GUT Hormones with an overview of GI NET

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Overview of Noncarcinoid GI NETs

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GUT Hormones with an overview of GI NET with a focus on Gastrinoma:

GUT Hormones with an overview of GI NET with a focus on Gastrinoma GUT Hormones with an overview of GI NET with a focus on Gastrinoma Venkata Lekharaju ( Pawan ) SPR GASTROENTEROLOGY 09/11/2012

Overview:

Overview NETs GEP NETs CASE SCENARIO GASTRINOMA HYPERGASTRINEMIA GUT HORMONES

NET (definition):

NET (definition) Neuroendocrine neoplasms , defined as epithelial neoplasms with predominant neuroendocrine differentiation, arise in most organs of the body

Synonyms to define NET:

Synonyms to define NET

PowerPoint Presentation:

GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS ( NONCARCINOID )

GEP NET:

GEP NET Neuroendocrine tumors comprise approximately 2% of all malignant tumors of the gastrointestinal system Incidence of all noncarcinoid NETs is approximately one half that of all carcinoids Noncarcinoid NETs have been reported to occur in 0.4–1.5/100,000 of the population

Epidemiology:

Epidemiology

Basic biology of NET:

Basic biology of NET 14 endocrine cell types in the gut Produce at least 33 hormones and biogenic amines

Types of NET:

Types of NET The cell type-specific hormonal substance produced by the enteroendocrine cell defines the type of NETs originating from that cell Serotonin- carcinoid , Gastrin-gastrinoma , Vasoactive intestinal peptide- VIPoma , Insulin- insulinoma , Glucagon- glucagonoma

Genetics:

Genetics MEN type 1 Von- Hippel Lindau disease Neurofibromatosis type 1

Useful tips (if you can remember):

Useful tips (if you can remember) 57% of MEN type 1 has ZES 20% of ZES patients have MEN type 1 30% of all GFRomas are associated with MEN 1 4-5% of Insulinomas are associated with MEN 1 80% of MEN 1 develop PET No PETs are associated with MEN PETs occur in 12-17% of patients with VHL NF 1 is associated with duodenal somatostatinomas

Enteroendocrine tumor syndromes other than Carcinoid:

Enteroendocrine tumor syndromes other than Carcinoid

Insulinoma:

Insulinoma Syndrome: Insulinoma Hormone: Insulin, Proinsulin Clinical features: Hypoglycaemia, wt loss Site: >95% pancreas Malignant: >10% Treatment: Surgery, Diet, IV dextrose, chemotherapy, Diazoxide , SSTA

VIPOMA:

VIPOMA Syndrome: Verner -Morrison pancreatic cholera WDHA Hormone: VIP Clinical features: Secretory diarrhoea, hypokalemia , achlorhydria , metabolic acidosis, flushing, wt. loss Site: 90% pancreas Malignant: >50% Treatment: Surgery, IV fluids, chemotherapy, SSTA

Glucagonoma:

Glucagonoma Syndrome: Glucagonoma syndrome Hormone: Glucagon Clinical features: Hyperglycaemia, necrolytic migratory erythema , DVT, depression Site: >90% pancreas Malignant: >50% Treatment: Surgery, Diet, Insulin, chemotherapy, SSTA

Somatostatinoma:

Somatostatinoma Syndrome: Somatostatinoma syndrome Hormone: Somatostatin Clinical features: Diabetes, gallstones, wtloss , steatorrhea Site: Pancreas Malignant: 70-80% Treatment: Surgery, Insulin, pancreatic enzymes

Extremely rare:

Extremely rare

Extremely rare:

Extremely rare Tumor Syndrome Hormone Features Site Malignant Treatment ACTHoma Ectopic Cushing’s syndorme ACTH HTN, DM Pancreas Lung >99% Surgery Chemo SSTA PTHrPoma Hyper parathyroidism PTHrP Hyper calcaemia Renal stones Pancreas >99% Surgery Chemo Neurotensinoma ? N eurotensin ? Pancreas Lung ? Surgery Chemo Calcitoninoma ? Calcitonin ? Pancreas Lung >80% Surgery Chemo GRFoma Acromegaly GHRF Acromegaly Pancreas Lung Thymus 30% Surgery SSTA

Nonspecific markers:

Nonspecific markers Chromogranin A Chromogranin B Pancreastatin Pancreatic polypeptide Neuron specific enolase Alpha and beta subunits of chorionic gonadotropin 5 HIAA (24hr Urine) (diet and meds)

Imaging:

Imaging Imaging is indicated at different stages in the patient’s care 1. Screening of at-risk populations 2. Primary lesion detection 3. Assessing extent of disease 4. Follow-up and assessing response to treatment.

Imaging:

Imaging US EUS CT MRI

Sensitivities:

Sensitivities

Gold standard:

Gold standard SRS ( Somatostatin receptor scintigraphy ) 68 Ga DOTATOC PET Octreoscan = 111 In-DTPAOC SPECT Density of receptors (type 2 and 5) determines the result and not the tumor size Functionality of the tumor is not relevant Not useful if you are suspecting Insulinoma

Octreoscan:

Octreoscan Confirms the diagnosis and localizes a NET, Imaging metastases or staging, Monitoring progression or regression of tumors , Predicts response to cold somatostatin analog treatment (the more strongly positive SRS, the greater the likelihood of a favorable response to this treatment), and Predicts the likelihood of a favorable response to a therapeutic dose of radiolabeled somatostatin analog (peptide-receptor radionuclide therapy). A negative SRS in the presence of a progressing tumor could indicate more strongly the need for aggressive surgery and/or chemotherapy

Limitations:

Limitations Reduced sensitivity in smaller (sub-centimetre) lesions and in lesions exhibiting low receptor density; 2-day imaging protocol; and potential interference by co- adminstration of therapeutic somatostatin analogues

Histology:

Histology Mitotic rate Microscopic necrosis

Grading system:

Grading system

Prognosis:

Prognosis

GASTRINOMA:

GASTRINOMA

New GP referral in a Gastro clinic:

New GP referral in a Gastro clinic A 65-year-old woman Abdominal discomfort has been present intermittently for the past year and is described as burning epigastric pain that improves with meals and increases with fasting. Upper endoscopy performed 6 months ago revealed a duodenal ulcer and duodenitis . Antral biopsy specimens were negative for Helicobacter pylori . Treatment was initiated with a proton pump inhibitor (PPI) but her symptoms persisted. PPI= Omeprazole 20mg BD

Case continues:

Case continues Past medical history is notable for hypertension and coronary artery disease. Medications include a PPI, thiazide diuretic, β-blocker, angiotensin -converting enzyme inhibitor, low-dose aspirin, and a statin . She denies using over-the-counter medications.

Case continues:

Case continues Physical examination shows normal vital signs, and mild tenderness to palpation of the epigastrium . Hemoglobin level is 13 g/ dL with a normal white blood cell and platelet count. Serum creatinine , alkaline phosphatase , and aspartate aminotransferase levels are normal.

What will you do?:

What will you do? Repeat endoscopy? A repeat endoscopy revealed duodenal erosions with healing of the previously observed duodenal ulcer. Repeat antral biopsy specimens were negative for H pylori and duodenal biopsy procedures performed during the second endoscopy revealed a slight increase in neutrophils without evidence of neoplasm or infection.

Clever SPR:

Clever SPR Checks fasting Gastrin level Fasting gastrin is 310ng/L (SI units) Normal is <100ng/L

What should be the approach to this patient with documented peptic ulcer disease and elevated fasting gastrin level?:

What should be the approach to this patient with documented peptic ulcer disease and elevated fasting gastrin level?

Peptic ulcer disease:

Peptic ulcer disease Protective factors Aggressive factors Mucous Mucosal blood flow Growth factors Prostaglandins Acid Pepsin H.pylori NSAIDS What is refractory ulcer?

Causes of refractory ulcer:

Causes of refractory ulcer Ischaemia , Lymphoma, Crohn’s disease, Amyloidosis , Sarcoidosis , Systemic mastocytosis , Drugs/toxins ( bisphosphonates , potassium chloride, mycophenolate mofetil , and clopidogrel ), Eosinophilic gastroenteritis Infection (cytomegalovirus, herpes simplex virus, tuberculosis, and syphilis)

When to suspect Gastrinoma:

When to suspect Gastrinoma Ulcers in unusual locations (second part of the duodenum and beyond), Ulcers refractory to standard medical therapy, Ulcer recurrence after acid-reducing surgery, Ulcers presenting with frank complications (bleeding, obstruction, and perforation)

Hypergastrinemia:

Hypergastrinemia Gastric hypochlorhydria or achlorhydria ( eg , pernicious anemia ); Retained gastric antrum after gastric surgery; H pylori infection; Gastric outlet obstruction; Renal insufficiency; Small-bowel obstruction; and Conditions such as rheumatoid arthritis, vitiligo , diabetes mellitus, and pheochromocytoma

Hypergastrinemia:

Hypergastrinemia PPI H2 receptor blockers

Zollinger Ellison Syndrome:

Zollinger Ellison Syndrome Peptic ulcer Severe ulcerative oesophagitis Diarrhoea

Epidemiology:

Epidemiology Accurate incidence not known Very rare 0.1 to 1% of patients with peptic ulcer disease M>F Age group 30-50 years Diagnosis usually delayed (4-6 years) More than 50% have liver mets at the time of diagnosis

Site:

Site 70% occur in the duodenum Less often malignant Tend to be small May be multiple

Types:

Types Sporadic Familial Common Solitary More malignant More common site is pancreas Rare Multiple Smaller

MEN type 1:

MEN type 1 Autosomal -dominant disorder that involves primarily 3 organ sites Parathyroid glands (80%–90%), Pancreas (40%–80%), and Pituitary gland (30%–60%). Obtaining a thorough family history is important when considering multiple endocrine neoplasia type I.

Clinical predictors of poor survival:

Clinical predictors of poor survival Liver mets Diffuse extent Bone mets Size >3cm Cushings syndrome Female sex Absence of MEN 1 Markedly raised serum gastrin

Diagnostic tests:

Diagnostic tests Fasting hypergastrinemia Basal acid output (BAO) is greater than 10 mEq /h. Secretin stimulation test

Treatment:

Treatment Role of surgery is controversial More useful in MEN 1 association Usually is Whipples PPI SST Analogues 5FU based regimens

GUT Hormones:

GUT Hormones

PowerPoint Presentation:

Hormone/peptide neurocrine endocrine paracrine VIP + Substance P + Neuropeptide + Somotostatin + + + Cholecystokinin + + Gastrin + Secretin + GIP + Motilin + + Neurotensin ? + + Guanylin + +

Summation of GUT hormones:

Summation of GUT hormones

PowerPoint Presentation:

Hormone Source Target Action Cholecystokinin I cell in duo, jeju, neurons in ileum, colon Pancreas gallbladder ↑ enz secretion ↑ contraction GIP K cell in duo, jeuju pancreas ↓ fluid absorp ↑ insulin release Gastrin G cell in antrum, duo Parietal cell ↑ aci d secretion ↑ motility GRP Vagus nerve G cell Gastrin r elease

PowerPoint Presentation:

Hormone Source Target Action Glucagon Alpha cell in pancreatic islet liver ↑ glycogenolysis ↑ gluconeogenesis Guanylin Ileum, colon Small and large intestine ↑ fluid secretion Motilin EC cell, Mo cell in upper GI tract Eso sphincter Stomach, duo Smooth muscle contraction Neurote nsin Neurons, ECC in ileum Intestinal smooth muscle ↓ GI motility ↑ blood flow

PowerPoint Presentation:

Hormone Source Target Action Peptide YY L cell in ileum, colon Stomach Pancrease ↓ vagal mediated acid secretion ↓ enz and fluid secretion Secretin S cell in small intestine Pancrease Stomach ↑ HCO3 and fluid secretion by pancreatic ducts ↓ gastric a secretion Somatostatin D cell in stomach , duodenum, pancreatic islet Stomach Intestine Pancrease Liver ↓ gastrin release ↑fluid absorption ↑ smm contraction ↓ endo /exocrine secretion ↓ bile flow

PowerPoint Presentation:

Hormone Source Target Action Substance P Enteric neurons Intestine Pancrease ↑ GI motility ↓ HCO3 secretion VIP ENS neurons Small intestine Pancrease smm contraction ↑SB secretion ↑pancreatic secretion

PowerPoint Presentation:

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