Case 6-2013:

A 54-Year-Old Man
with Recurrent Diarrhea
Pembimbing:
Prof. dr. W.H. Sibuea, SpPD

 Dr. Michael T. Forrester (Medicine): A

54-year-old man was admitted to this
hospital because of diarrhea,
vomiting, and weight loss

 abdominal cramping
and nonbloody
diarrhea developed 1
day after he few
from the Northeast
to Colorado for a
skiing trip; the
symptoms persisted
for the duration of
his 4-day vacation

2.5
years
before
admissi
on

History

 4 days after returning home emergency

department of another hospital because of
persistent symptomsa stomach virus
The next day, he saw his primary care provider
ciprofoxacin was administered, without benefit
1 month later a gastroenterologist. Routine
laboratory studies were normal. A stool specimen
showed many leukocytes and no ova or
parasites; a stool assay for Clostridium difficile
and a stool culture were negative. A course of
metronidazole was administered for 10 days, and
the symptoms nearly resolved

Two years before admission

Esophagogastroduodenoscopy:
An inlet patch (i.e., an area of ectopic gastric
mucosa) involving the circumference of the cervical
esophagus and extending at least 4 cm in length
Multiple erosions of the gastric antrum
Antral gastritis
Superficial ulcerations in the duodenum and
A prominent mucosal fold in the gastric side of the
gastroesophageal junction
Pathological (biopsy of the esophagus)
squamous mucosa and gastric-type mucosa, with
intestinal metaplasia that was thought to be
consistent with Barretts esophagus

Inlet patch

Two years before admission

Colonoscopy : several small polyps
Pathological examination (biopsy specimen of a
polyp in the transverse colon):
adenomatous changes and low-grade dysplasia
a hyperplastic rectal polyp
normal fragments of duodenal mucosa
Testing for Helicobacter pylori and giardia was
negative.
Proton-pump inhibitors were prescribed.

Nine months later

(15 month before admission)
1 day after another fight to Colorado
awoke with abdominal cramps and watery
diarrhea (up to one episode per hour)
3 days later, nausea and vomiting
developed
Examination of a stool specimen at that
time revealed Blastocystis hominis, and
the symptoms again resolved after
treatment with metronidazole.

Four months before admission

The patient traveled to the Middle East
The day after arrivalabdominal cramping
developed, with watery, nonbloody diarrhea
occurring every 1 to 2 hours during the day and
occasionally awakening him at night. His
discomfort increased with eating.
On the sixth day, nausea and nonbloody,
nonbilious vomiting (two to three episodes daily)
occurred, in association with increased diarrhea
and without fevers or diaphoresis.
None of his 15 travel companions had symptoms.

Twelve days later

The patient returned home. His symptoms
persistedhe went to a second hospital for
evaluation; intravenous fuids and metronidazole
were administered, but the symptoms worsened.
Examination of the stool for pathogens and
screening for H. pylori were negative.
During the next 3 months, anorexia developed,
and the patient lost 15.9 kg.
Approximately 2 weeks before admission, his
physician prescribed trimethoprim
sulfamethoxazole, with partial improvement of
diarrhea.

Eight days before admission

In the infectious-disease clinic of this hospital.
On examination, the blood pressure was
114/86 mm Hg and the pulse was 88 beats
per
minute; the remainder of the physical
examination was normal
Laboratory : normal (Table 1)
Stool specimens showed no enteric
pathogens, ova, or parasites, and testing for
C. difficile toxin was negative

 During the ensuing week, the

patients symptoms worsened and
included diarrhea (occurring hourly
throughout the day), constant
nausea, vomiting within 3 minutes
after oral intake, and weakness, with
orthostatic lightheadedness.

Anamnesis
On admission
No fever, chills, sweats, fushing, or headache.
His only medication was omeprazole, 20 mg
daily, which he took for symptoms of
gastroesophageal refux.
He had no known allergies.
He drank alcohol in moderation, had smoked
as a young adult, and did not use illicit drugs.
His father was 82 years of age and had
dementia
His mother was deceased and had a history of
Parkinsons disease and heart disease,
Uncle reportedly had stomach cancer.

Examination
The blood pressure was 133/94 mm Hg
and the pulse 120 beats per minute;
the temperature, respirations, and
oxygen saturation were normal, as was
the remainder of the examination.
Laboratoty are shown in Table 1.
An electrocardiogram was normal.
Normal saline was infused. The patient
was admitted to this hospital.

CT + contras abdomen and pelvis

Thickening and enhancement of the
proximal small-bowel walls, mild
dilatation in the small bowel, a large
amount of fuid in the small bowel and
colon with airfuid levels, an enlarged
retroperitoneal node (1.3 cm in the
short axis), calcific atherosclerosisof
the aorta, and a ground-glass nodule
(0.7 cm in diameter) in the lower lobe
of the right lung

 Testing for human immunodeficiency

virus (HIV) antibodies was negative;
other test results are shown in Table
1.
Stool studies were again unrevealing.
On the fourth day, the level of
potassium in the stool was 21.7
mmol per liter (serum level, 3.4
mmol per liter) and stool fat was 37%
(reference range, 0 to 19)

Esophagogastroduodenoscopy

Revealed erosive or exudative circumferential

lesions (grade III esophagitis, according to the
modified SavaryMiller classification, which
consists of grades I through V, with grade V
indicating the metaplasia seen in Barretts
esophagus)
Excessive fuid (1600 ml) in the gastric body;
A partially obstructing duodenal ulcer (30 mm in
the largest dimension) in the duodenal bulb,
with an ulcer crater that was suspicious for
perforation; and multiple ulcers, up to 6 mm in
the largest dimension, in the second part of the
duodenum.

 Pathological examination: Duodenal

mucosa with ulceration, foveolar
metaplasia, and hyperplasia of the
Brunners glands, with no evidence of
malignant cells.
Grams staining of an aspirate of the
duodenum revealed few
polymorphonuclear cells and few yeast
forms; no ova or parasites were seen.
Cultures of the duodenal aspirate grew
Candida albicans and three colony types
of alpha-hemolytic streptococcus.

Differential considerations
Differential considerations for duodenal
ulcers include acid exposure, acid-producing
tumors (the ZollingerEllison syndrome), or
peptic ulcer disease.
Differential considerations for solid tumors
of the pancreas should always include
pancreatic adenocarcinoma, metastases
(most commonly from renal-cell carcinoma
or melanoma, and occasionally from ovarian
cancer), and neuroendocrine tumors.

Differential considerations
Classic findings for pancreatic
adenocarcinoma include ductal dilatation
of the pancreas, biliary dilatation, and
jaundice, and this patient had none of
those.
Therefore, the pertinent negative findings
associated with this case steer us away
from a diagnosis of pancreatic
adenocarcinoma X

Acute diarrheal illness

This patients initial episodes of diarrheal
illness were typical of acute
gastroenteritis, for which a definite cause
is often not identified.
Most acute diarrheal episodes (those
lasting >7 days) are caused by self-limited
bacterial or viral infections; more
prolonged courses of acute diarrheal
illness are caused by protozoans, including
cryptosporidium and Giardia lamblia.

 During the patients second diarrheal

illness, the finding of B. hominis in the
stool specimen was of debatable clinical
relevance. This organism is commonly
found in stool samples, and the response
to treatment is variable.
Thus, his improvement after treatment
suggests that he may have had a
symptomatic B. hominis infection,
although we cannot be certain that this
was the cause of his illness.

 At this point, the main diagnostic

considerations include recurrent infectious
gastroenteritis or the initial presentation of
inflammatory bowel disease.
The initial endoscopic studies revealed no
evidence of colitis, but the upper
endoscopy revealed erosions of the gastric
antrum and duodenum. Crohns disease
should be considered, because smallbowel involvement in patients with Crohns
disease can cause a large-volume, watery
diarrheal illness.

 During the last 4 months before this

patients hospitalization, he had an
acceleration of his clinical course.
Therefore, the differential diagnosis
for his illness must broaden to
include the causes of chronic
diarrhea, which is defined as
diarrheal illness lasting for more
than 4 weeks

 The major causes of chronic diarrhea

can be assessed by combining a
patients history and classification of
the stool (infammatory, fatty, or
watery).
This patient had no blood in his
stools and little evidence of
infammation or infection, and
endoscopic evaluation 2 years before
admission revealed no conclusive
evidence of infammatory bowel

Celiac disease
Should be considered, given his weight loss and
diarrhea, but he did not have greasy or
malodorous stools, and tests for IgA antibodies
to endomysial antigen and tissue
transglutaminase were negative
Finally, examination of the patients duodenalbiopsy specimen did not show the villous atrophy
that is the signature pathological feature of
celiac disease
His clinical picture is most notable for chronic
watery stools

Chronic watery stools

Stool osmotic gap

Stool osmolality {2 x (stool Na + stool K)}

Potassium (mmol/liter)

21,7

306 - {2 x (96+ 21,7)} = 306 235,4

= 70,6

Stool osmotic gap

High osmotic gap (>125 mosm/kg)
causes of osmotic diarrhea
Low osmotic gap (<50 mosm/kg)
causes of secretory diarrhea
this patients calculated stool osmotic
gap was in the lowintermediate range
at 70, with a high level of sodium in the
stool, suggesting that a secretory
process is more likely than osmotic
diarrhea

Endocrinopathy
This patient was appropriately evaluated for
the most common endocrinologic causes of
diarrhea, including diabetes mellitus,
hyperthyroidism, and adrenal insufficiency.
Systemic mastocytosis could be a unifying
diagnosis for peptic ulcer disease and diarrhea;
however, the absence of a history of urticaria
and the absence of findings of mast-cell
infiltration on examination of the previous
esophageal-biopsy specimens make this
diagnosis unlikely

Peptide-Secreting Tumors
The major peptide-secreting tumors to
be considered in this patient are
carcinoid tumor, vasoactive intestinal
peptideproducing tumor (VIPoma), and
gastrinoma. The absence of fushing
makes carcinoid tumor less likely.
VIPoma is classically associated with
profound hypokalemia and
hypochlorhydria, which were not present

Gastrinoma
On the patients second upper endoscopy, the
finding of a large duodenal ulcer with a crater,
as well as multiple smaller ulcers, raises
concern for gastric-acid hypersecretion. This
patient had a negative test for H. pylori
antibody and did not use nonsteroidal
antiinfammatory drugs, ruling out the two
most common causes of peptic ulcer disease.
Ulcers developed despite his regular use of a
proton-pump inhibitor, which is an unusual
finding that deserves further investigation

Gastrinoma
Gastrinoma, a rare tumor of the
pancreas and duodenum, causes
ectopic hypersecretion of gastrin and
results in the hypersecretion of gastric
acid, leading to severe peptic ulcer
disease; this complex of findings is
known as the Zollinger Ellison
syndrome and is often accompanied by
esophageal refux disease and diarrhea

 On this patients first upper endoscopy (2

years before admission), mention was
made of a prominent gastric fold, an
unusual finding.
In one series, a prominent gastric fold was
found in more than 90% of patients
with the ZollingerEllison syndrome.
The factors that contribute to gastrinomaassociated diarrhea are a high volume of
gastric acid; inactivation of pancreatic
digestive enzymes by gastric acid, causing
steatorrhea; and inhibition of sodium
and water reabsorption by the small
intestine, causing a secretory diarrhea

Gastrinoma
Slightly more common in men than in
women, and the age at onset is
generally between 41 and 53 years
of age.
On average, the diagnosis is made 5
years after the onset of symptoms.
This patient was 51 years of age at
the onset of his symptoms, which is
typical

 Twenty to 25% of patients with

gastrinoma have the multiple
endocrine neoplasia type 1 (MEN-1)
syndrome. Almost all patients with
MEN-1 have primary
hyperparathyroidism.
Since this patients calcium levels
remained normal, even when he was in
a volume-depleted state, it is unlikely
that he had hyperparathyroidism

 Testing for gastrinoma starts with

measurement of a fasting serum gastrin
level. The gastrin level is elevated in virtually
all patients with the ZollingerEllison
syndrome; therefore, a normal level
essentially rules out this condition. However,
our measurements could be confounded by
the patients recent use of proton-pump
inhibitors, which can raise the fasting gastrin
levels markedly
A gastrin level that increases by more than
120 pg per milliliter in response to secretin is
diagnostic of a gastrinoma

 CLINICAL DIAGNOSIS:
Neuroendocrine tumor of the
pancreas
DR. LEIGH H. SIMMONSs
DIAGNOSIS:
Sporadic (nonmultiple endocrine
neoplasia type 1) ZollingerEllison
syndrome (gastrinoma)

Pathological discussion

stomach,
6.5 cm in length,
attached to
a segment of
duodenum, 25
cm in length,
surrounding the
head of the pancreas,
which
contained a mass that
measured 6.2 cm in
diameter.
An ulcer (2 cm in
diameter)
without heaped-up

The pancreatic mass

was circumscribed
and was composed of
firm, white tissue and
darker, more
hemorrhagic tissue
adjacent to the
normal-appearing
yellow-tan pancreas

Microscopically, nests
of tumor cells were
separated by fibrous
tissue. The tumor cells
were relatively uniform
and round, with pink
cytoplasm and central
round nuclei with the
fine salt and pepper
chromatin that is
characteristic of
neuroendocrine cells

Immunohistochemica
l
staining of the tumor
cells
was positive for
gastrin

 The World Health Organization distinguishes among three

grades of neuroendocrine tumors:
Grades 1 and 2 consist of well-differentiated tumors, and grade
3 consists of poorly differentiated tumors, including small-cell
carcinoma. Grade 1 and grade 2 are separated by mitoses and
the proliferation index, assessed with Ki67 immunostaining.
The tumor in this case had fewer than two mitoses per 10 highpower fields, had a Ki67 index of less than 3%, and expressed
the neuroendocrine markers chromogranin and synaptophysin,
as well as gastrin. Thus, the tumor is classified as a welldifferentiated pancreatic neuroendocrine neoplasm
(gastrinoma), grade 1.
Lymphatic invasion was present, the margins were negative,
and 4 out of 31 lymph nodes were positive. On the basis of size
and the involvement of peripancreatic tissue, as well as the
number of positive lymph nodes, the stage was determined to
be pT3N1Mx

Final Diagnosis
Serum gastrin levels measured at the
time of surgery were markedly
elevated, at 1329 pg per milliliter.
After surgery, the gastrin levels have
remained normal.
Therefore, the final diagnosis in this
case is the ZollingerEllison syndrome,
caused by pancreatic gastrin-secreting
neuroendocrine neoplasm (gastrinoma).

Follow up
Dr. Lawrence S. Blaszkowsky
(HematologyOncology): I was asked
to see the patient to assess the need
for adjuvant therapy because of a
posterior (retroperitoneal) margin of
less than 1 mm.

 There is no established role for adjuvant

therapy in this disease. We consider
adjuvant therapy in cases of a close or
positive surgical margin, but there is a
paucity of data to support such therapy.
Our standard approach is to offer
radiotherapy in combination with
chemotherapy to serve as a radiation
sensitizer.
In this patient, we were unable to initiate
adjuvant therapy for about 3 months
because a fuid collection developed that
required percutaneous drainage.

 Approximately 3 weeks after the

completion of chemoradiation, the patient
presented to another hospital with severe
abdominal pain, and imaging studies
suggested a perforated viscus. He was
transferred to this hospital, and the
surgeon repaired the ulcer and removed
the residual lymph node that had been
seen on postoperative imaging.
Twenty months after chemoradiation, the
patient is doing well. The gastrin level is
normal, and he has no evidence of
recurrent disease.

Prognosis
The estimated 5-year survival rate among
patients with regional disease is more than
50%.
Recurrence is possible, but neuroendocrine
tumors tend to be relatively indolent as
compared with adenocarcinoma.
Agents such as sunitinib and everolimus
may be options for this patient if the
disease recurs

Anatomical diagnosis
Gastrinoma

Thank You