The n e w e ng l a n d j o u r na l of m e dic i n e

Clinical Problem-Solving

Caren G. Solomon, M.D., M.P.H., Editor

Going from A to Z
Deepak Atri, M.D., David Furfaro, M.D., Gurpreet Dhaliwal, M.D.,
Kenneth R. Feingold, M.D., and Reza Manesh, M.D.​​

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert
clinician, who responds to the information, sharing his or her reasoning with the reader (regular type).
The authors’ commentary follows.

A 70-year-old man presented to the emergency department with a 3-month history of From the Department of Medicine, Johns
diarrhea. The diarrhea varied between semiformed and liquid, but it never contained Hopkins Hospital and Johns Hopkins
University School of Medicine, Baltimore
blood or mucus. On most days, he had hourly bowel movements over a period of 12 (D.A., D.F., R.M.); and the Department
to 18 hours, but he was able to sleep through the night without bowel movements. of Medicine, University of California, San
The diarrhea was associated with nausea, nonbloody emesis, and a weight loss of Francisco, and the Medical Service, San
Francisco Veterans Affairs Medical Center
5.9 kg (13 lb). He reported no fevers or diaphoresis. Three weeks before the onset — both in San Francisco (G.D., K.R.F.).
of diarrhea, intermittent episodes of severe nonradiating epigastric pain had devel- Address reprint requests to Dr. Manesh
oped that lasted for hours. at the Division of General Internal Medi-
cine, Johns Hopkins Hospital, 600 N.
Wolfe St., Meyer 8-34D, Baltimore, MD
Chronic diarrhea, which is defined as persistently loose stools for more than 21287, or at rsedigh1@jhmi.edu.
4 weeks, may be caused by infection, noninfectious inflammation, malabsorption, Drs. Atri and Furfaro contributed equally
or functional disorders. The stool consistency can suggest the mechanism and to this article.
cause of diarrhea. Inflammatory bowel disease frequently manifests with bloody N Engl J Med 2018;378:73-9.
stools and systemic symptoms such as fever. Malabsorptive syndromes such as DOI: 10.1056/NEJMcps1701264
celiac disease may cause steatorrhea. Watery diarrhea can result from osmotic Copyright © 2018 Massachusetts Medical Society.

(e.g., undigested disaccharides) or secretory (e.g., microscopic colitis) mechanisms.

The intermittent epigastric pain could reflect peptic ulcer disease, gastritis, gas-
troesophageal reflux disease (GERD), or functional dyspepsia, although none of
these conditions cause diarrhea. The duration of abdominal pain in this case makes
acute, life-threatening processes such as perforation, obstruction, or ischemia
unlikely.

The patient’s abdominal pain and diarrhea began during a trip to Sri Lanka and con-
tinued on his return to the United States. His diarrhea was not ameliorated by
changes in diet, which included fasting and the avoidance of lactose.

Bacteria such as enterotoxigenic Escherichia coli, salmonella species, and Campylo-

bacter jejuni account for most cases of travelers’ diarrhea. However, the long dura-
tion of the illness in this patient makes parasitic infections such as giardiasis,
cryptosporidiosis, strongyloidiasis, and amebiasis more likely. An extended stay in
Sri Lanka raises the possibility of tropical sprue, which is characterized by chronic
diarrhea and resembles celiac disease clinically and histologically but is associated
with seronegative findings and is thought to be infectious in origin. Human im-
munodeficiency virus (HIV) infection could confer a predisposition to diarrhea
caused by opportunistic infections or cancers such as gastrointestinal lymphoma.
The lack of improvement with fasting favors a secretory cause of chronic diarrhea.

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 The n e w e ng l a n d j o u r na l
The patient’s medical history included hyperten-
sion, hyperlipidemia, transient ischemic attack
(5 years earlier), and a traumatic subdural hema-
toma (6 years earlier). He had had idiopathic
erythrocytosis for more than 20 years; testing
over the years had included a normal erythropoi-
etin level, a bone marrow biopsy showing mildly
hypercellular marrow, negative Janus kinase 2
(JAK2) V617F and JAK2 exon 12 and 13 mutation
assays, and normal results on echocardiography
and renal ultrasonography. After his transient
ischemic attack, he underwent scheduled phlebot-
omy to maintain his hematocrit below 50%.
His medications included losartan, simvastatin,
atenolol, aspirin, and levetiracetam. He reported
no recent exposure to antibiotic agents, no recent
medication changes, and no recent use of nonpre-
scribed therapies including laxatives. He drank
one to two glasses of wine per week and did not
smoke or use recreational drugs. He was married.
His father had coronary artery disease, and his
sister had breast cancer.
The listed medications are not commonly linked
to diarrhea. Aspirin can precipitate or exacerbate
microscopic colitis, which is a well-characterized
cause of chronic watery diarrhea. Alcohol can
cause loose bowel movements through multiple
mechanisms, including impaired nutrient and
fluid absorption and increased mucosal secre-
tions, but the modest intake in this patient
would not explain the chronic symptoms.
While the patient was in Sri Lanka, omeprazole, at
a dose of 20 mg daily, was prescribed for him, but
it did not appreciably alleviate his abdominal pain
or diarrhea. In the United States, his primary care
physician discontinued omeprazole (after a 2-month
course), and the pain and diarrhea worsened.
Esophagogastroduodenoscopy revealed evidence
of mild GERD without ulceration or Helicobacter
pylori infection. He presented to the emergency
department twice with abdominal pain, dehydra-
tion, and acute kidney injury. On both occasions,
he was treated with intravenous fluids and was
discharged. A polymerase-chain-reaction (PCR)
assay of a stool specimen was negative for Clos-
tridium difficile toxin. No ova or parasites were de-
tected in the stool specimen. No other tests of the
stool specimen were performed. After his second
emergency department visit, rifaximin and probi-
otics were prescribed for suspected bacterial over-
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of m e dic i n e
growth in the small intestine. He was referred to
a gastroenterologist.
Proton-pump inhibitors are associated with an in-
creased risk of microscopic colitis and C. difficile
infection; however, omeprazole is an unlikely
culprit, given that the diarrhea worsened after
discontinuation of the drug. GERD might ex-
plain the patient’s epigastric pain, but it would
not explain the chronic diarrhea. Whipple’s dis-
ease, caused by Tropheryma whipplei infection, can
cause chronic diarrhea and weight loss; however,
the lack of preceding migratory arthralgias makes
this diagnosis unlikely. Chronic watery diarrhea
can be categorized as osmotic or secretory by
calculation of a stool osmotic gap (the difference
between stool osmolality [in milliosmoles per
kilogram of water] and twice the sum of the
sodium and potassium levels in the stool [in mil-
limoles per liter]). A gap of less than 50 mOsm
per kilogram suggests a secretory cause, whereas
a gap greater than 125 mOsm per kilogram sug-
gests an osmotic cause. A colonoscopy should
also be performed. Even if the colon appears
endoscopically normal, biopsies should be ob-
tained to evaluate for microscopic colitis, eosin-
ophilic colitis, and amyloidosis.
The patient returned to the emergency department
for a third time with persistent symptoms and
was admitted to the hospital. He was afebrile and
had a blood pressure of 102/67 mm Hg and a heart
rate of 60 beats per minute. He had dry mucous
membranes. The findings from heart, lung, skin,
and musculoskeletal examinations were normal.
His abdomen was soft, nontender, and nondis-
tended. Blood tests showed a leukocyte count of
10,960 per cubic millimeter with a normal differ-
ential, a hemoglobin level of 18.9 g per deciliter,
and a platelet count of 167,000 per cubic millime-
ter. The serum sodium level was 126 mmol per
liter, the potassium level 3.9 mmol per liter, the
chloride level 85 mmol per liter, the bicarbonate
level 28 mmol per liter, the blood urea nitrogen
level 14 mg per deciliter (5.0 mmol per liter), the
creatinine level 1.8 mg per deciliter (159 μmol per
liter) (baseline level, 1.2 mg per deciliter [106 μmol
per liter]), and the calcium level 9.5 mg per decili-
ter (2.4 mmol per liter). The total serum protein
level was 7.9 g per deciliter (normal range, 6.0 to
8.2), with an albumin level of 4.4 g per deciliter.
The quantitative serum immunoglobulin levels
 Clinical Problem-Solving

were normal. The serum levels of aminotransfer-

ases, alkaline phosphatase, and bilirubin were
within the normal ranges. The lipase level was
137 U per liter (normal range, 16 to 63) but de-
creased to 84 U per liter after intravenous hydra-
tion. The erythrocyte sedimentation rate was 3 mm
per hour (normal range, 0 to 20), and the C-reac-
tive protein level was 2.1 mg per liter (normal value,
<5). The results of a urinalysis were normal.

Hypovolemia probably accounts for the hypona-

tremia and acute kidney injury. The elevated
hemoglobin level probably reflects hemoconcen-
tration superimposed on the patient’s idiopathic
erythrocytosis. The normal immunoglobulin lev-
els rule out common variable immunodeficiency,
which can manifest as chronic diarrhea but is
Figure 1. Contrast-Enhanced MRI of the Abdomen.
unlikely to manifest at this patient’s age. There
T2-weighted MRI shows a hyperintense spherical hepat-
are no extraintestinal manifestations of inflam- ic mass measuring 2.4 cm by 2.0 cm by 1.8 cm at the
matory bowel disease such as uveitis, rash, or ar- bifurcation of the portal vein (arrow). This mass showed
thritis, and the low levels of inflammatory mark- enhancement on arterial-phase imaging.
ers make inflammatory bowel disease less likely.

After fluid resuscitation, the patient’s hyponatre- An intraabdominal mass along with the pres-
mia resolved, and the hemoglobin and creatinine ence of unremitting diarrhea arouses suspicion
levels decreased to 15.9 g per deciliter and 1.1 mg for a neuroendocrine tumor such as a carcinoid
tumor, gastrinoma, or vasoactive intestinal pep-
per deciliter (97 μmol per liter), respectively. A re-
peat esophagogastroduodenoscopy revealed gas- tide–secreting tumor (VIPoma). Carcinoid tumors
tritis and esophagitis with no ulceration or H. pylori
commonly originate in the small intestine. He-
infection. A colonoscopy was normal; no biopsy patic metastases may induce the carcinoid syn-
specimens were obtained. Abdominal ultrasonog- drome by secreting bioactive tumor products
raphy showed a 2.2-cm spherical mass in the liver. directly into the systemic circulation, which by-
Magnetic resonance imaging (MRI) confirmed passes hepatic inactivation. A VIPoma typically
the solitary liver mass (Fig. 1), with contrast en- manifests as a pancreatic mass. The absence of
hancement suggestive of hepatocellular carcinoma. ulcers on endoscopy makes gastrinoma less like-
Alpha-fetoprotein, carcinoembryonic antigen, and ly. Urine levels of 5-hydroxyindoleacetic acid (a
CA 19-9 levels were not elevated. serotonin metabolite) and serum levels of gas-
trin, vasoactive intestinal peptide, and chromo-
Common benign liver masses include adenoma, granin A (a neuroendocrine tumor marker) should
hemangioma, and focal nodular hyperplasia. The be measured.
most frequently encountered malignant hepatic
masses are metastases, hepatocellular carcinoma, His pain and nausea resolved with antiemetic
and cholangiocarcinoma. There were no physi- therapy, and the patient was discharged from the
cal, biochemical, or imaging findings character- hospital. Over the subsequent week, his diarrhea
istic of cirrhosis, which is a common precursor persisted and epigastric pain and nausea recurred,
to hepatocellular carcinoma. However, this diag- which prompted a fourth visit to the emergency
nosis is more likely than metastasis given the department and readmission to the hospital. Re-
presence of a solitary and spherical lesion with peat testing for C. difficile toxin (with the use of a
specified MRI characteristics. A subacute liver PCR assay) and for ova and parasites (with the use
infection such as Entamoeba histolytica is unlikely of light microscopy) was negative. A stool culture
given the watery diarrhea, imaging characteris- was negative for enteric pathogens and cytomega-
tics, and absence of fever. lovirus. Stool antigen tests for strains of E. coli that

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 The n e w e ng l a n d j o u r na l of m e dic i n e

produce Shiga-like toxins and for giardia were A

negative, as were stains for cryptosporidium, cys-
toisospora, and microsporidium. A serum PCR
assay for T. whipplei was negative. The patient de-
clined HIV testing. The fecal fat and pancreatic
elastase levels were normal. Testing for tissue
transglutaminase and gliadin IgA antibodies was
negative.
The level of 5-hydroxyindoleacetic acid in a
24-hour urine sample was normal. Serum vasoac-
tive intestinal peptide and serotonin levels were
normal. The serum gastrin level was 2678 pg per
milliliter (normal value, <100), and the chromo-
granin A level was 144 ng per milliliter (normal
value, <15).

Common causes of secondary hypergastrinemia B

include acid-suppressive medications and chronic
autoimmune atrophic gastritis. Primary hyper-
gastrinemia is caused by gastrin-secreting tu-
mors. A gastrinoma (the Zollinger–Ellison syn- *
drome) would explain the patient’s abdominal
pain, diarrhea, and hepatic mass, although the
absence of peptic ulcers is atypical. A fasting
gastric pH below 2 is necessary to rule out sec-
ondary hypergastrinemia.

Aspiration of fasting gastric contents yielded clear

fluid with a pH of 1 (normal range, 1 to 4). Posi-
tron-emission tomography (PET) showed 18F-flu-
orodeoxyglucose uptake of the solitary liver mass
with no extrahepatic uptake (Fig. 2A). An octreo-
tide radionuclide scan showed intense radiotracer
uptake corresponding to the liver mass and a faint
focus of radiotracer activity at the duodenojejunal
junction (Fig. 2B). Push enteroscopy that extend-
ed throughout the jejunum and endoscopic ultra-
sonography that extended to the duodenojejunal
junction did not reveal an intestinal tumor.
The hepatic mass was biopsied. Immunohisto-
chemical analysis showed cells with strong ex-
pression of chromogranin A and gastrin, find-
ings consistent with gastrinoma (Fig. 3). The
hypergastrinemia, low gastric pH, imaging re-
sults, and biopsy results were diagnostic of gastri-
noma. The primary tumor location was uncertain.
Multiple endocrine neoplasia type 1 (MEN1) should
be considered in patients with gastrinomas. How-
ever, MEN1 is unlikely given the patient’s age,
absence of family members with endocrine tu-
Figure 2. Imaging Studies in the Patient.
Total-body 18F-fluorodeoxyglucose (FDG) positron-
emission tomography–computed tomography shows
uptake of FDG in a 2.3 cm by 2.3 cm liver mass (Panel A,
arrowhead). A scintigraphic scan obtained after injec-
tion of indium-111–labeled pentetreotide (octreoscan)
shows a solitary liver mass (Panel B, arrowhead) and
expected radiopharmaceutical uptake in the gallbladder
(Panel B, asterisk).
mors, and normal calcium level. Hypercalcemia
due to primary hyperparathyroidism is present in
most patients with MEN1.
Therapy consisting of a proton-pump inhibitor,
administered twice daily, and loperamide as
needed was initiated, and the patient’s abdominal
pain and diarrhea were reduced. The tumor was
located at the bifurcation of the main portal vein
and abutted the middle hepatic vein, which made

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 Clinical Problem-Solving

surgical resection a high-risk procedure. The pa- A

tient declined surgery and underwent transcathe-
ter arterial chemoembolization. One month after
the chemoembolization, the serum gastrin level
had fallen to 950 pg per milliliter. Three months
after the chemoembolization, the diarrhea and
abdominal pain had resolved, and the patient’s
weight had increased from 68 kg to 72 kg (150 lb
to 159 lb).
The patient subsequently transferred his care
to another institution. He underwent cryoabla-
tion of a residual hepatic tumor detected on MRI.
Two months later, another MRI revealed further
tumor expansion, which was treated with percu-
B
taneous microwave ablation. One year after the
initial diagnosis, gallium-68 (68Ga)–Dotatate
PET–computed tomography (CT) showed radio-
tracer uptake in a 1.8-cm mass adjacent to the
previously treated hepatic lesion — a finding sug-
gestive of recurrent or residual disease — but no
intestinal uptake. Radiotracer uptake in a 1.5-cm
periportal lymph node and in the right anterior
iliac bone was suggestive of metastatic disease. At
the time of the PET-CT scan, he had no gastroin-
testinal symptoms and was under the care of a
multidisciplinary medical team.
C
C om men ta r y
The Zollinger–Ellison syndrome is caused by a
gastrin-producing neuroendocrine tumor.1 Gas-
trin is a peptide hormone that activates gastric
enterochromaffin-like cells to release histamine,
which in turn stimulates hydrochloric acid pro-
duction by parietal cells. The most common
symptoms of the Zollinger–Ellison syndrome are
abdominal pain, diarrhea, and heartburn.1,2 Ul-
cers and prominent gastric folds are present on
endoscopy in more than 90% of patients with
this syndrome,2,3 although both were absent in Figure 3. Biopsy Specimen of the Liver Mass.
our patient. A needle-biopsy specimen of the liver mass shows a
Diarrhea develops in up to 75% of patients well-differentiated neuroendocrine neoplasm (Panel A;
with the Zollinger–Ellison syndrome, and 3 to hematoxylin and eosin). Immunohistochemical staining
20% of patients present with diarrhea alone.1,2,4 of the lesional cells shows weak chromogranin A expres-
sion (Panel B) and strong gastrin expression (Panel C).
In a study involving 261 patients with the syn-
drome, the diarrhea was reported to be mild in
most patients, with fewer than 10% of the pa-
tients reporting more than 1 liter of stool output osmotic load from gastric secretions, gastrin-
per day.2 This contrasts with the severe diarrhea stimulated intestinal and colonic secretions, and
reported by our patient. Diarrhea resulting from fat malabsorption as a result of the inactivation
the Zollinger–Ellison syndrome is caused by the of pancreatic enzymes by acids.1,5 When a neuro-

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 The n e w e ng l a n d j o u r na l
endocrine tumor is suspected as a cause of
chronic diarrhea, the serum gastrin, vasoactive
intestinal peptide, and chromogranin A and urine
5-hydroxyindoleacetic acid levels should be mea-
sured.6
Hypergastrinemia is a necessary but insuffi-
cient finding for the diagnosis of the Zollinger–
Ellison syndrome. Atrophic gastritis, vagotomy,
and acid-suppressive medications all cause achlor-
hydria and a compensatory rise in gastrin lev-
els.4,7 The Zollinger–Ellison syndrome is charac-
terized by an elevated serum gastrin level (in
40% of patients, the fasting serum gastrin level
exceeds 10 times the upper limit of the normal
range) and fasting gastric pH below 2.7
Gastrinomas most commonly arise in the duo-
denum (40 to 90%) but may originate in the
pancreas, stomach, liver, ovary, or extraabdomi-
nal sites.1,4,8 Noninvasive imaging methods that
are used to localize primary tumors not seen on
CT or MRI and to detect occult metastases in-
clude somatostatin receptor scintigraphy (71%
sensitivity and 86% specificity) and 68Ga-Dotatate
PET-CT (97% sensitivity and 95% specificity).9,10
Endoscopic ultrasonography can detect subcen-
timeter tumors in the pancreas and duodenum
and is commonly used when other techniques
fail to identify the primary tumor.1 Surgery can
identify the primary tumor in more than 90% of
patients.11
More than half of gastrinomas are malignant,
and liver metastases are present in 25 to 50% of
patients with the Zollinger–Ellison syndrome at
the time of diagnosis.3 In this case, the patient
had a solitary liver lesion and no evidence of
extrahepatic tumor on CT, MRI, PET, octreotide
scintigraphy, or endoscopic ultrasonography on
his initial evaluation. The results of 68Ga-Dotatate
PET-CT performed 1 year after the diagnosis were
suggestive of progressive metastatic disease but
did not show a primary tumor.
The treatment of the Zollinger–Ellison syn-
drome involves medical therapy to control symp-
toms and curative resection when possible.12
Proton-pump inhibitors, sometimes prescribed
at high dose, are first-line therapies.12 Cohort
studies have shown that proton-pump inhibitors
successfully control symptoms in the majority of
patients (>98%), with minimal side effects.8
In patients with sporadic Zollinger–Ellison
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of m e dic i n e
syndrome (not associated with MEN1) without
metastatic disease, the cure rate after duode-
notomy and resection can be as high as 60%,
with the 15-year survival rate approaching 98%.13
Inoperable disease may be amenable to treat-
ment with hepatic arterial embolization, radio-
frequency ablation, or cryoablation. Metastatic
gastrinomas can be treated with therapies that
inhibit vascular endothelial growth factor, mam-
malian target of rapamycin, or tyrosine kinases;
with cytotoxic chemotherapy such as doxorubi-
cin, streptozocin, or fluorouracil12,14; or with radio-
labeled somatostatin analogues. Long-term soma-
tostatin analogues can be used to control gastric
acid secretion and to inhibit tumor growth or
progression, although they rarely reduce tumor
size.15 Most of the data to support these thera-
pies come from small studies that often include
multiple types of pancreatic neuroendocrine
tumors.4
The average time from symptom onset to di-
agnosis of the Zollinger–Ellison syndrome is
more than 5 years.2,4 The initial manifestations
— diarrhea, abdominal pain, or GERD — are
commonly seen in primary care and are often
self-limited or controlled with empirical therapy.
GERD or peptic ulcer disease accompanied by
persistent diarrhea, refractory dyspeptic symp-
toms despite proton-pump inhibitor therapy, and
the complete resolution of diarrhea with proton-
pump inhibitors are potential clues to gastri-
noma, but even these scenarios have limited
specificity. In this case, the diagnosis of the
Zollinger–Ellison syndrome was facilitated when
imaging for abdominal pain revealed an unex-
pected hepatic mass. The persistent diarrhea and
hepatic mass justified the consideration of rare
disorders such as gastrinoma, carcinoid, and
VIPoma. It was the less common manifestation
of gastrinoma as an isolated hepatic mass that
allowed the clinicians to go expeditiously from
A (abdominal pain) to Z (Zollinger–Ellison syn-
drome).
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Christopher Bailey, M.D., for his interpretation of
the imaging studies; Robert A. Anders, M.D., Ph.D., for his in-
terpretation of the pathological images; and the Jeremiah A.
Barondess Fellowship in the Clinical Transaction of the New
York Academy of Medicine, in collaboration with the Accredita-
tion Council for Graduate Medical Education.
 Clinical Problem-Solving

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