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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.

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GI Endocrinology: 101

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

  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 SymptomsFrequency (%) • 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/SignsFrequency (%) 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)SomatostatinomaSomatostatin syndr. PancreaticIntestinalOverall • 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. IMAGING IN PANCREATIC ENDOCRINE TUMORS (PETS)

  44. 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 MEN syndromes

  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

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