubation (two hours at 25#{176}C),a

second washing step

was performed. Bound

perox-idase activity was determined in a reaction using

hydrogen

peroxide

as substrate and

o-phenylene-diamine as chromogen. The reaction was stopped

using

sulfuric acid and the lipase concentration measured photometrically at 492 nm. Cationic

tryp-sinogen

was measured in each serum sample using

the double-antibody radioimmunoassay technique

of Geokas

et al’6 which

has previously

been

de-scribed

in detail.’7

DATA

ANALYSIS

Geometric means were calculated because of the

unequal distribution of the results. Comparisons were made with age, trypsinogen, and lipase, and the standard error of the estimate was calculated.’8 Serum trypsinogen and lipase values were com-pared using regression analysis, single factor anal-ysis of variance by ranks, and also with the

duo-denal outputs of trypsin and total lipase values obtained from the quantitative stimulation tests.

RESULTS

The individual data points ofboth serum trypsin-ogen and lipase, respectively, were plotted against age for all of the patients with cystic fibrosis studied (Figs 1 and 2). The interrupted horizontal lines in

each figure represents the 97.5th percentile of the

standard

error of the estimate for trypsinogen and

SERUM TRYPSINOGEN ,g/L

180

(4)

175#{149}

150

125

100

80

70

60

50

40

30

20

10

#{149}1#{149}#{149}#{149} #{149}

TABLE.

Sensitivities and Specificities of Serum

Pan-creatic Lipase and Cationic Trypsinogen in Detecting

Steatorrhea in Patients With Cystic Fibrosis Older Than

5 Years*

Sensitivity 95% (39/41) 93% (38/41) 88% (36/41)

Specificity 86% (31/36) 92% (33/36) 94% (34/36)

* Results are percentages of patients with (sensitivity)

and without (specificity) steatorrhea. Numbers of

pa-tients are in parentheses.

lipase for the patients with pancreatic insufficiency. SERUM TRYPSINOGEN ng/mI

The open circles represent the trypsinogen and

lipase values

for the patients with cystic

fibrosis

without steatorrhea, and the closed circles

repre-sent

those patients with pancreatic insufficiency.

Unlike

our previous data in children with cystic

fibrosis

younger than 5 years,7 no age-related trends were apparent for either trypsinogen or lipase.

Serum trypsinogen clearly distinguished between

the cystic fibrosis patients with and without

stea-torrhea. Ninety-three percent (38/41) of the cystic

fibrosis patients with pancreatic insufficiency had

serum trypsinogen values below the 97.5th

percent-ile for the standard error of the estimate for pan-creatic insufficiency. Only three of 36 (8%) patients with pancreatic sufficiency had trypsinogen values

below

this point (Fig 1). Serum lipase was equally

useful

in screening for pancreatic insufficiency

be-cause 95% (39/41) of the cystic fibrosis patients

with pancreatic insufficiency had serum lipase

val-ues

below

the 97.5th percentile for the standard

error

of the estimate for pancreatic insufficiency

and only five (14%) of the 36 patients with

pan-creatic sufficiency had lipase values below this point (Fig 2).

We assessed the usefulness of the combined

mea-surements

of

trypsinogen and lipase in screening

for pancreatic insufficiency in these patients.

En-zyme measurements for each patient were

com-pared with one another (Fig 3). The intersecting

horizontal

and vertical lines in Fig 3 represent the

97.5th percentile for the standard error of the

esti-mate for pancreatic insufficiency for trypsinogen

and lipase, respectively. Serum trypsinogen and

lipase levels were highly correlated in both the

pancreatic insufficient (r =

.77,

P

< .001) and pancreatic sufficient (r

=

.90, P < .001) groups. In

88%

(36/41)

of the

cystic

fibrosis

patients

with

pancreatic

insufficiency, the combined

measure-ment of trypsinogen and lipase were below the 97.5th percentile limits, whereas only two of 36 (6%) of the pancreatic sufficient patients had com-bined measurements below this point. The

sensitiv-ities

and specificities of the individual enzymes

alone and for the combined measurements of

tryp-sinogen and lipase

in detecting pancreatic

insuffi-ciency are shown in the Table. Both enzymes are

highly specific and sensitive when measured

mdi-vidually;

however, there is no improvement when

trypsinogen and lipase values are combined.

As previously mentioned, the quantitative

pan-creatic

stimulation test is the most specific and

accurate method of measuring the entire range of pancreatic exocrine function. The serum

trypsino-gen and lipase values for the “low” and “adequate” pancreatic function groups are shown in Fig 4. The

0 10 20 30 40 50 100 150 200 250

SERUM LIPASE gIL

Fig 3.

Serum trypsinogen compared with serum

pan-creatic lipase in patients with cystic fibrosis older than 5

years.

0,

Patients without steatorrhea;

#{149},

patients with

steatorrhea; intersecting horizontal and vertical lines,

97.5th percentile for standard error of estimate for cystic

fibrosis patients with steatorrhea for trypsinogen and

lipase, respectively. Significant correlations existed for

both pancreatic insufficient (r = .77,

P

< .001) and

sufficient (r = .90, P < .001) patients.

Lipase Trypsinogen Lipase -I’

Trypsinogen

horizontal lines represent the two standard

devia-tions of the normal age-related range for serum trypsinogen (16 to 46 tg/L) and lipase (10 to 40.5 tg/L). In the low trypsin output group, the geomet-rid mean serum trypsinogen value was 6.1 tg/mL, and for the adequate trypsin output group, it was 48.2 tg/L. The geometric mean serum lipase values were 4.6 tg/L and 32.3 g/L for the low and ade-quate total lipase output groups, respectively. There was, however, great variability in the serum

tryp-sinogen and lipase levels within the adequate

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220 200 -180 120 100-#{163} -J DI

z

w 0 0

_z

C,)

>-a:

w U) s-s. 60 LOW ADEQUATE

TOTAL LIPASE OUTPUT

[#{174}JL

LOW ADEQUATE

DUODENAL TRYPSIN OUTPUT

Fig 4. Comparison between serum pancreatic trypsino-gen, lipase, and pancreatic function as determined by

quantitative stimulation testing. Low = duodenal trypsin output 50 U/kg/h, duodenal lipase output 250 U/kg/ h. Adequate = duodenal trypsin output > 50 U/kg/h,

duodenal lipase output > 250 U/kg/h.

between serum trypsinogen and duodenal trypsin output and pancreatic lipase and total lipase output revealed a gross separation into very low output and adequate output groups. There was, however, no overall correlation between the serum and duo-denal enzyme levels (trypsinogen v duodenal

tryp-sin, r

=

.10, not significant; pancreatic lipase v total lipase, r

=

.01, not significant) because of

abnor-mally elevated serum levels of both enzymes in

many pancreatic sufficient patients.

DISCUSSION

This study has shown that either serum cationic trypsinogen or lipase measurements will detect in excess of 90% of patients with cystic fibrosis older than 5 years who have steatorrhea. Although each enzyme appears to be equally as efficient in detect-ing steatorrhea, the specificity is not significantly increased by the combined measurement of both

enzymes simultaneously.

In a previous publication involving a limited number of patients,’9 we suggested that serum cat-ionic trypsinogen levels were possibly as effective

as duodenal trypsin output levels in determining

subtle changes in pancreatic function in older

pa-tients with cystic fibrosis. From the present study, based on a larger number of patients, it is apparent that this is not the case. Because many of the

pancreatic sufficient patients with cystic fibrosis

had diminished exocrine pancreatic function, as

shown by quantitative pancreatic stimulation

test-ing, one would expect similarly diminished levels of circulating trypsinogen and lipase. In fact, many of

these patients had normal or even elevated circu-lating enzyme levels. This suggests that there may be an element of pancreatic ductular obstruction with resultant reflux of trypsinogen and lipase into the circulation. Recently, we showed that patients with cystic fibrosis at all levels of pancreatic

func-tion secrete significantly less water than controls

without cystic fibrosis with equivalent pancreatic exocrine function.2#{176} It is possible that this defect in

pancreatic water secretion could cause increased

viscosity of secretions and obstruction in the pan-creatic ductules of patients with cystic fibrosis,

which, in turn, could lead to increased reflux of

pancreatic enzymes into the circulation. These

con-cepts will be the subject of further communications

from our laboratory.

We

conclude from this study that serum lipase

and trypsinogen values are equally effective in

de-tecting pancreatic insufficiency, manifest clinically

as steatorrhea, in patients with cystic fibrosis who

are older than 5 years, but neither appear to be

precise indicators of the exact level of exocrine pancreatic function. However, the ELISA method

used for detecting serum pancreatic lipase in this

study does not involve the use of radioisotopes and is much quicker, and, hence, preferable for routine

clinical studies, than the radioimmunoassay tech-nique for cationic trypsinogen. Clinically, the de-termination of pancreatic function in patients with

cystic fibrosis is vital at the time of diagnosis, which in the majority of patients is in the first few years

of life. Unfortunately, neither serum lipase nor trypsinogen are of use in assessing pancreatic

func-tion in this age group and some other method of

testing pancreatic functions such as the serum

p-aminobenzoic acid test may be useful.’#{176}’2’We

spec-ulate, however, that patients with cystic fibrosis

older than 5 years who have elevated levels of serum

trypsinogen or lipase are at risk for failing exocrine pancreatic function and that it may be possible to monitor the pancreatic function of these patients

using either serum trypsinogen or lipase

determi-nations. However, only a long-term, longitudinal, comparative study between serum lipase and

tryp-sinogen and quantitative pancreatic stimulation

data will

resolve this question.

ACKNOWLEDGMENTS

This work was supported by a grant from the Canadian

Cystic Fibrosis Foundation. Dr Cleghorn was a recipient

of a research fellowship from the Canadian Cystic Fibro-sis Foundation.

The ELISA kits for serum lipase were donated by

Behringwerke AG, Marburg, Federal Republic of

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DESCARTES

ON TRUTH

AND PROBABILITY

It

is a truth very certain that when it is not in our power to determine what

is

true we ought to follow what is most probable.

(7)

1986;77;301

Pediatrics

Peter Durie

Geoffrey Cleghorn, Lynne Benjamin, Mary Corey, Gordon Forstner, Francesco Dati and

Assessment of Exocrine Pancreatic Function in Older Patients With Cystic Fibrosis

Serum Immunoreactive Pancreatic Lipase and Cationic Trypsinogen for the

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