3 GI Hormones

Three main stimulants for gastric acid secretion

#1: G cells sends gastrin directly to Parietal cell CCKb receptor #2: G cells activates ECL cells to send histamine to parietal cell H2 receptor #3: Parasympathetic Vagus nerve send M3 acetylcholine

#3: Parasympathetic Vagus nerve stimulate Parietal cells in two ways

3a - send M3 acetylcholine to Parietal cells directly 3b - use GRP (Gastrin releasing peptide) to activate G cells to send gastrin to parietal cells indirectly

Parietal cells make IF

A cofactor required to reuptake B12 cobalamin

Signs of Gastrinoma

Abdominal pain that improves with food because food makes the environment in the duodenum alkaline so it stops the acidity from killing the duodenum Chronic diarrhea Duodenum ulcers Heart burn

Second messenger in Parietal cells

Acetylcholine and Gastrin use Gq -> IP3 and calcium Histamine use Gs -> Increase cAMP Somatostatin and prostaglandin use Gi -> Decrease cAMP

Stimulants for somatostatin release

Acidity will stimulate more somatostatin release

Misoprostol is a PGE1 agonist

Acts like a prostaglandin to bind to prostaglandin receptor on parietal cells to stimulate Gi to stop cAMP production to stop HCL secretion

VIPoma case

Adult who is 30 to 50 years old Long term watery diarrhea with no blood or pus Tried to change his diet but no result Endoscopy shows alkaline environment in the stomach Hypokalemia and achlorhydria

Parietal cells

Are eosinophilic stomach cells found in the gastric glands located in the mucosal layer. They secrete HCL to maintain a very low pH in the stomach in order to protect the body against infectious bacteria and break down proteins for absorption. They also produce Intrinsic factor as a cofactor to reuptake B12 Cobalamin

Atropine does not work to stop excess gastric acid production

Atropine is an muscarinic blocker to it uses acetylcholine to block parietal cells but it does not block Vagus' GRP production

Erythromycin is a motilin stimulator

Binds to motilin receptor in the intestine so it will stimulate peristalsis

Somatostatin effects

Block blood flow Block HCL production Block pepsinogen Block gallbladder contraction Block pancreatic fluid secretion Block intestinal fluid secretion Block both insulin and glucagon

GIP and secretin

Blocks the gastrin production in the stomach because food is no longer in the stomach so stomach does not need it anymore

Parietal cells secrete hydrogen out to the lumen using a H/K ATPase

Carbonic anhydrase takes H2O and CO2 from the body to convert them into HCO3 and H+. HCO3 leaves the parietal cell into the bloodstream using the HCO3/Cl pump to use the HCO3 as base and pull Chloride into the parietal cell. H+ leaves the parietal cell into the lumen using the H/K ATPase

Octreotide is used to treat Carcinoid syndrome

Carcinoid tumor is a tumor that secretes high amount of serotonin leading to skin flushing and diarrhea. Octreotide is a somatostatin to block the carcinoid tumor

Secretin test for Gastrinoma

Differentiate gastrinomas from other causes of excess gastrin secretion: Secretin block normal healthy G cells Secretin stimulates Gastrinoma cells When you give a patient excess secretin and their gastrin level increases, then you will know that they have a gastrinoma

Anti-diarrheals are on the DL

Diphenoxylate Loperamide

Atropine

Do not block GRP

Secretin is the main hormone to force

Duodenum to do its job

Diarrheals

Erythgomycin

Heartburn in Gastrinoma

Excess acid can leak into the esophagus leading to heartburn feeling

Duodenum ulcer is resistant to PPI in Gastrinoma

Excess acid leaks into the late duodenum and jejunum causing ulcers. They are resistant to PPI medication because there just way too much gastric secretion that it overtakes the PPI

Chronic diarrhea seen in Gastrinoma

Excessive acid leaks into the duodenum stops pancreas from releasing his enzymes. No pancreatic digestion enzymes and high acidity both block sodium and water reuptake in the duodenum causes excess electrolytes to become osmotic agents leads to steatorrhea and watery diarrhea

Diagnosis for Gastrinoma

Fasting gastrin level that is 10x above the normal limit Secretin test

Chief cells

Found in gastric glands in the mucosal layer of stomach. Chief cells are dark color basophilic cells to secrete pepsinogen. Pepsinogen is cleaved into pepsin using HCL. Pepsin is used to cleave proteins such as

GI hormones

Gastrin Secretin Cholecystokinin VIP Somatostatin

Gastrin MOA

Gastrin can go directly to Parietal cells G cells induce Enterochromaffin like cells (ECL) to release histamine then to Parietal cells to make HCL acid (major pathway) and increase stomach empty

#1: G cells sends gastrin directly to Parietal cells

Gastrin go to bind to Parietal cell's CCKb receptor

Parietal cells have three receptors (3)

Gastrin receptor Histamine receptor Acetylcholine receptor for Vagus nerve

Gastrin disorder

Gastrinoma Pernicious anemia

Ghrelin is made in the stomach

Ghrelin go up right before meals and quickly falls after eating. Ghrelin stimulates appetite and promotes weight gain. Patients who have undergo procedures that remove a portion of the stomach (Gastric bypass, sleeve gastrectomy) will lose a significant number of ghrelin-secreting cells. This leads to no ghrelin production and no stimulation of appetite caused by hunger so it promotes weight loss

Pernicious anemia signs

High G cells High gastrin level No parietal cells No IF in the blood No cobalamin B12 in the blood Peripheral neuropathy

Somatostatin is blocked by

High Vagus nerve stimulation because Parasympathetic vagus nerve wants to stimulate more digestion

Hypokalemia seen in VIPoma

High diarrhea leads to excess potassium excretion out of the feces

Gastrinoma treatment

High dose proton pump inhibitor Octreotide Surgery

Stimulants for CCK secretion

High fatty acids and monoglycerides High amino acids

GIP release is stimulated by

High food breakdown products such as oral glucose, fatty acids and amino acids

#2: G cells activates ECL cells to send histamine to parietal cells

Histamine binds to Parietal cell's H2 receptor to force it to secrete HCL

Diarrhea always causes

Hypokalemia, achlorhydria and metabolic alkalosis

Oral glucose metabolizes a lot faster than IV glucose

IV glucose does not stimulate GIP release because it does not go through the intestines

Ghrelin function

Increase with fasting, sleep deprivation, and strenuous exercise Decrease after food intake Stimulates the release of hypothalamic neuropeptide Y (NPY) and Anterior pituitary GH release

Ghrelin

Is a hormone secreted by the stomach that stimulates appetite via several different mechanisms, including via a direct effect on the lateral hypothalamus

Gastrin

Is a hormone that stimulates acid secretion in the stomach. Gastrin is released to act on parietal cells to make more HCL so it will increase gastric emptying

Secretin

Is made by S cells in the Duodenum to increase pH to make the duodenum more alkaline. When the stomach secretes too much acid into the duodenum, S cells must secrete Secretin in order to bring the pH back up to normal levels High fatty acids will also induce secretin secretions

Glucagon like peptide (GLP)

Is secreted by L cells located in the duodenum. GLP promotes gastric relaxation and pyloric contraction, thereby reducing gastric emptying. GLP also plays an important role as an incretin to help reduce serum glucose levels

Octreotide

Is synthetic somatostatin that is used to treat: Esophageal varices Carcinoid syndrome Acromegaly Gastrinoma Glucagonoma

Eryth(go)mycin

Is to make your colon go

Urinary chloride test

Is used to measure a patients chloride level in his urine when you don't know what's the reason for his metabolic alkalosis. If his urine chloride is below 20 and he is vomiting, then we know that he is losing a lot of HCL. If his urine chloride level is above 20, then that must mean he is taking a diuretic because Diuretic use blocks NaCl reuptake and forces it to go out the lumen into the urine

Prader willi syndrome

Is when the person has ghrelin levels are high and do not decrease after a meal

VIPoma

Is when you have a VIP secreting tumor in the pancreas. Because VIP promotes more bicarbonate and water release, it will lead to water diarrhea, hypokalemia, achlorhydria called WDHA syndrome Most common in middle age adult

Things that will block gastrin secretion

Low pH because that means there is high acid in the stomach so digestion is already done and food has left the stomach Somatostatin

Alkaline tide

Occur right after you eat, all the food causes the stomach to make excess acid production. High acid production stimulates Carbonic anhydrase to convert H2O and CO2 into more HCO3 and H+ so the body can use HCO3 into the blood to neutralize the excess acid so that is why right after a meal, you will have high amount of bicarbonate in your blood

Treatment for VIPoma

Octreotide IV Fluid and electrolyte

Octreotide in varices treatment

Octreotide is used to treat gastrointestinal varices because it will stop blood flow so people will not bleed to death

Two types of drugs to stop Parietal cell gastric acid secretion

PPI (Proton pump inhibitor) - Histamine H2 blocker - PGE1 agonist

Secretions of the Stomach

Parietal cells make HCL and IF Neck cells make bicarbonate and mucous

Secretin stimulation test for Gastrinoma

Secretin blocks normal healthy G cells. In gastrinoma, secretin will induce G cells to make more gastrin production

Secretin stimulates bicarbonate secretion into the Duodenum so it does not cause pain after a meal

Secretin inhibits stomach acid secretion and stimulated when there is an increase in acid or fatty acids in the duodenum and is not associated with pain after consumption of a meal

Somatostatinoma

Somatostatin is an inhibitory hormone that is normally produced in D cells of the pancreas. It inhibits the secretion of gastric acid, pepsinogen, insulin, glucagon, pancreatic fluid, and small intestinal fluid. It also inhibits gallbladder contraction. Somatostatin secretion is induced by amino acids, free fatty acids, glucose, glucagon, and beta adrenergic neurotransmitters. It is inhibited by α-adrenergic and cholinergic neurotransmitters and insulin. Somatostatin secreting tumors are rare and generally have a poor prognosis, because they are usually discovered at a late stage. They commonly manifest with a triad of steatorrhea, diabetes mellitus, and gallstones. These tumors are most commonly found in the pancreas but can also be found in the small intestine

This patient presents with late onset insulin-dependent diabetes mellitus, recent development of cholelithiasis, unintentional weight loss and steatorrhea. These findings are caused by decreased secretion of amylase, lipase, insulin, pepsinogen and glucagon and a pancreatic mass

Somatostatinoma

Action of Cholecystokinin (CCK)

Stimulate gallbladder contraction by relaxing sphincter of Oddi Promote pancreatic enzyme secretion Stop gastric emptying so it will give Duodenum time to digest its food

Secretin function

Stimulate pancreatic duct cells to release bicarbonate, block stomach acid production, increases bile production and promote pancreatic hormone into the duodenum

Things (4) that will stimulate gastrin secretion

Stomach distention Alkaline pH High phenylalanine and tryptophan Parasympathetic vagus nerve via Gastrin-releasing peptide (GRP)

Histamine H2 blockers include Cimetidine Ranitidine Famotidine Nizatidine

They block H2 receptor on parietal cells so it stops cAMP so no

Parietal cells uses two different channels to secrete both H and CL

They secrete hydrogen using a H/K ATPase They secrete Chloride using a Chloride pump

CCK relaxes the Sphincter of Oddi

This allows Gallbladder to release bile that will flow into the Duodenum

Neonates also have an increased proportion of total body water with a lower content of body fat compared to adults

This difference results in water-soluble drugs (aminoglycosides, vancomycin) having a larger than expected volume of distribution relative to body mass leads to lower plasma concentrations when the drug is administered at the same weight-based dosage as given to adult patients. Furthermore, neonates have an immature blood-brain barrier that increases the permeability of many substances into the CNS compartment that will increase the risk of CNS toxicity

VIP stimulates pancreatic bicarbonate secretion

To make duodenum more alkaline and watery. Excess bicarbonate also transport more water into the the lumen in order to allow the pancreas to release more digestion enzymes

Stomach neck cells make bicarbonate and mucous

To protect the body against HCL

Gastrin have three jobs

To stimulate parietal cells to make more HCL acid To stimulate gastric mucosa layer growth To increase gastric emptying

Erythromycin binds to motilin receptor in the intestines so it will stimulate peristalsis

To treat constipation

Watery diarrhea (secretory diarrhea) seen in VIPoma

VIP promotes bicarbonate secretion into the lumen and that stimulates more water to flow out of the cells into the lumen so it will result in a tea colored odorless watery diarrhea that resembles cholera

Chief cells are stimulated by Vagus

Vagus nerve stimulates

CCK stimulates the Vagus nerve

Vagus nerve will release acetylcholine to the Pancreas to contract and empty its hormones

VIP is

Vasoactive Increase alkaline Pancreas

Parietal cell pathological disorders

Vomit

WDHA syndrome seen in VIPoma

Watery Diarrhea, Hypokalemia, Achlorhydria

HIDA scan uses CCK to diagnose other disorders

When a patient comes in with RUQ pain, you will give them a HIDA scan. You give the patient 99mTc-hepatic iminodiacetic that will go into the Gallbladder and then out of the Intestines. 99mTc hepatic iminodiacetic is radioactive so it will light up when you scan it and when the gallbladder does not light up, then you know there is a obstruction. You will also give them CCK to stimulate gallbladder contraction to figure out the gallbladder ejection fraction

Vomit leads to metabolic alkalosis

When you throw up your stomach acids, you will lose a lot of acid so the body will compensate by creating more HCL. For every 1 HCL produced, 1 HCO3 is also produced but HCO remains in the body so it makes the bloodstream very alkaline. When H+ is pushed into the cell, one potassium is push out of the parietal cells and then into the lumen so vomiting also makes the bloodstream hypokalemia Urine chloride is really low at below 20

Increased acid content and fatty acids in lumen of duodenum

Will stimulate Secretin release

Vomiting case

Young woman who have really low urine chloride with unexplained metabolic alkalosis. You will then measure her urine chloride level and it is below 20 and hypokalemia so that indicates that she is surreptitious vomiting

Gastrinoma (Zollinger ellison syndrome)

is a gastrin-secreting tumor occur in Duodenum and pancreas where they produce excess amount of gastrin G cells are found in stomach, duodenum and pancreas in fetus Creates hypertrophy and hyperplasia of the mucosa layer

Leptin

is a hormone produced in adipose tissue to block hunger. Its release is not related to individual meals but to the circadian rhythm (highest at night, lowest in the morning). A daily injection of leptin would increase satiety but not hunger or weight gain

Cholecystokinin (CCK)

is a hormone to stimulate gallbladder contraction and pancreas to release its hormones. Duodenum and Jejunum have I cells that makes cholecystokinin to the pancreas and gallbladder

Motilin

is a hormone to stimulate peristalsis in the stomach, intestines and colon. It promotes motility in the fasting state so highest level of motilin in the body is when the person is not eating

VIP (vasoactive intestinal peptide)

is a neurocrine peptide made by neurons in GI tract to GI smooth muscle cells, increases pancreatic bicarbonate secretion and block gastric acid secretion

Vagotomy

is an old treatment for gastric ulcers when they cut the Vagus nerve to the stomach to stop excess gastric acid secretion

Glucose dependent insulinotropic peptide (GIP)

is made by K cells in duodenum and jejunum where it stimulates pancreatic insulin release and block acid production

Somatostatin

is the main hormone that blocks everything. Pancreatic D cells and peripheral nerves make somatostatin to act as both as hormone and a paracrine signal

Achlorhydria seen in VIPoma

is when you do not have any gastric acid in the stomach because high VIP hormone will block HCL production in the stomach

Pernicious anemia

is when you have an autoimmune disorder where you have antibody to kill parietal cells. No parietal cells means you cannot make Intrinsic factor so IF is required for vitamin B12 reuptake. Because you cannot reuptake vitamin B12, you will have hand and foot neuropathy. Because parietal cells are defective, Stomach compensate by increasing the proliferation of G cells and therefore leading to high gastrin levels

Leptin function

stimulates lipolysis, increases energy consumption, and acts as an anorexigenic hormone, which decreases hypothalamic neuropeptide Y (NPY) and promotes satiety.