GI Endocrinology: 101

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GI Endocrinology 101

• Mark Feldman, MD

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Case Presentation

• A 56 year old woman has had diarrhea for 8
  years, initially intermittent and now daily for 3
  years. She stated theres not a bathroom in the
  state that I have not visited. Diarrhea did not
  respond to OTC medications.

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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.

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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

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Biochemical tests

• Fasting serum gastrin 1,200 pg/ml (normal, lt 100)
• Basal acid output after referral and on
  medication
• 57.4 mmol per hr (normal, lt 5 mmol/hr)
• Diagnosis Zollinger-Ellison syndrome

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GI Endocrine System vs. Other Endocrine Tissues
Non-GI GI
Distribution of cells Discrete Glands Scattered cells or islands of cells (islets) in GI tract/panc.
Regulation by Hypothalamus/Pituitary Common Minimal to non-existent
Hormonal assays readily available Yes No
Knowledge about physiology High Variable
Functional tumors Common Uncommon
Non-GI and GI tumors may coexist in the MEN-1
and MEN-2b syndromes
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D cells, G cells, and islets
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GI/Pancreatic Peptides That Function Mainly as
Hormones

• 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)

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Gastrin-releasing peptide (GRP) nerves in human
gastric mucosa
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GI Peptides That Act Principally as Neuropeptides

• 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 cyclaseactivating peptide
  (PACAP)
• Substance P and other tachykinins (neurokinin A,
  neurokinin B)
• Thyrotropin-releasing hormone (TRH)
• VIP

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Paracrine inhibition of G cell release by
somatostatin (STS) from adjacent D cells
Gastric antral mucosa
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GI/Panreatic Peptides That May Function as
Hormones, Neuropeptides, or Paracrine Agents

• Somatostatin
• Cholecystokinin (CCK)
• Corticotropin-releasing factor (CRF)
• Endothelin
• Neurotensin

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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, TGFß
• Vascular endothelial growth factor, VEGF

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Peptides That Act asInflammatory Mediators

• Interferons
• Interleukins, e.g., IL-1, IL-6, IL-12
• Lymphokines
• Monokines
• TNFa

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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

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GI peptides that regulate postprandial blood
glucose (incretins)

• Glucagon-like peptide-1 (GLP-1)
• Glucose-dependent insulinotropic peptide (GIP)
• Gastrin releasing peptide
• Cholecystokinin (potentiates amino
  acid-stimulated 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

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GI Pancreatic Neoplasms

• GI
• GASTRINOMA
• SOMATOSTATINOMA
• CARCINOID
• OTHERS (RARE)

• PANCREATIC
• GASTRINOMA
• SOMATOSTATINOMA
• VIPOMA
• GLUCAGONOMA
• INSULINOMA
• PPOMA
• NONFUNCTIONAL

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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

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Epidemiology of Z-E syndrome

• Any age group ( mean age ? 50 years)
• Male Female ? 32
• Annual incidence ? 0.5 - 1.0 per million
• MEN-1 in approximately 25 of cases

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Classification of Z-E syndrome

• Sporadic 75-80
• MEN-1(autosomal dominant) 20-25
• Ectopic gastrin- producing tumors lt 1
• ovary
• lung
• cardiac (ventricular septum)
• Non-gastrinoma islet tumor lt 1

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The Gastrinoma Triangle
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Pancreatic gastrinoma gross pathology
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Pancreatic gastrinoma histopathology
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Duodenal gastrinoma low-power histopathology
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Duodenal gastrinoma immunostaining for gastrin
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Histamine-producing (enterochromaffin-like) cell
Parietal cell
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Gastrin stimulates parietal cells via neighboring
ECL cells
Serum Gastrin ECL CCKBR ?
hyperplasia Histamine H2R (PC) cAMPCa G
astric Acid Secretion ? hyperplasia
CCKBR (PC)
Ca
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Enterochromaffin-like (ECL) cell hyperplasia
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Big folds
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Symptoms in patients with the Zollinger-Ellison
syndrome

• Pain and diarrhea 50-60
• Pain without diarrhea 25
• Diarrhea without pain 20
• Heartburn dysphagia 30
• MEN-1 features 20-25

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Locations of peptic ulcers in ZE syndrome

• Duodenal bulb
• Post-bulbar duodenum
• Jejunum
• Esophagus
• Stomach
• Marginal (stomal)

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Clinical features suspicious for
Zollinger-Ellison syndrome (ZES)

• History of PUD and nephrolithiasis
• Family history of PUD, kidney stones
• PUD in the absence of Helicobacter pylori or
  NSAID usage

• PUD in association with chronic diarrhea
• Post-bulbar duodenal ulcer
• Multiple duodenal and/or jejunal ulcers
• PUD refractory to standard medical therapy

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Diagnosis of ZE Syndrome

• Begins with clinical suspicion
• (pretest probability)
• Fasting serum gastrin measurement
• high sensitivity (gt 95)
• poor specificity, even at high levels
• modest positive predictive value
• excellent negative predictive value

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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

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Diagnosis of ZE Syndrome

• Fasting serum gastrin measurement
• high sensitivity (gt 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

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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

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Clinical symptoms and laboratory findings in
patients with glucagonoma

• Clinical Symptoms Frequency ()
  
• Dermatitis 64-90
• Diabetes/glucose intolerance 38-90
• Weight loss 56-96
• Glossitis/stomatitis/cheilitis 29-40
• Diarrhea 14-15
• Abdominal pain 12
• Thromboembolic disease 12-35
• Venous thrombosis 24
• Pulmonary emboli 11
• Psychiatric disturbance uncommon
• Laboratory Abnormality
• Anemia 33-85
• Hypoaminoacidemia 26-100
• Hypocholesterolemia 80
• Renal glycosuria unknown

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Glucagonoma syndrome. Necrolytic migratory
erythema.
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Glucagonoma syndrome.Necrolytic migratory
erythema.
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Clinical symptoms and laboratory findings in
patients with the VIPoma syndrome (WDHA)

• Symptoms/Signs Frequency ()
• Watery (secretory) diarrhea 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

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Clinical and laboratory findings in patients
with somatostatinomas

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• Clinical Finding(s) Somatostatinoma
  Somatostatin syndr.
• Pancreatic Intestinal
  Overall
• Diabetes mellitus 95 21 95
• Gallbladder disease 94 43 68
• Diarrhea 66-97 11-36 37
• Weight loss 32-90 20-44 68
• Laboratory Finding(s)
• Steatorrhea 83 12 47
• Hypochlorhydria 86 17 26

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PANCREATIC IMAGING IN PANCREATIC ENDOCRINE TUMORS
(PETS)
GI IMAGING IS BY ENDOSCOPY IN MOST CASES
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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

IMAGING IN PANCREATIC ENDOCRINE TUMORS (PETS)
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MEN syndromes

• MEN-1
• MEN 2a
• MEN 2b

• Parathyroid tumor(s)
• Pancreatic tumor
• gastrin, insulin, VIP
• Pituitary tumor
• prolactin, ACTH
• Medullary thyroid Ca or hyperplasia
• Pheochromocytoma
• Parathyroid disease
• 2b , without parathyroid
• 2b, with gangioneuromatosis, Marfanoid habitus

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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

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PETs in multiple endocrine neoplasia type I (MEN
1) syndrome
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Insulinomas in MEN-I
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Somatostatin-receptor scan in patient with MEN-1
and previous partial parathyroidectomy
prolactinoma
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PET scan in same patient
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Prolactinoma removed by trans-sphenoidal
resection in a young woman with amenorrhea
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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 lt 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 gt 1,000 pg/ml.

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Clinical Course

• CT scans show variable changes in the head of the
  pancreas and a few tiny low-density 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.

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(No Transcript)
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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
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Influence of liver metastases on survival in
gastrinoma patients undergoing surgery
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Prognostic factors in various PETs for
decreased survival

• 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
  lt0.01)
• Development of ectopic Cushings syndrome
  (gastrinomas)
• Increased depth of tumor invasion
• Primary tumor size (gt3 cm)
• Various histologic features

• Flow cytometric features (i.e., aneuploidy)
• Increased chromogranin A in some studies
• Increased gastrin level (p lt0.001) (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