diabetes managment

1. GI Endocrinology: 101
Mark Feldman, MD

2. 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.

3. 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.

4. 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

5. 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

6. 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

7. D cells, G cells, and islets

8. 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)

9. Gastrin-releasing peptide (GRP)
nerves in human gastric mucosa

10. 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 cyclase–activating peptide (PACAP)
• Substance P and other tachykinins (neurokinin A, neurokinin B)
• Thyrotropin-releasing hormone (TRH)
• VIP

11. Paracrine inhibition of G cell release by
somatostatin (STS) from adjacent D cells
Gastric antral mucosa

12. GI/Panreatic Peptides That May
Function as Hormones, Neuropeptides,
or Paracrine Agents
• Somatostatin
• Cholecystokinin (CCK)
• Corticotropin-releasing factor (CRF)
• Endothelin
• Neurotensin

13. 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

14. Peptides That Act as
Inflammatory Mediators
• Interferons
• Interleukins, e.g., IL-1, IL-6, IL-12
• Lymphokines
• Monokines
• TNFα

15. 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

16. 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

17. GI Pancreatic Neoplasms
GI
GASTRINOMA
SOMATOSTATINOMA
CARCINOID
OTHERS (RARE)
PANCREATIC
GASTRINOMA
SOMATOSTATINOMA
VIPOMA
GLUCAGONOMA
INSULINOMA
PPOMA
NONFUNCTIONAL

18. 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

19. 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

20. 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%

21. The Gastrinoma Triangle

22. Pancreatic gastrinoma:
gross pathology

23. Pancreatic gastrinoma:
histopathology

24. Duodenal gastrinoma:
low-power histopathology

25. Duodenal gastrinoma:
immunostaining for gastrin

26. Histamine-producing
(enterochromaffin-like) cell
Parietal cell

27. Gastrin stimulates parietal cells
via neighboring ECL cells
Serum Gastrin
ECL CCKBR  hyperplasia
Histamine
H2R (PC)
cAMP±Ca
Gastric Acid Secretion  hyperplasia
CCKBR (PC)
Ca

28. Enterochromaffin-like (ECL)
cell hyperplasia

29. Big folds

30. 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%

31. Locations of peptic ulcers
in ZE syndrome
• Duodenal bulb
• Post-bulbar
duodenum
• Jejunum
• Esophagus
• Stomach
• Marginal (stomal)

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. Glucagonoma syndrome.
Necrolytic migratory erythema.

39. Glucagonoma syndrome.
Necrolytic migratory erythema.

40. 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

41. Clinical and laboratory findings
in patients with somatostatinomas
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

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

43. 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)

44. 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

45. 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

46. PETs in multiple endocrine neoplasia
type I (MEN 1) syndrome

47. Insulinomas in MEN-I

48. Somatostatin-receptor scan in
patient with MEN-1 and previous
partial parathyroidectomy
prolactinoma

49. PET scan in same patient

50. Prolactinoma removed by trans-
sphenoidal resection in a young
woman with amenorrhea

51. 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.

52. 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.

54. 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

55. Influence of liver metastases on
survival in gastrinoma patients
undergoing surgery

56. 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 <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