Download GI Endocrinology: 101

GI Endocrinology: 101
Mark Feldman, MD
Case Presentation
A 56 year old woman has had diarrhea for
8 years, initially intermittent and now daily
for 3 years. She stated “there’s not a
bathroom in the state that I have not
visited”. Diarrhea did not respond to OTC
medications.
56 y.o. with diarrhea, continued
Past medical/surgical history:
– morbid obesity (BMI 42 kg/m2)
– status post TAH with BSO
• Family history:
– Mother: COPD, ulcers, kidney stones
– Father: MI
• Social history: negative
• ROS: negative
• Physical exam: morbid obesity.
• CBC and chem 14: all normal except for ALT 54.
• Stool microbiology studies negative.
• Sigmoidoscopy were normal.
Case: Imaging
• Upper GI/SBFT : thickening of folds of stomach
and proximal small intestine
• Abdominal CT scan: thick gastric folds; slight
prominence of the pancreatic head without a
distinct mass; single gallstone; diffuse fatty
infiltration of the liver.
• EGD: prominent gastric folds; excessive gastric
secretions (400 ml); no esophagitis or ulcers; 4
mm duodenal nodule biopsy: gastric
metaplasia
Biochemical tests
• Fasting serum gastrin 1,200 pg/ml
(normal, < 100)
• Basal acid output after referral and on
medication:
– 57.4 mmol per hr (normal, < 5 mmol/hr)
• Diagnosis: Zollinger-Ellison syndrome
GI Endocrine System vs.
Other Endocrine Tissues
Non-GI
GI
Discrete Glands
Scattered cells or islands of
cells (islets) in GI tract/panc.
Common
Minimal to non-existent
Hormonal assays
readily available
Yes
No
Knowledge about physiology
High
Variable
Common
Uncommon
Distribution of cells
Regulation by
Hypothalamus/Pituitary
Functional tumors*
* Non-GI and GI tumors may coexist in the MEN-1 and MEN-2b syndromes
D cells, G cells, and islets
GI/Pancreatic Peptides That
Function Mainly as Hormones
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Secretin, the first hormone (1905)
Gastrin
Insulin
Glucagon, and related gene products (GLP-1,
GLP-2, glicentin, oxyntomodulin)
Glucose-dependent insulinotropic peptide (GIP)
Motilin
Pancreatic polypeptide
Peptide tyrosine tyrosine (PYY)
Gastrin-releasing peptide (GRP)
nerves in human gastric mucosa
GI Peptides That Act
Principally as Neuropeptides
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•
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•
•
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•
•
•
•
Calcitonin gene-related peptide (CGRP)
Dynorphin and related gene products
Enkephalin and related gene products
Galanin
Gastrin-releasing peptide (GRP)
Neuromedin U
Neuropeptide Y
Peptide histidine isoleucine (PHI) or peptide histidine methionine
(PHM)
Pituitary adenylate cyclase–activating peptide (PACAP)
Substance P and other tachykinins (neurokinin A, neurokinin B)
Thyrotropin-releasing hormone (TRH)
VIP
Paracrine inhibition of G cell release by
somatostatin (STS) from adjacent D cells
Gastric antral mucosa
GI/Panreatic Peptides That May
Function as Hormones, Neuropeptides,
or Paracrine Agents
• Somatostatin
• Cholecystokinin (CCK)
• Corticotropin-releasing factor (CRF)
• Endothelin
• Neurotensin
GI/Pancreatic Peptides That Act as
Growth Factors
• Epidermal growth factor, EGF
• Fibroblast growth factor, FGF
• Insulin-like growth factors, IGF
• Nerve growth factor, NGF
• Platelet-derived growth factor, PDGF
• Transforming growth factor-beta, TGFβ
• Vascular endothelial growth factor, VEGF
Peptides That Act as
Inflammatory Mediators
• Interferons
• Interleukins, e.g., IL-1, IL-6, IL-12
• Lymphokines
• Monokines
• TNFα
Gastrointestinal peptides that
regulate satiety and food intake
Reduce meal size
Increase meal size
CCK
ghrelin
GLP-1
PYY(3-36)
gastrin releasing peptide
amylin
apolipoprotein A-IV
somatostatin
GI peptides that regulate
postprandial blood glucose (incretins)
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•
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Glucagon-like peptide-1 (GLP-1)
Glucose-dependent insulinotropic peptide (GIP)
Gastrin releasing peptide
Cholecystokinin (potentiates amino acidstimulated insulin release)
Gastrin (in presence of amino acids)
Vasoactive intestinal peptide (potentiates
glucose-stimulated insulin release)
Pituitary adenylate cyclase activating peptide
(potentiates glucose-stimulated insulin release)
Motilin
GI Pancreatic Neoplasms
GI
PANCREATIC
GASTRINOMA
SOMATOSTATINOMA
CARCINOID
OTHERS (RARE)
GASTRINOMA
SOMATOSTATINOMA
VIPOMA
GLUCAGONOMA
INSULINOMA
PPOMA
NONFUNCTIONAL
Zollinger-Ellison Syndrome
• “Islet cell” tumor of the pancreas [or of the
duodenum] 
• Hypergastrinemia 
• Gastric acid hypersecretion 
• Consequences of acid hypersecretion :
– PUD, GERD [ with or without complications]
– Diarrhea, malabsorption
Epidemiology of
Z-E syndrome
•
•
•
•
Any age group ( mean age  50 years)
Male : Female  3:2
Annual incidence  0.5 - 1.0 per million
MEN-1 in approximately 25% of cases
Classification of
Z-E syndrome
• Sporadic
75-80%
• MEN-1(autosomal dominant)
20-25%
• Ectopic gastrin- producing tumors < 1%
• ovary
• lung
• cardiac (ventricular septum)
• Non-gastrinoma islet tumor
< 1%
The Gastrinoma Triangle
Pancreatic gastrinoma:
gross pathology
Pancreatic gastrinoma:
histopathology
Duodenal gastrinoma:
low-power histopathology
Duodenal gastrinoma:
immunostaining for gastrin
Histamine-producing
(enterochromaffin-like) cell
Parietal cell
Gastrin stimulates parietal cells
via neighboring ECL cells
Serum Gastrin
ECL CCKBR  hyperplasia
Histamine
CCKBR (PC)
Ca
H2R (PC)
cAMP±Ca
Gastric Acid Secretion  hyperplasia
Enterochromaffin-like (ECL)
cell hyperplasia
Big folds
Symptoms in patients with the
Zollinger-Ellison syndrome
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Pain and diarrhea
Pain without diarrhea
Diarrhea without pain
Heartburn ± dysphagia
MEN-1 features
50-60%
25%
20%
30%
20-25%
Locations of peptic ulcers
in ZE syndrome
• Duodenal bulb
• Post-bulbar
duodenum
• Jejunum
• Esophagus
• Stomach
• Marginal (stomal)
Clinical features suspicious for
Zollinger-Ellison syndrome (ZES)
• History of PUD and
nephrolithiasis
• PUD in association with
chronic diarrhea
• Family history of PUD, kidney
stones
• Post-bulbar duodenal ulcer
• PUD in the absence of
Helicobacter pylori or
NSAID usage
• Multiple duodenal and/or
jejunal ulcers
•PUD refractory to standard
medical therapy
Diagnosis of ZE Syndrome
• Begins with clinical suspicion
(pretest probability)
• Fasting serum gastrin measurement
– high sensitivity (> 95%)
– poor specificity, even at high levels
– modest positive predictive value
– excellent negative predictive value
Other causes of elevated
fasting serum gastrin
 Achlorhydria / hypochlorhydria,
usu. due to chronic gastritis
 Medications: antacids, PPIs,
H2 blockers
 Postoperative: vagotomy, retained
antrum syndrome
 Renal failure
 Gastric outlet obstruction
 Diabetes mellitus
 Hypertriglyceridemia
Diagnosis of ZE Syndrome
• Fasting serum gastrin measurement
– high sensitivity (> 95%)
– low specificity and modest positive predictive
value can be enhanced with provocative
testing with secretin (2 IU/kg or 0.4 ug/kg i.v.)
or calcium infusion (4 mg/kg calcium
gluconate per hour for 3 hours), where
likelihood ratios increase 10-15 fold with a +
test result and decrease 10-fold with a - test
result
Management of ZE syndrome:
• Acid control takes precedence over tumor
search
• Tumor search is designed to find tumor
and to stage its/their extent
• Tumor search and possible resection for
cure is only prudent for patients who are
surgical candidates
Clinical symptoms and laboratory findings
in patients with glucagonoma
Clinical Symptoms
•
Dermatitis
•
Diabetes/glucose intolerance
•
Weight loss
•
Glossitis/stomatitis/cheilitis
•
Diarrhea
•
Abdominal pain
Frequency (%)
64-90
38-90
56-96
29-40
14-15
12
•
•
Thromboembolic disease
Venous thrombosis
12-35
24
•
Pulmonary emboli
•
Psychiatric disturbance
Laboratory Abnormality
•
Anemia
•
Hypoaminoacidemia
•
Hypocholesterolemia
•
Renal glycosuria
11
uncommon
33-85
26-100
80
unknown
Glucagonoma syndrome.
Necrolytic migratory erythema.
Glucagonoma syndrome.
Necrolytic migratory erythema.
Clinical symptoms and laboratory findings in
patients with the VIPoma syndrome (WDHA)
Symptoms/Signs
Watery (secretory) diarrhea
Frequency (%)
89-100
Dehydration
44-100
Weight loss
36-100
Abdominal cramps, colic
10-63
Flushing
14-33
Laboratory Findings
Hypokalemia
67-100
Hypochlorhydria
34-72
Hypercalcemia
41-50
Hyperglycemia
18-100
Clinical and laboratory findings
in patients with somatostatinomas
Clinical Finding(s)
• Diabetes mellitus
• Gallbladder disease
• Diarrhea
• Weight loss
Laboratory Finding(s)
• Steatorrhea
• Hypochlorhydria
Somatostatinoma
Pancreatic
95
94
66-97
32-90
83
86
Intestinal
21
43
11-36
20-44
12
17
Somatostatin syndr.
Overall
95
68
37
68
47
26
PANCREATIC IMAGING IN PANCREATIC
ENDOCRINE TUMORS (PETS) *
* GI IMAGING IS BY ENDOSCOPY IN MOST CASES
IMAGING IN PANCREATIC ENDOCRINE TUMORS (PETS)
INSULINOMAS
OTHER
LIVER METS.
Ultrasound
30
22
44
CT Scan
31
42
70
MRI
10
27
80
Arteriography
60
70
71
Somatostatin receptor
scintigraphy
54
70
93
Endoscopic ultrasound
81
70
N/A
MEN syndromes
• MEN-1:
• Parathyroid tumor(s)
• Pancreatic tumor
– gastrin, insulin, VIP
• Pituitary tumor
•
• MEN 2a:
• MEN 2b:
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•
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– prolactin, ACTH
Medullary thyroid Ca or
hyperplasia
Pheochromocytoma
Parathyroid disease
2b , without parathyroid
2b, with gangioneuromatosis,
Marfanoid habitus
Genetics of MEN-1
• Germ cell mutation at 11q13 in 90% of
MEN-1, with loss of heterozygosity
implicated in endocrine tumorigenesis
• Chromosome 11q13 product is menin
• Function of menin ?
• Mutations in 11q13 also occur in several
cases of “sporadic” islet cell tumors such
as gastrinomas
PETs in multiple endocrine neoplasia
type I (MEN 1) syndrome
Insulinomas in MEN-I
Somatostatin-receptor scan in
patient with MEN-1 and previous
partial parathyroidectomy
prolactinoma
PET scan in same patient
Prolactinoma removed by transsphenoidal resection in a young
woman with amenorrhea
Case, continued
• She was felt to be a poor surgical
candidate.
• In 1985 ranitidine was increased to 300
mg q6h and propantheline 7.5 mg q6h
added, with basal acid output < 5 mmol
per hr and relief of all symptoms.
• She was switched to a PPI in 1989 and
has remained asymptomatic despite
fasting serum gastrins > 1,000 pg/ml.
Clinical Course
• CT scans show variable changes in the
head of the pancreas and a few tiny lowdensity hepatic lesions, cysts vs mets vs
focal fat.
• Current meds: glyburide, risedronate,
atorvastatin, and lansoprazole.
• Her basal acid output 24 hours after
lansoprazole (trough) was  0.
What about her serum calcium?
1985: Ca 10.3, 9.4, 10.0, 10.1
PTH: 47 (0-50) ; 127 (50-150)
1989: Ca 9.7
1993: Ca 10.4
1994: Ca 9.7
2003: Ca 10.4 at PHD
PTH (intact): 76 (0-54)
Diagnosis: MEN-1 with ZE and hyperparathyroidism
Influence of liver metastases on
survival in gastrinoma patients
undergoing surgery
Prognostic factors in various
PETs for decreased survival
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Female gender
Absence of MEN1 syndrome
Presence of liver metastases
Extent of liver metastases
Presence of lymph node
metastases
Growth of liver metastases
Presence of bone metastases
Incomplete tumor resection
Nonfunctional tumor (worse
than functional) (p <0.01)
Development of ectopic
Cushing’s syndrome
(gastrinomas)
Increased depth of tumor
invasion
Primary tumor size (>3 cm)
Various histologic features
• Flow cytometric features (i.e.,
aneuploidy)
• Increased chromogranin A in
some studies
• Increased gastrin level (p
<0.001) (gastrinomas)
• Lack of progesterone
receptors
• Ha-Ras oncogene or p53
overexpression
• High HER2/neu gene
expression (gastrinomas)
• High 1q loss of heterozygosity
(gastrinomas)
• Increased EGF or IGF receptor
expression (gastrinomas)
• Loss of 1p, 3p, 3q, 6q; gain of
7q, 17, 17p, 20q