1 What is the major stimulus for gastrin secretion? What are the physiologic actions of gastrin in the stomach?

Protein in the stomach is the primary stimulus for the secretion of gastrin by G cells in the antrum of the stomach (other stimuli include stomach distention, stomach alkalinization, and vagal stimulation). The secreted gastrin stimulates the secretion of hydrochloric acid and intrinsic factor (IF) by the gastric parietal cells and stimulates secretion of pepsinogen by the chief cells. Notice that all these secretions are important in protein/meat digestion, because the acid environment created helps hydrolyze proteins and creates an optimal pH in which pepsin works (~ pH 2). Additionally, the secreted IF binds and protects the vitamin B₁₂ that is present in meat. A major inhibitor of gastrin secretion is decreased gastric pH, which stimulates somatostatin secretion from D cells in the pancreas and gastrointestinal mucosa. Somatostatin and decreased pH are both negative feedback mechanisms to keep the stomach from becoming too acidic.

2 What are the main pancreatic enzymes and what are their functions?

Pancreatic enzymes are all involved in digestion (degradation) of food macromolecules. Pancreatic amylase degrades starch/complex carbohydrate, trypsin and chymotrypsin degrade proteins, and lipase hydrolyzes triglycerides; there are also DNase and RNase enzymes in pancreatic secretions. The pancreas also secretes bicarbonate, which neutralizes acidic chyme entering the duodenum and creates the pH necessary for pancreatic enzymes to work.

Pancreatic enzymes are secreted as zymogens (inactive precursor molecules), which are cleaved into their active form within the intestinal lumen. This prevents autodigestion of the pancreatic tissue by the active enzyme forms. Trypsinogen is cleaved into trypsin by enterokinase within the intestinal mucosa. Trypsin then activates more trypsinogen as well as other pancreatic enzymes.

Note: The pancreatic acinar cells are rich in secretory granules full of enzymes, and the pancreatic ductal cells are principally responsible for bicarbonate and fluid secretion.

3 What are the primary hormonal stimuli for the pancreatic exocrine secretions and how do these secretions differ in content?

Cholecystokinin (CKK) primarily stimulates the secretion of enzymes (e.g., proteases such as trypsinogen) from the pancreatic acinar cells, whereas secretin primarily stimulates the secretion of a bicarbonate-rich fluid from pancreatic ductal cells.

4 What are the primary stimuli for the secretion of cholecystokinin and secretin and from where are these hormones secreted?

CCK is secreted primarily in response to fatty acids entering the duodenum, whereas secretin is released primarily in response to acidification of the duodenum. Both are secreted from the duodenum.

5 What other digestive processes does cholecystokinin stimulate?

CCK also stimulates contraction of the gallbladder and relaxation of the sphincter of Oddi (where the common bile duct enters the duodenum), thereby promoting bile entry into the duodenum. By stimulating pancreatic secretion of lipolytic enzymes as well as the delivery of bile to the small intestine, this hormone creates the appropriate milieu for the digestion of fats.

Note: CCK also delays gastric emptying. This explains why the sensation of fullness lasts longer after a fatty meal.

6 What is the function of the bile salts? How are they formed?

The bile salts solubilize fats in meals, creating a bigger surface area on which pancreatic lipase can work. They additionally form micelles that facilitate the delivery of fatty acids to the intestinal enterocytes for absorption. Bile salts are formed from the degradation of cholesterol in the liver via the enzyme 7α-hydroxylase. As a point of interest, this is the primary method the body has for eliminating cholesterol.

7 What is the enterohepatic circulation and why is it important in the digestion of fats?

Enterohepatic circulation occurs when substances are secreted by the liver, reabsorbed by the intestine, and returned to the liver. The majority of the bile salts that are delivered to the intestine during digestion are from intestinal reabsorption of secreted bile salts. In diseases that decrease bile salt reabsorption (e.g., Crohn’s disease), the enterohepatic circulation and secretion of bile salts from the liver are impaired, resulting in impaired fat digestion.

8 What defines the foregut, midgut, and hindgut anatomically? Which main arteries provide the blood supply to each segment? What nerves supply these regions?

The foregut comprises the upper gastrointestinal (GI) tract down to a site just distal to the ampulla of Vater (where the common bile duct empties into the secondary part of the duodenum). Its main vascular supply comes from the celiac artery. The midgut extends from the second part of the duodenum down to the splenic flexure of the colon and is served by the superior mesenteric artery. The hindgut extends from the splenic flexure of the colon to the anus and is supplied by the inferior mesenteric artery. The foregut and midgut are innervated by the vagus nerve, and the hindgut is innervated by the pelvic nerve.

Note: The pancreas and liver are embryologic outgrowths of the foregut and share the vascular supply of the foregut (i.e., celiac artery). Although the spleen is not an embryologic derivative of the foregut (it is mesodermal in origin), it is supplied by the celiac artery as well.

9 What are the anatomic layers of the gut wall?

From the lumen out, the layers of the GI tract are as follows: (1) mucosa, comprising the mucosal epithelium, lamina propria, and muscularis mucosae; (2) submucosa, which contains the submucosal (Meissner’s) nerve plexus; (3) muscularis propria, comprising an inner circular smooth muscle layer, myenteric plexus, and outer longitudinal smooth muscle layer; and (4) serosa (adventitia), which is the fibrous outer covering (Fig. 6-1).

Figure 6-1 Layers of the gut wall.

(From Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007.)

Note: The taeniae coli are band-like muscles composing the outer longitudinal smooth muscle layer of the large intestine, except in the appendix and the rectum.

1 What is the differential diagnosis?

The differential diagnosis includes gastroesophageal reflux disease (GERD), esophageal spasm, and myocardial ischemia. Note that myocardial infarction and angina should be part of the differential diagnosis in any case in which there is chest discomfort/pain, especially considering that this patient is a middle-aged, obese male, all of which are risk factors for heart disease. GERD characteristically presents with heartburn, which can mimic myocardial ischemia, and regurgitation of sour material into the mouth. The heartburn from GERD is typically exacerbated by both eating large meals and bending over or being recumbent in bed. In addition to heartburn, patients with GERD can also present with chronic cough from gastric acid irritation of the tracheobronchial tree and a hoarse voice in the morning from the gastric acid irritation of the vocal cords at night.

Case 6-1 continued:

Physical examination is significant for obesity. There is no chest wall tenderness. Cardiac examination is unremarkable, except for auscultating bowel sounds in the patient’s chest. A cardiac stress test is negative for inducible ischemia. A barium swallow is shown in Figure 6-2.

Figure 6-2 Sliding hiatal hernia. A bulbous collection of contrast representing the stomach herniated is evident above the diaphragm. Gastric folds are present in the hernia, identifying it as part of the stomach (solid white arrow). Notice the esophagus does not narrow as it normally does when passing through the esophageal hiatus (dashed white arrow). Just above the hernia is a thin, weblike filling defect characteristic of a Schatzki’s ring (dotted white arrow). The Schatzki’s ring marks the level of the esophagogastric junction.

(From Herring W: Learning Radiology: Recognizing the Basics, 2nd ed. Philadelphia, Saunders, 2012.)

2 Based on the findings in Figure 6-2, what is the patient’s likely diagnosis?

The patient has a sliding hiatal hernia. In a sliding hiatal hernia, the gastroesophageal junction herniates upward through the esophageal hiatus in the diaphragm. The additional sphincteric pressure that is provided by the diaphragm is then lost, allowing reflux of gastric contents to occur more easily. This contrasts with a paraesophageal hiatal hernia, in which a portion of the gastric fundus “rolls” into and herniates through the diaphragm but the gastroesophageal junction remains in place. Although paraesophageal hiatal hernias usually do not cause reflux, they are more serious because they can become incarcerated (strangulated) and ischemic.

3 Discuss the pathophysiology of gastroesophageal reflux disease

GERD is caused by the reflux of acidic or bilious gastric contents into the esophagus, which irritates the esophageal mucosa and causes pain. Many factors can predispose to this reflux. One of the most important factors is abnormal transient relaxation of the lower esophageal sphincter (LES) unrelated to swallowing. A continually relaxed (atonic) LES will also allow reflux. Increased intra-abdominal pressure (due to obesity, pregnancy, Valsalva maneuver, etc.), increased gastric volume (due to eating a large meal or gastroparesis), and decreasing distance of gastric contents from the gastroesophageal junction (occurring when lying down or with hiatal hernia) may exacerbate reflux of gastric contents into the esophagus.

4 Cover the far left column of Table 6-1 and attempt to name the drugs used in the treatment of GERD based on the class of drug, the mechanism of action, and the primary side effects listed in the table

Table 6-1 Drugs Used for Treatment of Gastroesophageal Reflux Disease

5 Which of the drugs in Table 6-1 are contraindicated in a patient in whom bowel obstruction is suspected and why?

Prokinetic drugs should be avoided whenever bowel obstruction is suspected, as they can exacerbate the obstruction and potentially cause perforation.

6 Why may the omeprazole this patient was given cause him to develop hypergastrinemia?

Proton pump inhibitors such as omeprazole inhibit gastric hydrochloric acid (HCl) secretion by irreversibly inhibiting the H⁺/K⁺-ATPase pump on gastric parietal cells. This raises gastric pH, which disinhibits gastric secretion by the G cells, resulting in hypergastrinemia.

7 Which complications of gastroesophageal reflux disease could be responsible for the patient’s difficulty swallowing?

Esophageal stricture results from fibrosing and scarring of the esophageal mucosa from chronic irritation by gastric acid. This scarring narrows the lumen, which prevents a food bolus from passing through, causing food to get stuck. Another complication of GERD is Barrett’s esophagus, which is columnar metaplasia of stratified squamous esophageal epithelium that can lead to esophageal adenocarcinoma. Esophageal carcinoma usually presents with rapidly progressive dysphagia and weight loss.

8 Differentiate between the two types of esophageal cancers—adenocarcinoma and squamous cell carcinoma—in terms of risk factors and location

Adenocarcinoma typically occurs in the lower one third of the esophagus. Barrett’s esophagus and chronic irritation of esophageal epithelium from untreated GERD are risk factors for this type of cancer. Squamous cell carcinoma usually occurs in the upper two thirds of the esophagus. Smoking and alcohol, especially together (synergistic effect), increase the risk for this type of cancer. Both of these esophageal cancers can cause dysphagia to solids.

9 Why would a patient with Sjögren’s syndrome be more susceptible to esophageal pathology in gastroesophageal reflux disease?

Sjögren’s syndrome is an autoimmune disease characterized by lymphocytic infiltration of the lacrimal and salivary glands, causing dry eyes and dry mouth due to deficient secretions. Because saliva is rich in bicarbonate, it functions to neutralize acid in the esophagus. The absence of this protective function predisposes patients with this condition to esophageal damage with even minimal gastroesophageal reflux.

1 In pathophysiologic terms, how do you approach dysphagia?

Dysphagia can be approached in terms of oropharyngeal or esophageal etiology.

Oropharyngeal dysphagia is caused by difficulty initiating a swallow reflex, due to either neurologic or muscular problems. Typical causes include stroke, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and myasthenia gravis. Patients usually have coughing or choking with dysphagia of oropharyngeal etiology.

Esophageal dysphagia is caused by food getting “stuck” in the esophagus after being swallowed. This is due to either mechanical obstruction or esophageal dysmotility. History can often distinguish between an obstructive etiology or a motility disorder. If the patient has problems with only solid foods initially, then this suggests mechanical obstruction. This can progress to advanced obstruction, such as from esophageal adenocarcinoma, causing dysphagia to both solids and liquids. If the patient has dysphagia to both solids and liquids from the beginning, this suggests a dysmotility disorder, such as achalasia, scleroderma-like esophagus, or diffuse esophageal spasm.

Case 6-2 continued:

The patient also notes occasional chest pain with eating, nocturnal cough, and an unintentional 15-lb weight loss in the last 2 months. She was recently admitted to the hospital for treatment of pneumonia. Esophageal manometry shows increased LES pressure with incomplete LES relaxation and a complete absence of peristalsis in the lower esophagus. A barium swallow is shown in Figure 6-3.

Figure 6-3 Barium swallow of patient in case 6-2.

(From Cummings CW, Flint PW, Haughey BH, et al: Otolaryngology: Head and Neck Surgery, 4th ed. Philadelphia, Mosby, 2005.)

2 What is the likely diagnosis in this woman? Describe the pathophysiology of this disease

The initial dysphagia to solids and liquids, barium swallow showing the classic “bird’s beak” appearance, and esophageal manometry findings of aperistalsis and increased LES pressure are classic for achalasia.

The LES is normally tonically constricted, generating enough intraluminal pressure to prevent the reflux of gastric contents into the esophagus. During the esophageal phase of swallowing, the LES relaxes in response to a food bolus descending through the esophagus, a phenomenon referred to as receptive relaxation. In achalasia, there is destruction of the myenteric plexus, which mediates receptive relaxation and also mediates esophageal peristalsis (hence the aperistalsis). Although the exact mechanism of increased LES tone in patients with achalasia is not known, research suggests that these patients have loss of nitric oxide–secreting neurons, a key factor in LES relaxation. The failure of the LES to relax together with the failure of the distal esophagus to undergo peristalsis allows food to accumulate and dilate the lower esophagus, creating the “bird’s beak” appearance on barium swallow (Fig. 6-3).

Note: The myenteric (Auerbach’s) plexus is located between the inner circular and the outer longitudinal smooth muscle layers (muscularis propria) of the esophagus.

3 Chagas’ disease is also known to be a cause of achalasia. What is the pathologic mechanism and what organism is the primary culprit?

Chagas’ disease (American trypanosomiasis) can cause destruction of the myenteric plexus in the esophagus. This disease is caused by the protozoal parasite Trypanosoma cruzi and is particularly common in South America. In addition to achalasia, Chagas’ disease can also cause megacolon by destroying the myenteric plexus of the colon.

4 What was the likely cause of this woman’s previous episode of pneumonia?

The pneumonia was probably caused by aspiration of esophageal contents, especially while sleeping, due to the presence of undigested material in the esophagus.

5 In addition to pneumatic dilatation of the lower esophageal sphincter and surgical myotomy, injection of botulinum toxin into the lower esophageal sphincter is a treatment option for this woman. What is this drug’s mechanism of action in this context?

Much of the tonic constriction of the LES is due to vagal cholinergic innervation. Because botulinum toxin exerts its effects by inhibiting the release of acetylcholine from nerve endings, it reduces this input to LES tone.

1 What is the differential diagnosis?

The differential diagnosis of postprandial epigastric pain includes biliary colic, GERD, irritable bowel syndrome (IBS), and peptic ulcer disease (PUD). Biliary colic is severe, right upper quadrant pain caused by gallstones and usually precipitated by fatty meals. It has a higher frequency in women but is still common in men. GERD may cause epigastric or substernal discomfort that worsens with large meals, bending over, or lying flat. IBS can produce abdominal pain and bloating that is worsened by stress or food but relieved by defecation. Patients typically have altered bowel habits (e.g., diarrhea or constipation), which this patient’s history does not mention. PUD encompasses both gastric and duodenal ulcers. Duodenal ulcers typically cause most pain 1 to 3 hours after a meal, when the acidic chyme enters the small bowel. Pain also occurs at night, due to circadian rhythm–induced acid secretion. Food or antacids can relieve the epigastric pain. Gastric ulcers have a more variable presentation, but epigastric pain is typically precipitated by food and therefore patients may experience weight loss due to food avoidance. Based on the patient’s history, duodenal ulcer is the most likely diagnosis.

2 If you were this man’s physician, what would you have done differently in the treatment of this patient?

The patient with epigastric pain warrants a thorough history and physical examination, looking for any “red-flag” symptoms, such as GI bleeding, anemia, dysphagia, persistent vomiting, or unintentional weight loss, as these problems could point toward more serious pathologic process, such as malignancy. The two usual culprits for PUD are nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori. A more thorough history could have discovered if the patient was taking NSAIDs, which you would have recommended that he stop taking. Testing for H. pylori would also be necessary to prevent recurrence.

In the absence of red-flag symptoms in a young adult with suspected PUD, visualization of the ulcer by upper endoscopy or barium swallow is not necessary, and the patient can be empirically treated with H₂ receptor antagonists (e.g., ranitidine) or proton pump inhibitors.

3 How are nonsteroidal anti-inflammatory drugs thought to predispose to the formation of gastric ulcers? What alternatives exist to lessen gastrointestinal side effects?

NSAIDs inhibit the production of prostaglandins in the gastric mucosa. These prostaglandins normally function to protect the gastric mucosa by increasing mucus and bicarbonate secretion and by stimulating local vasodilation, which maintains mucosal perfusion and prevents ischemic injury.

Two options exist to circumvent this problem: taking misoprostol with NSAIDs (rarely done) or using cyclooxygenase (COX)-2 inhibitors. Misoprostol is a prostaglandin E₁ analog that decreases gastric acid secretion and increases mucus and bicarbonate secretion, thereby decreasing the deleterious effects of NSAIDs. As the name indicates, COX-2 inhibitors selectively inhibit COX-2 and do not affect COX-1 activity. The constitutively expressed form, COX-1, is present in multiple tissues and is responsible for the production of protective prostaglandins in the stomach. The inducible form, COX-2, is present primarily in inflammatory cells and is responsible for producing proinflammatory substances. By potently inhibiting COX-2 and minimally inhibiting COX-1, COX-2 inhibitors cause fewer GI side effects. Unfortunately, COX-2 inhibitors can be prothrombotic and exacerbate hypertension, increasing the risk of myocardial infarction and stroke. This major side effect led to rofecoxib (Vioxx) being pulled from the U.S. market in recent years.

4 Based on the appearance of the stool, is this more likely a lower gastrointestinal bleed or an upper gastrointestinal bleed?

Our patient presents with melena, paleness, and fatigue, the latter two of which are suggestive of anemia. The melena indicates an upper GI bleed (UGIB), likely caused by a bleeding duodenal ulcer. UGIB is anatomically distinguished from a lower GI bleed (LGIB) in that it occurs proximal to the ligament of Treitz. UGIB presents with either hematemesis or melena. Melena occurs because the hemoglobin has time to be broken down by bacteria in the gut to give dark, tarry stools. Hematochezia (bright red rectal bleeding) is typically indicative of LGIB, in which bacteria do not have the time to break down hemoglobin. However, brisk UGIBs such as bleeding esophageal varices can present with hematochezia because blood stimulates GI motility and decreases transit time.