The n e w e ng l a n d j o u r na l
case records of the massachusetts general hospital
From the Departments of Pediatric Gas-
troenterology, Hepatology, and Nutrition
(U.S.), and Radiology (A.S.S.-B.), Massa-
chusetts General Hospital; and the De-
partments of Pediatrics (U.S.) and Radi-
ology (A.S.S.-B.), Harvard Medical
School — both in Boston.
N Engl J Med 2011;365:1528-36.
Copyright © 2011 Massachusetts Medical Society.
1528
Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor
Case 32-2011: A 19-Year-Old Man
with Recurrent Pancreatitis
Uzma Shah, M.D., and Anuradha S. Shenoy-Bhangle, M.D.
Pr e sen tat ion of C a se
Dr. Christopher J. Moran (Pediatric Gastroenterology): A 19-year-old man was admitted
to this hospital because of recurrent pancreatitis.
The patient had been well until approximately 6 months earlier, when lethargy
and epigastric pain developed, associated with a dry throat, subjective fever, and
frontal headache, which were relieved by acetaminophen. He went to a clinic for
evaluation. He reported that 3 days earlier he had consumed six alcoholic beverages
in one sitting (0.7 to 1.0 liters of vodka and two beers). On examination, the blood
pressure was reportedly 140/100 mm Hg. A rapid screening test for streptococcus
was positive. Penicillin and an antacid were prescribed, without improvement in the
pain. Two days after the onset of pain, the patient saw his pediatrician. On examina-
tion, the blood pressure was 142/100 to 152/100 mm Hg. A monospot test was
negative. The epigastric pain decreased slightly, and pain in the flanks and back
developed. He returned to his pediatrician; laboratory-test results are shown in
Table 1. Computed tomography (CT) of the abdomen reportedly showed fat strand-
ing and inflammation of the pancreas, features consistent with pancreatitis, with
a normal gallbladder and no evidence of dilatation or obstruction of the biliary tree.
He was transferred to this hospital.
The patient reported constant epigastric pain, which he rated at 7 on a scale of
0 to 10, with 10 indicating the most severe pain. The pain intermittently increased
in intensity and changed location with positioning. The patient had had constipa-
tion, difficulty sleeping because of the pain, decreased appetite, and during the
previous week, weight loss of approximately 4.5 kg, without nausea, vomiting, or
hematuria. His symptoms were not relieved by the administration of antacids, acet-
aminophen, lansoprazole, psyllium fiber supplement, polyethylene glycol, or defeca-
tion. The temperature was 38.1°C, the blood pressure 139 to 162 mm Hg systolic
and 77 to 90 mm Hg diastolic, and the pulse 96 beats per minute; the respiratory
rate was normal, and the oxygen saturation was 95% while he was breathing am-
bient air. The weight was 142.2 kg, the height 188 cm, and the body-mass index
(BMI, the weight in kilograms divided by the square of the height in meters) 40
(>97th percentile). The posterior oropharynx was erythematous, with moist mucous
membranes; there was white plaque on the tongue. The abdomen was soft, with
decreased bowel sounds, tenderness to deep palpation in the epigastrium, and slight
n engl j med 365;16  nejm.org  october 20, 2011
The New England Journal of Medicine
 case records of the massachusetts gener al hospital
guarding; there was no distention or rebound.
There was tenderness in the midback and no ten-
derness at the costovertebral angle. The skin was
diffusely flushed on the cheeks, extremities, and
trunk. The red-cell indexes and platelet count were
normal, as were tests of renal function and mea-
surements of electrolytes, glucose, phosphorus,
calcium, protein, albumin, total and direct biliru-
bin, alkaline phosphatase, aspartate aminotrans-
ferase, cholesterol, triglycerides, and low-density
lipoprotein cholesterol; other test results are shown
in Table 1. Urinalysis revealed 1+ ketones and bili-
rubin and trace urobilinogen.
The patient was admitted to this hospital. In-
travenous fluids, narcotic analgesia, and omepra-
zole were administered, with improvement. Ini-
tial restriction of oral intake was followed by a
gradually increasing diet. He was discharged on
the fifth day on a low-fat diet and referred to the
Division of Adolescent and Young Adult Medicine
for primary care, blood-pressure monitoring,
a weight-loss program, and a discussion about
high-risk behaviors, including binge drinking. At
follow-up, results of thyroid-function tests were
normal and testing for hepatitis B and C viruses
was negative; other test results are shown in
Table 1.
The patient abstained from alcohol for 3 months
and then began to drink socially again. Two weeks
later, severe abdominal pain recurred, with radia-
tion to the back and decreased appetite. On the
fifth day of symptoms, he was readmitted to this
hospital. On examination, the blood pressure was
142/98 mm Hg; other vital signs were normal.
There were abdominal striae, decreased bowel
sounds, a palpable liver edge, and mild tenderness
to deep palpation in the epigastrium; the re-
mainder of the examination was normal. The
prothrombin time was 14.4 seconds (reference
range, 10.3 to 13.2); other tests of coagulation and
renal function were normal, as were measure-
ments of electrolytes, glucose, protein, albumin,
globulin, bilirubin, alkaline phosphatase, and as-
partate aminotransferase. Other test results are
shown in Table 1. Results of an abdominal ul-
trasound examination were normal. Intravenous
fluids and morphine were administered, with im-
provement. The patient was discharged on the
fourth day.
At follow-up visits in the Adolescent and Young
Adult Medicine Division during the next 6 weeks,
the patient felt well and the blood pressure was
n engl j med 365;16  nejm.org  october 20, 2011
The New England Journal of Medicine
Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
normal; test results are shown in Table 1. Dur-
ing the next 5 weeks, he consumed one or two
alcoholic beverages approximately twice a week.
Three days before this admission, abdominal pain
(rated at up to 9 on a scale of 0 to 10) recurred that
was associated with nausea, decreased appetite,
clamminess, and light-headedness. He was read-
mitted to this hospital.
The patient had received all routine immuni-
zations and had been well. He was a college stu-
dent and lived in an apartment with other students
when not living with his parents and sibling. He
smoked one or two cigarettes weekly and report-
ed no use of illicit drugs. His girlfriend had re-
cently had infectious mononucleosis. His father
had high cholesterol, his maternal grandfather
had coronary artery disease, his maternal grand-
mother had throat cancer, and other maternal
relatives had type 1 diabetes mellitus and gall-
stones; paternal and maternal family members
reportedly had alcoholism.
On examination, the blood pressure was
160/93 mm Hg and the weight 133.5 kg; other
vital signs and the oxygen saturation were normal.
There were decreased bowel sounds, pain in the
upper quadrants that radiated to the back and
occurred at rest and with palpation, and no dis-
tention or rebound. The remainder of the exami-
nation was normal. Urinalysis revealed clear, am-
ber urine with 1+ bilirubin, 2+ ketones, and trace
albumin and urobilinogen; it was otherwise nor-
mal. Laboratory-test results are shown in Table 1.
Ultrasonography of the abdomen revealed mild
splenomegaly (14 cm). Intravenous fluids, raniti-
dine, and narcotic analgesics were administered,
with symptomatic improvement. On the second
day, tests for heterophile antibody and antibodies
to Epstein–Barr virus (EBV) were negative; T-lym-
phocyte subsets were normal.
Magnetic resonance imaging (MRI) of the ab-
domen after the administration of gadolinium and
magnetic resonance cholangiopancreatography
(MRCP) revealed a normal pancreas and pancre-
atic duct. The common bile duct was normal, with
no calculi.
A diagnostic test was performed.
Differ en t i a l Di agnosis
Dr. Uzma Shah: When he was 19 years of age, this
previously well young man began to have recur-
rent episodes of abdominal pain, with laboratory
1529
 1530
Table 1. Laboratory Data.*

Reference Range, Pediatrician’s

Variable Age-Adjusted† Office This Hospital
Outpatient Outpatient Outpatient
Follow-up, 2nd Admission, Follow-up, Follow-up, 3rd Admission,
5 Days before Day of 1st 15 Days after 3.5 Mo after 3.75 Mo after 4.75 Mo after 6 Mo after
Admission Admission Admission 1st Admission 1st Admission 1st Admission 1st Admission
The

Hematocrit (%) 41.0–53.0 (men) 39.9 44.4 46.4

Hemoglobin (g/dl) 13.5–17.5 (men) 14.5 16.2 17.2
White-cell count (per mm 3) 4500–13,000 16,200 18,100 6000 4700
Differential count (%)
Neutrophils 40–62 80 87 66 66
Lymphocytes 27–40 8 8 23 23
Monocytes 4–11 4 8 9
Eosinophils 0–8 1 3 1
n e w e ng l a n d j o u r na l

Basophils 0–3 0 0 1

The New England Journal of Medicine

of

Magnesium (mmol/liter) 0.7–1.0 1.2 1.1

Lipase (U/liter) 13–60 74 47 440 47 256
Amylase (U/liter) 3–100 99 69 246 54 54 180

n engl j med 365;16  nejm.org  october 20, 2011

Alanine aminotransferase (U/liter) 10–55 31 92 29 30 41 59

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

m e dic i n e

High-density lipoprotein cholesterol (mg/dl) 35–100 21

* To convert the values for magnesium to milligrams per deciliter, divide by 0.4114. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are age-adjusted
for patients who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.

Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
 case records of the massachusetts gener al hospital
evidence of acute pancreatitis, that required re-
peated hospitalizations.
Causes of Recurrent Acute Pancreatitis
When acute episodes of pancreatitis occur repeat-
edly, as they have in this patient, the condition is
described as recurrent acute pancreatitis. Acute
pancreatitis is much less common in children and
adolescents than in adults, and the causes differ
between the two groups.1 It is important to deter-
mine the cause in this patient and treat it, since
recurrent acute pancreatitis may result in injury
to the pancreatic duct and progressive inflamma-
tion and scarring of the duct, leading to chronic
pancreatitis. Chronic pancreatitis may result in
exocrine and endocrine pancreatic insufficiency
and an increased risk of pancreatic cancer. In
this case, I would first investigate the most com-
mon causes of acute and chronic pancreatitis
(Table 2).2,3
Structural abnormalities
One of the most common causes of acute pancre-
atitis is obstruction of the pancreatobiliary tree.2‑6
It is important to rule out gallstones, structural
anomalies of the duct, and cysts. Although 40% of
episodes of acute pancreatitis in adults are caused
by gallstones, pancreatitis developed in only 4%
of 382 children with gallstones in one study.7 It
would nonetheless be important to consider a di-
agnosis of gallstones in this adolescent, in view
of the high BMI and family history of elevated
cholesterol levels and cholelithiasis.
Other, rarer structural anomalies that should
be considered include pancreas divisum, chole-
dochal cysts, annular pancreas, and dysfunction
of the sphincter of Oddi.7,8 In this case, the first
imaging study was CT, performed at another fa-
cility, rather than ultrasonography, which is pre-
ferred. On the CT scan, the gallbladder appeared
normal, with no evidence of biliary-duct dilata-
tion or obstruction. MRCP or endoscopic retro-
grade cholangiopancreatography (ERCP) would al-
low better examination of the biliary tree for
evidence of pancreas divisum.9
May we review the imaging studies?
Dr. Anuradha S. Shenoy-Bhangle: Ultrasound ex-
amination of the abdomen was the first study
performed at this hospital. In pediatric patients
with pancreatitis, our initial screening tool is
ultrasonography.10,11 It is a noninvasive bedside
procedure, involves no radiation, and is the best
n engl j med 365;16  nejm.org  october 20, 2011
The New England Journal of Medicine
Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Table 2. Causes of Acute and Chronic Pancreatitis
in Children.*
Acute Chronic
Cause Pancreatitis Pancreatitis
percent
Biliary-duct obstruction 26.2 40.6
Idiopathic 18.5 31.2
Medication 20.3 6.25
Trauma 7.7
Systemic disease 7.4
Viral infection 5.5 3.1
Metabolic 0.8
Genetic 18.75
* Data are from Clifton et al.2 for chronic pancreatitis (per-
centages do not total 100 because of rounding) and from
Park et al.3 for acute pancreatitis (some patients had
more than one cause).
imaging method for seeing gallstones. Biliary ob-
struction and choledochal cysts are also evident.
The disadvantage is poor visualization of the pan-
creas and pancreatic ductal anatomy, so that con-
genital anomalies such as pancreas divisum or
annular pancreas, which are the most common
causes of pediatric pancreatitis, are not shown
well. In this case, ultrasonography revealed an
absence of cholelithiasis, cholecystitis, ascites, or
loculated fluid collections in the abdomen. The
pancreas was obscured by bowel gas and thus was
poorly visualized. There was borderline spleno-
megaly and no imaging evidence of portal hy-
pertension.
After recurrent episodes of pancreatitis, secre-
tin-enhanced MRCP and MRI of the abdomen were
performed. At this hospital, we find that MRCP
is the best method for assessing pancreatic duc-
tal anatomy and congenital anomalies of the pan-
creaticobiliary system. It is noninvasive (in con-
trast to ERCP), does not involve radiation, and can
reveal congenital anomalies and cysts. Secretin
can be administered to distend the pancreatic
duct, allowing better visualization of the ductal
anatomy and quantification of pancreatic exocrine
function.12 A disadvantage of MRI in young chil-
dren is that sedation or anesthesia may be re-
quired. We do not use CT as a primary diagnos-
tic tool for acute pancreatitis; it is reserved for
diagnostic mysteries or the evaluation of compli-
cations. In this case, MRCP revealed a single,
normal-size pancreatic duct, with no evidence of
1531
 The n e w e ng l a n d j o u r na l of m e dic i n e

and gallstones. Metabolic causes of chronic pan-

A creatitis include hyperlipidemias (due to lipopro-
tein lipase deficiency and apolipoprotein C2 defi-
ciency) and less common causes, such as defective
transport of amino acids. Hypertriglyceridemia in
particular may be a risk factor for acute pancre-
atitis in patients who have some genetic muta-
tions that increase the risk of pancreatitis.13 This
patient’s lipid profile, blood chemical profile, and
thyroid screening were normal.

Toxins
Although there is a long list of drugs that lead to
B pancreatitis, the most common are anticonvulsant
agents, chemotherapy agents for the treatment of
cancer, and diuretics. This patient received peni-
cillin during the first episode of pancreatitis. This
antibiotic has been associated with pancreatitis
but would be unlikely to cause recurrent episodes.
Drug-induced injury was unlikely to have been
the cause of his symptoms.

Figure 1. Imaging of the Pancreas.
A contrast-enhanced MRI scan (Panel A) shows a ho-
mogeneously enhancing pancreas (arrow) with no evi-
dence of annular pancreas. Magnetic resonance chol-
angiopancreatography (Panel B) reveals a normal-size
pancreatic duct (arrow) and a normal common bile
duct (arrowhead). No pancreas divisum is identified.
pancreas divisum or annular pancreas (Fig. 1).
The duct distended normally in response to the
administration of secretin and reverted back to
normal size within 10 minutes after administra-
tion. The common bile duct was normal and had
no calculi in it. There was no pancreatic paren-
chymal necrosis.
Dr. Shah: Structural and obstructive causes of
the patient’s pancreatitis are ruled out by these
studies.
Metabolic causes
This patient had a high BMI and had been hyper-
tensive on many occasions. Although hyperten-
sion may be a clinical manifestation of acute pan-
creatitis and pain, it was unclear whether the
patient had had hypertension before these epi-
sodes. Because of his high BMI, a metabolic dis-
ease should be considered. His family history in-
cluded hypercholesterolemia, diabetes mellitus,
Infection
The patient was febrile and had an elevated white-
cell count during the episodes of pancreatitis;
therefore, infectious causes should be considered.
He had intermittent mild elevations in serum al-
anine aminotransferase levels. Although a rapid
streptococcal screen was positive on his initial pre-
sentation, tests for other infectious agents associ-
ated with acute pancreatitis (e.g., EBV) and tests
for infectious agents associated with recurrent
inflammation (e.g., hepatitis B and C viruses and
the human immunodeficiency virus) were nega-
tive. His girlfriend reportedly had had infectious
mononucleosis, but repeat testing of the patient
for acute EBV infection was negative. An infec-
tious cause for his pancreatitis seemed unlikely.
Systemic diseases
On ultrasound examination, mild splenomegaly
was identified. Splenomegaly is occasionally seen
during episodes of pancreatitis, but it may be a
clinical feature of systemic autoimmune diseases
such as autoimmune pancreatitis, inflammatory
bowel disease, and primary sclerosing cholangi-
tis. Therefore, an evaluation for autoimmune pan-
creatitis was indicated, including measurement
of serum IgG4, antinuclear antibody, and rheu-
matoid factor.14 The patient’s IgG4 level was nor-
mal, and there was no evidence of beading of the
biliary duct on imaging, as would be seen with
sclerosing cholangitis.

1532 n engl j med 365;16 nejm.org october 20, 2011

The New England Journal of Medicine

Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 case records of the massachusetts gener al hospital
Genetic causes
An alcohol binge preceded the first episode of
acute pancreatitis in this patient. In adults, alco-
hol accounts for 35 to 40% of all cases of acute
pancreatitis; in children, this would be unusual.4
However, alcohol is a trigger for pancreatitis in
children with an underlying genetic or metabolic
predisposition. Genetic mutations are an impor-
tant cause of recurrent and chronic pancreatitis
in pediatric patients (Table 2), and the episodes
of pancreatitis are frequently triggered by hy-
perlipidemia or, as in this patient, alcohol con-
sumption.13,15,16 Among children with chronic
pancreatitis, 30% of cases are considered to be
idiopathic, possibly because of mutations that have
not yet been identified.2 Identifying a genetic
mutation in this patient would have important
implications for his future, since mutations are
associated with an increased risk of the develop-
ment of pancreatic insufficiency and pancreatic
cancer.17-19
How could a genetic abnormality cause the re-
current episodes of pancreatitis in this patient? In
the pancreas, there is a delicate balance between
trypsinogen and its activated form, trypsin (Fig.
2).16 Uncontrolled action of trypsin causes inflam-
mation and pancreatitis. Genetic factors can in-
fluence this balance. Cationic trypsinogen (en-
coded by PRSS1), a high calcium level, and a low
pH promote activation of trypsinogen to trypsin.
Calcium levels are regulated in part by the calcium-
sensing receptor (encoded by CASR) and dysregu-
lated by ethanol. Trypsin is removed both by deg-
radation and by excretion via the pancreatic duct.
Degradation is facilitated by chymotrypsin C (en-
coded by CTRC), and the cystic fibrosis transmem-
brane conductance regulator (encoded by CFTR)
functions to eliminate trypsin by flushing the
pancreatic duct. If inflammation occurs, it leads
to up-regulation of expression of the serine pro-
tease inhibitor Kazal type 1 (encoded by SPINK1),
which blocks trypsin, prevents further activation
of trypsinogen, and limits further tissue injury.
PRSS1
Gain-of-function mutations in the PRSS1 (serine
protease 1) gene are the most common cause of
autosomal dominant hereditary pancreatitis. These
mutations lead to increased trypsin in the cells,
which promotes inflammation.17-19 A diagnosis is
made in adolescence in most patients. Alcohol,
smoking, and dietary fat are triggers for inflam-
mation.
n engl j med 365;16  nejm.org  october 20, 2011
The New England Journal of Medicine
Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
SPINK1
Mutations in SPINK1, also called the pancreatic se-
cretory trypsin inhibitor gene, confer an increased
risk of pancreatitis due to an inability of the pan-
creatic acinar cells to inhibit intracellular tryp-
sin. A combination of genetic and environmental
factors influences the development of pancreati-
tis. In several series,17-19 16 to 23% of previous­
ly “idiopathic” cases of pancreatitis were due to
SPINK1 mutations. The N34S mutation, in par-
ticular, has frequently been associated with pan-
creatitis.20
CFTR
Mutations in the CFTR gene, inherited in an auto-
somal recessive pattern, are an important cause
of chronic pancreatitis. Several studies have shown
that CFTR mutations, including uncommon or mild
mutations, may be identified in patients with id-
iopathic chronic pancreatitis, suggesting that ad-
ditional genetic or environmental disease modi-
fiers may be present.21,22 Four subtypes of CFTR
mutations have been proposed as causes of chron-
ic pancreatitis. Type 1 is associated with two se-
vere mutations and is the classical form of cystic
fibrosis. In type 2, which has variable severity,
one allele has a severe mutation and one has a
mild mutation. Type 3 is characterized by CTFR
mutations that are similar to those seen in type 2,
but with an additional mutation in a susceptibil-
ity gene such as SPINK1; and type 4 has a hetero-
zygous CFTR mutation with a strong environmen-
tal trigger factor, such as alcohol.
CTRC
CTRC destroys activated trypsin. CTRC mutations,
in particular the R254W mutation, have been iden-
tified in pancreatitis.23
Summary
The recurrent theme in this case is alcohol expo-
sure followed by pancreatic inflammation. I think
the most probable cause of recurrent pancreatitis
in this adolescent, in view of his history and the
absence of structural or obstructive lesions, in-
fectious agents, or other metabolic disease, is an
underlying genetic mutation. The alcohol proba-
bly triggered these episodes of pancreatitis. I would
recommend testing for mutations in PRSS1, SPINK1,
CFTR, and CTRC. The patient will also require ag-
gressive management of his high-risk behavior
(i.e., his alcohol and tobacco use) and will need
to address his overweight status.
1533
 The n e w e ng l a n d j o u r na l of m e dic i n e

CTRC
CASR
Ethanol Increased Ca2+
Cationic trypsinogen Trypsin degradation
(PRSS1) (Acinar cell)

Trypsinogen Trypsin Trypsin secretion

(Zymogen (Flushing into duodenum)
granule)
Low pH CFTR
Acute
Injury inflammatory
response

SPINK1
(Zymogen granule)

Figure 2. The Interaction between Genetic Factors and the Activation of Trypsinogen to Induce Pancreatitis. COLOR FIGURE

Draft 9 10/04/11
Pancreatitis can be triggered with the conversion of trypsinogen to trypsin inside the pancreas, where it causes tis-
Author Shah
sue damage through multiple mechanisms. Cationic trypsinogen (encoded by the gene PRSS1), Fig #
a
2 high calcium level,
and a low pH promote activation of trypsinogen to trypsin. Calcium levels are regulated inTitle part by the calcium-sens-
ing receptor (encoded by the gene CASR) and dysregulated by ethanol. Activating mutations in PRSS1 or inactivat-
ME
ing mutations in CASR may result in elevated trypsin levels, and ethanol may act as a trigger to pancreatitis by ele-
DE Harris
vating calcium levels. Trypsin is removed by degradation and by excretion through the pancreatic
Artist duct. Degradation
Knoper
of trypsin is facilitated by chymotrypsin C (encoded by the gene CTRC). The cystic fibrosis transmembrane
AUTHOR PLEASE NOTE: conduc-
Figure has been redrawn and type has been reset
tance regulator (encoded by the gene CFTR) eliminates trypsin by flushing the pancreatic duct. Inactivating muta-
Please check carefully

tions in either of these genes result in elevated levels of trypsin in the pancreas. Inflammation caused
Issue date 10/20/11by excess
trypsin leads to up-regulation of the serine protease inhibitor Kazal type 1 (encoded by the gene SPINK1), which
blocks trypsin, prevents further activation of trypsinogen, and limits further tissue injury. Mutations in this gene in-
crease the susceptibility to pancreatitis in persons who have mutations in other genes, particularly CFTR. Adapted
from Whitcomb16 with permission of the author.

Cl inic a l Di agnosis cystic fibrosis in the patient. In addition, the pa-

tient had a SPINK1 mutation. The PRSS1 gene was
Recurrent pancreatitis, due to a genetic abnor- normal. The final diagnosis was recurrent pan-
mality. creatitis due to mutations in the CFTR and SPINK1
genes, triggered by alcohol consumption.
Dr . Uzm a Sh a h’s Di agnosis Dr. Shah: It is important to note that a patient
with a CFTR mutation may have a normal sweat
Recurrent pancreatitis, due to a genetic abnor- test, because the mutations that affect the pan-
mality. creas affect the acinar cells, not the sweat glands.
This patient has compound heterozygosity for the
Di agnos t ic Te s t ing CTFR mutation, as well as a mutation in the sus-
ceptibility gene SPINK1, so he can be considered
Dr. Moran: The diagnostic test was screening for to have a type 3 CFTR mutation.
genetic mutations associated with pancreatitis. The
patient was found to have two CFTR mutations M a nagemen t a nd Fol l ow‑up
— ΔF508 and R31C. The ΔF508 mutation carries
the more severe phenotype. A sweat test was Dr. Moran: The patient recovered uneventfully from
equivocal. Genetic testing of the patient’s par- this episode of acute pancreatitis and was dis-
ents showed that both parents were carriers, a charged on the fourth day.
finding that was consistent with a diagnosis of The patient was counseled on his very strong

1534 n engl j med 365;16 nejm.org october 20, 2011

The New England Journal of Medicine

Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 case records of the massachusetts gener al hospital
genetic predisposition for pancreatitis (500 times
that of the general population) and the potential
for the development of exocrine pancreatic insuf-
ficiency, diabetes, and pancreatic cancer. He is at
particular risk for diabetes owing to pancreatic
insufficiency from recurrent pancreatitis and in-
sulin resistance due to his weight. He was coun-
seled on weight loss and on the need to minimize
all factors that could contribute to pancreatitis
(e.g., alcohol consumption and smoking), which
can increase his risk for pancreatic cancer.
In order to rule out a contribution of dysfunc-
tion of the sphincter of Oddi, we recommended
obtaining an ERCP, despite the risk that perform-
ing ERCP could trigger another episode of pan-
creatitis. The ERCP showed no evidence of an ana-
tomical abnormality that could contribute to the
patient’s recurrent pancreatitis, and there were
no signs of chronic pancreatitis. Nevertheless, a
sphincterotomy was performed, with stent place-
ment; this was complicated by a brief episode of
pancreatitis.
The patient was referred to Dr. Mary Shannon
Fracchia at the pediatric pulmonary service for
evaluation for pulmonary involvement due to cys-
tic fibrosis. He had no history of sinus or pulmo-
nary infections or symptoms, and the results of
pulmonary-function tests were normal. Dr. Frac-
chia recommended beginning treatment with oral
pancrelipase.
The patient and his family have been care-
fully and repeatedly counseled about the impli-
cations of recurrent pancreatitis and the need to
address the triggering factors. He and his fam-
ily have heard a consistent message, that alcohol
intake is going to affect his long-term health.
Each episode of pancreatitis carries a risk of
death, and the additive effect of recurrent pan-
creatitis increases his risks of diabetes and
pancreatic cancer.
We offered a referral to the weight center, but
the patient did not follow up with this referral.
He has quit smoking tobacco. We continue to
counsel him that the most important step toward
avoiding future episodes of pancreatitis is alcohol
abstinence. He has stopped binge drinking but
has refused to stop drinking altogether and has
declined referral to counseling. Two years after the
diagnosis, he continues to be readmitted approxi-
mately every 6 months for acute pancreatitis.
n engl j med 365;16  nejm.org  october 20, 2011
The New England Journal of Medicine
Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Dr. Nancy Lee Harris (Pathology): Dr. Goldstein,
you cared for this patient. Would you like to
comment?
Dr. Mark A. Goldstein (Adolescent and Young
Adult Medicine): I saw this patient recently for
another episode of acute pancreatitis. He reported
a 2-day history of right-upper-quadrant pain that
radiated to his back. He reported no intake of
alcohol in the preceding 24 hours. After the pain
began, he modified his diet to clear liquids only
and placed himself on bed rest. On examination,
his weight had increased to 150.8 kg, and the BMI
had increased to 43.3. There was upper abdomi-
nal tenderness. The serum amylase level was mod-
erately elevated, at 121 U per deciliter, and the
lipase level was elevated, at 131 U per liter (refer-
ence range, 13 to 60). The patient declined to be
admitted to the hospital. Together with the pedi-
atric gastroenterology service, we developed a plan
to treat him as an outpatient with narcotic anal-
gesic tablets and a clear liquid diet. Several days
later at a follow-up examination, he reported no
pain, and the amylase level was normal.
Dr. Harris: What is the likelihood of the devel-
opment of pancreatic insufficiency if the patient
doesn’t stop drinking altogether?
Dr. Shah: In hereditary pancreatitis, pancreatic
insufficiency may develop in 35 to 45% of pa-
tients.17,24 The risk depends on the number of epi-
sodes of pancreatitis and is likely to be acceler-
ated if the patient continues to drink alcohol.
A Physician: Although there is a sense of satis-
faction at having determined the cause of his pan-
creatitis, it is very unfortunate that we have been
unable to persuade this young man to accept the
only measure that might help him — cessation
of alcohol consumption.
Fina l Di agnosis
Recurrent pancreatitis due to CFTR and SPINK1 mu-
tations, triggered by alcohol.
This case was discussed at Pediatric Grand Rounds.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Drs. Mark Goldstein, Harland Winter, Aubrey
Katz, David Forcione, and Mary Shannon Fracchia for assisting
with the preparation of the case history, the management dis-
cussion, or both, Dr. David C. Whitcomb, University of Pitts-
burgh School of Medicine, for his advice about Figure 2, and
Dr. Michelle Duke for helping to organize the conference.
1535
 case records of the massachusetts gener al hospital

References
1. Lopez MJ. The changing incidence of
acute pancreatitis in children: a single-
institution perspective. J Pediatr 2002;140:
622-4.
2. Clifton MS, Pelayo JC, Cortes RA, et
al. Surgical treatment of childhood recur-
rent pancreatitis. J Pediatr Surg 2007;42:
1203-7.
3. Park AJ, Latif SU, Ahmad MU, et al.
A comparison of presentation and man-
agement trends in acute pancreatitis be-
tween infants/toddlers and older children.
J Pediatr Gastroenterol Nutr 2010;51:167-
70.
4. Werlin SL, Kugathasan S, Frautschy
BC. Pancreatitis in children. J Pediatr Gas-
troenterol Nutr 2003;37:591-5.
5. Choi BH, Lim YJ, Yoon CH, Kim EA,
Park YS, Kim KM. Acute pancreatitis as-
sociated with biliary disease in children.
J Gastroenterol Hepatol 2003;18:915-21.
6. Johnson C, Lévy P. Detection of gall-
stones in acute pancreatitis: when and
how? Pancreatology 2010;10:27-32.
7. Bogue CO, Murphy AJ, Gerstle JT,
Moineddin R, Daneman A. Risk factors,
complications, and outcomes of gallstones
in children: a single-center review. J Pedi-
atr Gastroenterol Nutr 2010;50:303-8.
8. Urushihara N, Fukumoto K, Fukuza-
wa H, et al. Recurrent pancreatitis caused
by pancreatobiliary anomalies in children
with annular pancreas. J Pediatr Surg
2010;45:741-6.
9. Fitoz S, Erden A, Boruban S. Magnetic
resonance cholangiopancreatography of
biliary system abnormalities in children.
Clin Imaging 2007;31:93-101.
10. Chavhan GB, Babyn PS, Manson D,
Vidarsson L. Pediatric MR cholangiopan-
creatography: principles, technique, and
clinical applications. Radiographics 2008;
28:1951-62.
11. Darge K, Anupindi S. Pancreatitis and
the role of US, MRCP and ERCP. Pediatr
Radiol 2009;39:Suppl 2:S153-S157.
12. Hellerhoff KJ, Helmberger H III,
Rösch T, Settles MR, Link TM, Rummeny
EJ. Dynamic MR pancreatography after
secretin administration: image quality
and diagnostic accuracy. AJR Am J Roent-
genol 2002;179:121-9.
13. Chang YT, Chang MC, Su TC, et al. As-
sociation of cystic fibrosis transmembrane
conductance regulator (CFTR) mutation/
variant/haplotype and tumor necrosis fac-
tor (TNF) promoter polymorphism in hy-
perlipidemic pancreatitis. Clin Chem 2008;
54:131-8.
14. Hamano H, Kawa S, Horiuchi A, et al.
High serum IgG4 concentrations in pa-
tients with sclerosing pancreatitis. N Engl
J Med 2001;344:732-8.
15. Chen JM, Férec C. Chronic pancreati-
tis: genetics and pathogenesis. Annu Rev
Genomics Hum Genet 2009;10:63-87.
16. Whitcomb DC. Genetic aspects of pan-
creatitis. Annu Rev Med 2010;61:413-24.
17. Rebours V, Boutron-Ruault MC, Schnee
M, et al. The natural history of hereditary
pancreatitis: a national series. Gut 2009;
58:97-103.
18. Ulrich CD. Pancreatic cancer in he-
reditary pancreatitis: consensus guide-
lines for prevention, screening and treat-
ment. Pancreatology 2001;1:416-22.
19. Whitcomb DC, Applebaum S, Martin
SP. Hereditary pancreatitis and pancreatic
carcinoma. Ann N Y Acad Sci 1999;880:
201-9.
20. Witt H, Luck W, Hennies HC, et al.
Mutations in the gene encoding the serine
protease inhibitor, Kazal type 1 are asso-
ciated with chronic pancreatitis. Nat Gen-
et 2000;25:213-6.
21. Audrézet MP, Chen JM, Le Maréchal
C, et al. Determination of the relative con-
tribution of three genes — the cystic fi-
brosis transmembrane conductance regu-
lator gene, the cationic trypsinogen gene,
and the pancreatic secretory trypsin in-
hibitor gene — to the etiology of idio-
pathic chronic pancreatitis. Eur J Hum
Genet 2002;10:100-6.
22. Cohn JA, Neoptolemos JP, Feng J, et
al. Increased risk of idiopathic chronic
pancreatitis in cystic fibrosis carriers.
Hum Mutat 2005;26:303-7.
23. Rosendahl J, Witt H, Szmola R, et al.
Chymotrypsin C (CTRC) variants that di-
minish activity or secretion are associated
with chronic pancreatitis. Nat Genet 2008;
40:78-82.
24. Joergensen MT, Brusgaard K, Crüger
DG, Gerdes AM, Schaffalitzky de Muck-
adell OB. Genetic, epidemiological, and
clinical aspects of hereditary pancreatitis:
a population-based cohort study in Den-
mark. Am J Gastroenterol 2010;105:1876-
83.
Copyright © 2011 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference
material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.

1536 n engl j med 365;16  nejm.org  october 20, 2011

The New England Journal of Medicine

Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on January 16, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.