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Stomach and Duodenum Anatomy, Histology and Physiology I

Stomach and Duodenum Anatomy, Histology and Physiology I

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ANATOMY, HISTOLOGY AND PHYSIOLOGY

I. and histology II. Functions of the stomach III. Review of gastric IV. Tests of gastric secretion (gastric analysis) V. Abnormalities of secretion VI. Gastric mucosal defense factors VII. Antibacterial function VIII. Pepsinogen secretion IX. B12 physiology X. physiology XI. Gastric Motility

I. Anatomy and Histology

Stomach: The four anatomical regions of the stomach are the cardia, fundus, body and antrum. The mucosa of each of these regions contains into which several types of mucosal glands empty. Cardiac glands are lined by mucous cells, which secrete and small amounts of pepsinogen. Oxyntic glands are found in the fundus and body of the stomach. These glands contain a variety of types including mucous cells, parietal cells, chief cells, endocrine cells and enterochromaffin-like (ECL) cells. The gastric antrum contains pyloric glands composed of mucous and endocrine cells, especially G cells which produce and D cells which produce . Table 1 lists the major cell types in the stomach, their respective products, and their functions.

Table 1: Review of the Cell Types in the Stomach Cell Type Product Function Kill enteric pathogens; facilitate activity of Cobalamin absorption Chief cell Pepsinogen I Digest Mucous cells Pepsinogen I and II Digest protein Stimulate ECL cell G Gastrin Stimulate parietal cell D Somatostatin Endogenous "brake" ECL Stimulate parietal cell

Pylorus: tubular structure separating the stomach from the duodenum and containing the circular muscle-pyloric .

Duodenum: The duodenal mucosa is characterized by the presence of Brunner’s glands, an important source of . These glands are located primarily in the .

Vascular Supply: The stomach and duodenum are furnished with blood from branches of the celiac trunk. This trunk can give rise to the common hepatic, left gastric, splenic artery, and the gastroduodenal artery. This generous blood supply explains why vascular insufficiency syndromes of the stomach are rare. Venous drainage follows the arterial system and empties into the portal , splenic or superior mesenteric . Lymphatic drainage is primarily into the celiac nodes.

Innervation: Sympathetic innervation is from fibers derived from the thoracic area T6 to T8. Parasympathetic innervation is primarily via branches of the vagus , which play important roles in gastric acid secretion, gastrin release and gastric motility. Vagal afferent fibers are important in several gastric reflexes. The stomach is also innervated by the intrinsic enteric , with cell bodies found in Meissner’s and Auerbach’s plexus.

II. Functions of the Stomach

The anatomy and histology of the stomach combine to partially digest food prior to passage into the . The digestive process requires the integration of two functions: motility and secretion. Gastric motility can be divided into 3 categories that are region specific: receptive relaxation of the fundus, of the body and antrum and antro-pyloric peristalsis. These 3 functions store the food, triturate (grind) it and empty the resulting chime into the small intestine in a coordinated manner. The interstitial cells of Cajal(ICC) are the gastric pacemakers and responsible for the generation of slow waves of the stomach. The pacemaker potentials originate from a site from an area in the greater curve in an area between the fundus and body.

The stomach secretes numerous compounds that are responsible for and regulation. The proximal stomach where oxyntic(parietal) cells are located secretes gastric acid whereas the pyloric gland area in the antrum acts as an endocrine releasing gastrin (to stimulate acid secretion) and somatostatin (a feedback inhibitor) to reduce acid secretion.. Additional functions of the stomach include facilitation of cobalamin () absorption via intrinsic factor secretion, initiation of protein digestion (via pepsinogen secretion and pH-dependent activity) and an antimicrobial function protecting against ingested pathogens (via the acidity of gastric juice). Ghrelin produced by endocrine cells of the gastric fundus and other and neurotransmitters are involved in the regulation of hunger and satiety.

III. Review of Gastric Secretion

Gastric acid secretion is the result of paracrine, neural, intracellular and hormonal regulatory pathways. Gastric juice is a combination of parietal (hydrochloric acid) and non-parietal . Parietal cells secrete pure hydrochloric acid at a concentration of 150-160 mmol/L. The volume secreted by parietal cells is determined by the number of actively-secreting cells and also varies according to food intake (low with fasting; high after meals). Non-parietal secretions

+ - + include water, electrolytes such as Na and HCO3 (but not H ), and mucus. The overall volume of gastric juice produced during any given period is determined by the relative proportions of parietal and non-parietal secretions and is roughly 2.5 L/day. The acidity (hydrogen ion concentration) of gastric juice depends on the relative proportions of parietal and non-parietal secretions.

The basolateral membrane of the parietal cell has receptors for three stimulatory ligands: a histamine (H2) receptor (for histamine released by ECL cells), a muscarinic (M3) cholinergic receptor (for released from postganglionic neurons), and a B (CCK-B) receptor for gastrin (released from pyloric and duodenal G cells) (Figure 1). Thus the parietal cell responds to paracrine, neurocrine and endocrine stimuli. The parietal cell also appears to have basolateral receptors for inhibitors of its function: somatostatin and (Figure 1).

Figure 1: Model of gastric acid secretion by the parietal cell:

Histamine is the most important stimulant of acid secretion. Released from ECL cells in the , histamine interacts in a paracrine manner with local parietal cell histamine H2 receptors to increase acid secretion (Figure 1). There is also recent evidence that histamine may also act through H3 receptors on D cells to suppress the release of somatostatin thereby further augmenting acid secretion.

Acetylcholine is released from postganglionic nerve endings as the final result of vagal nerve stimulation to interact with muscarinic M3 receptors located on a variety of cells in the stomach. This neurocrine/cholinergic action directly stimulates parietal cells and also stimulates the local release of histamine from ECL cells. Vagal activity also stimulates G cells to release gastrin, and suppresses the release of inhibitory somatostatin from D cells.

Gastrin is a true released into the bloodstream from G cells in the gastric antrum. Stimulation above basal levels results from the presence of food (particularly amino ) in the gastric as well as from vagal activity. There is still some controversy regarding how gastrin stimulates acid secretion in humans. Although gastrin binds directly to CCK-B (gastrin) receptors on the parietal cell basolateral surface, this action is likely to predominantly affect parietal cell proliferation and to be less important in mediating acid secretion than is its action on similar receptors located on ECL cells resulting in histamine release. Thus, gastrin's secretory effects on parietal cell acid production are probably mediated primarily through histamine release from ECL cells.

Somatostatin, an inhibitor of parietal cell function, plays an important role in modulating gastrin release. The proximity of D and G cells in the gastric antrum suggests that somatostatin serves a paracrine function as an endogenous "brake" on gastrin release. Hydrogen ions in the gastric lumen "turn on" D cells to assist in the feedback inhibition of gastrin release by acid. studies have also shown that acetylcholine, released via vagal stimulation, "turns off" D cells, thereby enhancing gastrin release providing an additional indirect means by which acetylcholine promotes acid secretion. Cholinergic release of gastrin does not appear to occur in humans.

Cholecystokinin (CCK) is released into the blood from duodenal and jejunal I cells in response to diet-derived amino acids and fatty acids. CCK acts on both CCK-1 and -2 receptors, but the former effect is more prominent at physiological concentrations, with the net effect on the stomach to inhibit acid secretion, mediated through stimulation of somatostatin released from D cells.

Prostaglandins are secreted by virtually every epithelial and non-epithelial cell in the stomach. The major prostaglandins produced by the human stomach are PGE2, PGF2α and PGI2 (prostacyclin). A receptor for PGE2 linked to an inhibitory G protein has been demonstrated on the parietal cell. Parietal cell PGE2 receptors have effects opposite to those of H2-receptors, i.e., they reduce adenylate cyclase activity, lower intracellular cyclic AMP (c-AMP) levels and protein kinase A activity thereby inhibiting acid production. E analogs, such as , reduce acid secretion.

Parietal cell stimulation and inhibition.

Following binding of a ligand to its receptor on the parietal cell, a second intracellular messenger is produced. For acetylcholine, this messenger is calcium, which is probably produced by hydrolysis of inositol trisphosphate. For histamine the second messenger is c-AMP. When histamine binds to the H2 receptor, a stimulatory G protein (G2) activates the intracellular , adenylate cyclase, which generates c-AMP. Calcium and c-AMP activate protein kinases, which result in the physical transformation of the parietal cell to expand the secretory canalicular surface of the cell culminating in the secretion of acid. Hydrogen ions are secreted into the secretory canalicular lumen in exchange for potassium ions by the enzymatic action of the (i.e. H+/K+-ATPase). This enzyme is always active, even when the cell is "resting" but it cannot pump hydrogen from the cell unless there is potassium in the lumen. Activation of the parietal cell to secrete acid occurs when transcellular pathways for potassium and chloride are opened, thereby providing the luminal potassium needed for exchange for intracellular hydrogen.

There are a number of substances, including prostaglandins and such as , gastric inhibitory polypeptide (GIP), YY, and somatostatin, which all serve to inhibit parietal cell function and suppress acid secretion. Prostaglandins and somatostatin act through inhibitory G (Gi) which inhibit adenylate cyclase and, thus the generation of c-AMP. Somatostatin also acts by inhibiting the ECL cell, thereby suppressing histamine release.

Physiology of gastric acid secretion

Basal acid secretion Acid secretion in the resting, unfed stomach has a diurnal pattern and varies widely in rate among normal subjects. While serum gastrin concentrations do not correlate with basal acid output, factors which are important include vagal "tone" and gender. There is evidence that high vagal "tone" may lead to sustained basal hypersecretion in some subjects and temporary hypersecretion during periods of stress in others. Women, on average, secrete less acid in the basal state than men.

Stimulated acid secretion The acid secretory response to food is divided into the cephalic, gastric, and intestinal phases. Cephalic phase: Acid secretion in response to the sight, smell, taste or thought of food is mediated by the . Vagal stimulation, which may be elicited by sham feeding (see below), results in release of histamine from ECL cells, direct activation of the parietal cell, and stimulation of the G cells through release of an unknown transmitter, eliciting a modest release of gastrin. Vagal stimulation may also inhibit somatostatin release, thereby permitting unrestrained parietal and function. Truncal abolishes both acid secretion and gastrin release during the cephalic phase.

Gastric phase: The gastric phase of acid secretion comprises the major component of acid secretion. It occurs when food reaches the stomach and is mediated both by distention of the stomach and by the action of food itself on gastrin release. Distention stimulates modest levels of acid secretion directly through gastrin release and via neural reflex pathways. More important, however, is the effect of food, primarily amino acids and other protein digestion products, which stimulate G cells to release gastrin. Gastrin release accounts for up to 90% of the gastric phase of acid secretion. The release of gastrin is inhibited by low pH levels, primarily via paracrine release of somatostatin.

Intestinal phase: Digested protein in the small intestine results in modest stimulation of acid secretion via the release of small amounts of gastrin (and perhaps other stimulatory peptides) and through the direct effect on the parietal cell of absorbed amino acids. The intestinal phase accounts, under normal circumstances, for only a small proportion of the acid secretory response to a meal. Gastric contents and food in the duodenum also serve to inhibit acid secretion, the former probably via release of secretin, CCK, somatostatin and other peptides.

IV. Tests of Gastric Acid Secretion (Gastric analysis) These tests are rarely done in practice but may be useful for examining the cause of hypergastrinemia such as Zollinger-Ellison syndrome and in managing these patients.

Basal acid output (BAO) measures resting acid secretion in the absence of any stimulation. The upper limits of normal BAO for men and women are approximately 10 and 6 mEq/hr, respectively. Peak acid output (PAO) and maximal acid output (MAO) measure response to an external stimulant such as . ( pentagastrin is no longer available in the USA).

V. Abnormalities of Gastric Acid Secretion Aging Acid output does not decrease with normal aging. Acid secretion is reduced only in older patients who have developed chronic atrophic , which is usually a result of chronic H. pylori infection (see below).

Helicobacter pylori pangastritis with/without Gastric Ulcer The relationship between H. pylori infection and acid secretion is complex. The pattern of acid secretion depends on whether the infection is acute or chronic, infection severity and distribution. In acute infections patients appear to be hypochlorhydric. In chronic infectons there appear to be three patterns of acid production; hypersecretion in antral-predominant infection (see below), hyposecretion in patients with severe chronic pangastritis and normosecretion in the majority of asymptomatic individuals with milder gastritis. There appears to be an inverse correlation between the severity of the body gastritis and acid secretion, with some subjects being hypo- or even achlorhydric.

As a group, patients with gastric ulcer (GU) have relatively normal levels of gastric acid secretion. However, many GU patients have levels of acid secretion below normal values. GU patients have variable degrees of gastric atrophy likely due to chronic pangastritis although requires the production of at least some acid.

Helicobacter pylori antral-predominant gastritis and Duodenal Ulcer As a group, H. pylori-infected patients with duodenal ulcer (DU) have higher mean values for BAO, PAO, and somewhat higher fasting gastrin concentrations than H. pylori-infected subjects without ulcers. The higher levels of acid secretion may be related to the observation that DU patients tend to have an antral-predominant gastritis with relative sparing of the gastric body. This may lead to antral G cell hyperplasia (due to inhibition of D cell function) and a tendency towards elevated acid output.

Gastric Cancer Only a minority of patients with gastric adenocarcinoma are achlorhydric.

Zollinger-Ellison Syndrome BAO in most untreated patients with ZES will be >15 mEq/hr. It should be noted that ZES patients classically develop duodenal ulceration rather than gastric ulceration, a consequence of overproduction of gastric acid rather than the presence of poor mucosal cytoprotection.

Idiopathic basal acid hypersecretion Idiopathic basal acid hypersecretion is a poorly characterized condition in which duodenal ulceration develops due to gastric acid hypersecretion without the presence of hypergastrinemia. The leading to acid hypersecretion in these patients is unknown but the condition should be considered in all patients with documented hypersecretion (a BAO > 10 mEq/hr) with a normal serum gastrin level (< 100 pg/ml).

Post Vagotomy with or without Antrectomy Proximal gastric vagotomy, if successful, results in about a 75% reduction in gastric acid secretion. Addition of an antrectomy results in an even greater reduction in gastric acid production.

VI. Gastric Mucosal Defense Factors

Because of their constant exposure to high concentrations of hydrochloric acid, gastro-duodenal epithelial cells would appear to be at risk of autodigestion. However, under normal circumstances mucosal protective factors prevent such self-destruction. These factors include prostaglandins and bicarbonate secretion. Non-steroidal anti-inflammatory drugs (NSAIDs) block the synthesis of prostaglandins and predispose to mucosal injury and peptic ulceration. The means by which prostaglandins protect the gastroduodenal mucosa include the secretion of mucus, stimulation of bicarbonate secretion, and maintenance of blood flow during periods of potential injury.

VII. Antibacterial Function

Hydrochloric acid is bactericidal to most . Thus, the stomach serves as a gatekeeper to the small intestine, keeping out potential bacterial pathogens. The stomach itself, because of its acidic milieu and gastric motility, is usually sterile. Only micro-aerophilic spiral organisms (i.e., Helicobacter pylori and Helicobacter heilmannii – previously called Gastrospirillum hominis) are able to survive in the healthy human stomach. Bacterial overgrowth of the stomach may occur under circumstances of hypo- or . In turn, gastric hypochlorhydria may predispose to small bowel bacterial overgrowth which can lead to steatorrhea, gas/bloat syndromes, or cobalamin .

VIII. Pepsinogen secretion

Pepsinogen is converted in the gastric lumen to pepsin by gastric acid. While important early in life for digestion of milk, pepsin's major substrates in later life are meat and other proteins. Relatively little digestion takes place in the stomach, but release of peptides and amino acids by pepsin helps trigger the release of other important GI hormones such as gastrin and cholecystokinin. There are both cephalic and gastric phases of pepsinogen secretion, with the major stimulus being cholinergic.

IX. Vitamin B12 Physiology Intrinsic factor (IF), a glycoprotein whose primary role is the facilitation of cobalamin (vitamin B12) absorption, is secreted by parietals cell under essentially the same stimulatory conditions as hydrochloric acid. Cobalamin, when freed from food (protein) by acid and pepsin, initially combines preferentially with R-proteins present in . Only in the alkaline environment of the duodenum, where the R-proteins are hydrolyzed by pancreatic , will vitamin B12 preferentially bind to IF. The IF-B12 complex then passes through the intestine to the , where it recognizes its receptor (amnionless/cubulin) and is actively absorbed. Failure to absorb vitamin B12 can occur because of IF deficiency associated with autoimmune gastritis, pancreatic exocrine insufficiency, small bowel bacterial overgrowth (usually in the presence of achlorhydria), or ileal disease (including absence of the amnionless/cubulin receptor or abnormal receptor function).

X. Regulation of Satiety: Ghrelin

The presence of food in the stomach stimulates a complex sequence of regulatory responses that are responsible for controlling behavior. Ghrelin appears to be a critical part of the regulatory process. Ghrelin is a gastric peptide released by endocrine P/D1 cells located primarily in the fundus. It is a member of the family that binds to the releasing hormone (GHRH) receptor which drives feeding behavior, gastric acid secretion and growth hormone release leading to weight gain. Like motilin, ghrelin increases gastric contractility and emptying rates. High levels occur in fasting states and the Prader-Willi syndrome whereas low levels occur in obesity states, postprandially or after .

XI. Gastric Motility A major function of the stomach is to serve as a reservoir in which food is stored, mixed, and then expelled into the duodenum in a controlled fashion. As food enters the proximal stomach, receptive relaxation occurs. This is a vagally-mediated inhibition of fundic tone which permits storage of food without a rise in intragastric pressure. Liquids are rapidly distributed throughout the stomach and emptied by a tonic pressure gradient from the proximal to distal stomach and then to the duodenum. After an initial storage period in the proximal stomach (approximately 30 minutes), solids move to the antrum. Segmental contractions originate in the mid-body of the greater curve (the gastric “pacemaker” associated with interstitial cells of Cajal). They occur approximately three times per minute to mix the food. This process is also under the influence of the vagus. Digestible solids are broken down by antral grinding to particle sizes <1mm in a process termed trituration and then emptied into the duodenum by these contractions and pressure gradients for further digestion and absorption. Non-digestible solids are emptied in the fasting state by interdigestive migrating motor complexes (MMC). This pattern of contraction occurs every 90 minutes to 2 hours and consists of a propulsive contraction which begins in the stomach, moving larger food particles through an open continuing down into the small bowel. This process of periodic sweeping of the gut by the MMC is termed the intestinal “housekeeper”. Vagal nerve or intrinsic neural plexus dysfunction or destruction leads to failure of receptive relaxation, causing early satiety and failure of antral grinding, leading to delayed emptying of gastric contents. Table 2 summarizes the motor and secretory functions of the vagus. Table 2: Functions of the Vagus  Mediates receptive relaxation of proximal stomach  Mediates antral contractions  Stimulates acid secretion by direct effect on M3 muscarinic receptors on parietal, ECL and D cells  Stimulates gastrin release of GRP and inhibition of somatostatin from D cells

Gastric contents entering the duodenum and upper small intestine stimulate receptors, which are responsive to physiological factors such as low pH, high osmolality (osmoreceptors), fatty acids and caloric density. Activation of these receptors, in turn, triggers enterogastric reflexes that function to slow gastric emptying. Hormones such as secretin, CCK, and GIP have also been hypothesized to play a role in these reflexes. The purpose of these inhibitory mechanisms is to prevent the small intestine from being overwhelmed by the rapid entry of nutrients from the stomach leading to the dumping syndrome. More recently, additional hormones such as and ghrelin have also been implicated in controlling gastric emptying and modifying satiety.

Barium x-rays are inadequate to measure gastric emptying because UGI series measure only the emptying of liquids. An UGI series should especially not be performed if there is strong suspicion that a patient has high-grade gastric outlet obstruction and is not particularly useful to differentiate between organic obstruction and a motility disorder anyway. If is negative, an UGI may be helpful to diagnose more distal duodenal obstruction beyond the reach of the endoscope.

Radiopaque markers provide a simple, inexpensive test to assess the emptying of indigestible solids. Ten markers are ingested with a high osmolar meal. After six hours, all of the markers should have left the stomach, as determined by plain film of the . This test has been used primarily in patients with diabetic , where the most marked defect in emptying is with indigestible solids. The most popular test to measure gastric emptying is a radiolabeled solid scintigraphy study. Although two-hour gastric emptying studies are most commonly performed, a four hour appears to be be more accurate. The test is non-invasive, results in relatively little radiation exposure, and can quantitate emptying times as well as provide patterns of emptying. The availability and interpretation of other tests of gastric motor or sensory function such as gastroduodenal manometry, electrogastrography, measures of gastric accommodation, the water load test, the octanoic acid breath test and ultrasound or MRI measures of gastric emptying are still mainly of research interest and not clinically useful at this time. Recently, the FDA approved a new device, the SmartPill, which is ingested and provides temperature and pH measurement over time. This device may become useful for measuring true gastric emptying (i.e., recovery of the MMC after a meal) when the capsule is ejected from the stomach and may also be helpful to identify achlorhydria in the absence of antisecretory therapy.

QUESTIONS 1) A 42 yr old male is referred for recurrent . He has a history of duodenal ulcer and H.pylori gastritis. He was treated for H. pylori. He denies NSAID or ASA exposure. The EGD demonstrates erosive , normal . Rapid urease testing of specimens was obtained in both the antrum and body. Gastric aspirate demonstrates a pH of 1.8. He is given a PPI but continues to have reflux symptoms. A serum gastrin comes is obtained and is 644 pg/ml.

This patient most likely has: a) H. pylori pangastritis b) c) Retained antrum syndrome d) Zollinger-Ellison syndrome

2) Hyperchlorhydria associated with Zollinger Ellison Syndrome is the due to which of the following?

a) Inhibition of somatostatin production b) Gastrin producing tumor cells c) Hypertrophy of antral G cells d) Hyperplastic oxyntic mucosa

3) Ghrelin performs which of the following functions:

a) decreases acid secretion

b) stimulates G cell proliferation

c) regulates satiety

d) increases bicarbonate section

e) delays gastric emptying

4) A 75 year old male is admitted with a history of . His past medical history includes coronary artery disease with prior stent placement. His surgical history includes peptic ulcer disease for which he had surgery 40 years ago. His current medications are atenolol, pravastatin, 81 mg. His BP is 127/60, pulse 76 and

he is not orthostatic. His examination reveals an abdominal scar and no tenderness. His Hgb/Hct is 8.5/27 and his BUN is 35, Creatinine 1.0. An endoscopy is performed which shows no evidence of active bleeding, a few non-bleeding erosions and a patulous pylorus.

Which of the following would you recommend? a) Stop ASA 81 mg b) Long-term PPI therapy c) Switch ASA to clopidogrel d) Switch ASA to naproxen

5) A 43 year old female presents with acute onset of melena dizziness. She is an active tennis player and has been taking high doses of aspirin and advil for pains. In the emergency department she is pale and her vital signs reveal a BP or 88/64 and pulse of 102. Her abdomen is soft and her stool shows reddish blood. Her Hgb/Hct is 7.2/25.6. She is resuscitated with normal saline and 2U of packed red blood cells. She continues to be tachycardic and an urgent endoscopy is performed. Fresh blood is seen in the stomach and duodenum. After lavage a clot and deep ulcer is seen in the posterior portion of the Which vessel is the most likely source of the bleeding? a) Superior mesenteric artery b) Gastro-epiploic c) Celiac d) Left Gastric e) Gastroduodenal

6) A 60-year-old woman is referred for evaluation of . She is healthy but drinks 2-3 glasses of wine per day. Her Hgb. = 9.0 g/dl and MCV = 115 fL and she is found to have a a low vitamin B12 level and normal iron. Which of the following is the most likely diagnosis?

a) Pernicious anemia b) Chronic use

c) Celiac disease d) Idiopathic megaloglastic anemia

ANSWERS

1) d. This patient has an elevated serum gastrin and a low pH. The key is the low pH on aspirate. Diffuse gastritis is associated with H pylori, as opposed to antral-predominant H. pylori infection, and atrophic gastritis are associated with hypergastrinemia due to hypochlorhydria. Only retained antrum after Billroth II resection and anastomosis and Zollinger-Ellison () syndromes are both associated with elevated gastrin levels (i.e., in the presence of low pH).

2) b. Zollinger – Ellison Syndrome is the result of increased gastrin secretion by a gastrin producing tumor. The other choices could result in hyperchlorhydria, a term synonymous with excess acid secretion, but ZE syndrome is the result of a neuroendocrine tumor that makes too much gastrin.

3) c

The primary role of Ghrelin is the regulation of satiety. It is a secreted by endocrine cells of the fundus that acts to regulate the satiety signal. Ghrelin has other actions such as altering gastric motility and emptying because it is a member of the motilin family of peptides. Levels are high in fasting states and very low after gastric bypass. Praeder-Willi syndrome is manifested by low ghrelin levels and severe hyperphagia, growth hormone deficiency, and hypogonadism.

4) b

This patient is at high risk for recurrent bleeding and his CAD requires ASA. From a risk benefit standpoint the use of ASA is likely the better option for long term management for CAD and the addition of PPI will reduce risk.

5) e The gastroduodenal artery is a branch of the hepatic artery that passes behind the duodenum near the bulb and is the vessel most likely associated the bleeding. Treatment of deep ulcers with coagulation may worsen the bleeding.

6) a Low B-12 can occur with decreased intake, intrinsic factor deficiency (i.e., pernicious anemia), pancreatic exocrine insufficiency (i.e., chronic ), small bowel bacterial overgrowth

(usually in the presence of achlorhydria), or ileal disease. The most common cause is autoimmune gastritis which is associated with the presence of ant-intrinsic factor antibodies.

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