CASE 28 A 43-year-old woman presents to the emergency department with the acute onset of abdominal pain. Her pain is located to the right upper quadrant (RUQ) and radiates to the right shoulder. She reports nausea and vomiting but no fever or chills. The RUQ pain is worse after she eats fatty meals. On examination, the patient has severe RUQ tenderness. Her white blood cell count is elevated, as are her liver function tests and alkaline phosphatase level. The amylase and lipase levels are normal. An abdominal ultrasound reveals an enlarged gallbladder with multiple stones and gallbladder wall thickening. She subsequently is admitted to the hospital and undergoes a cholecystectomy. Why would fatty foods aggravate the patient s RUQ pain? What effect does cholecystokinin (CCK) have on gastric emptying? Why does CCK have some gastrin-like properties?
234 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 28: GASTROINTESTINAL REGULATION Summary: A 43-year-old woman has acute-onset RUQ pain that worsens with fatty foods and an ultrasound demonstrating signs of gallstones and acute cholecystitis. Effect of fatty foods on gallstones: Fatty foods cause secretion of CCK, which causes contraction of the gallbladder and relaxation of the sphincter of Oddi. Because gallstones are blocking the outflow of bile, when the gallbladder is stimulated to contract, the obstruction leads to increased pain. CCK and gastric emptying: Delays gastric emptying to allow for a longer period of time to digest the fatty meal. CCK and gastrin: Five C-terminal amino acids the same as gastrin, and this terminal heptapeptide is where the biologic activity resides. CLINICAL CORRELATION The incidence of cholelithiasis increases with age, and this condition is more common in females. Most gallstones are not symptomatic and do not require treatment. However, when acute cholecystitis develops, surgery often is required. Typical symptoms include biliary colic and RUQ pain with radiation to the right shoulder, nausea, vomiting, fever, leukocytosis, and elevated alkaline phosphatase. The gallstones can be visualized without difficulty with an abdominal ultrasound. Immediate consultation with a surgeon is indicated when acute cholecystitis develops. The patient is immediately made nothing by mouth (NPO). Antibiotics often are begun. Pain medication can be given, but morphine should not be used because it will cause constriction of the sphincter of Oddi and increase the biliary pressure. When the patient is made NPO, the CCK level is decreased and contractions of the gallbladder will begin to diminish. Patients with asymptomatic gallstones are instructed to follow low-fat diets to try to diminish the secretion of CCK. APPROACH TO GASTROINTESTINAL REGULATION Objectives 1. Understand the difference between the mechanisms of stimulation of hormones (endocrines), paracrines, and neurocrines. 2. Know and understand the role of various gastrointestinal (GI) hormones (gastrin, CCK, secretin, glucose-dependent insulinotropic peptide [GIP]).
CLINICAL CASES 235 3. Know and understand the role of various paracrines (somatostatin, histamine). 4. Know and understand the role of various neurocrines (vasoactive intestinal peptide [VIP], serotonin, nitric oxide [NO]). Definitions Neurocrine: An endogenous chemical released from nerve endings to act on cells innervated by those nerves. Endocrine: An endogenous chemical released from endocrine cells into the circulation to act on distant cells that possess receptors for that chemical Paracrine: An endogenous chemical released from one cell to act on adjacent cells that possess receptors for that chemical DISCUSSION The GI tract can be viewed as a food-processing line in which the complex foodstuffs that are ingested are broken down into simpler molecules that can be absorbed and utilized in the body. Each organ in the tract plays a role in this processing as the ingested material is propelled aborally. The overall chemical and mechanical processes involved are divided into secretory, digestive, absorptive, and motility processes. For the processes to proceed in an orderly fashion, numerous control mechanisms come in to play. There are chemical and mechanical receptors within the organs of the tract that, when stimulated, initiate regulatory events that are mediated by chemicals that in turn modulate the secretory, absorptive, and motility functions of the effector cells. The manner by which these chemicals are delivered to the effector cells can be neurocrine (released from nerve endings innervating the effector cells), endocrine (released from distant cells and delivered to the effector cells by the circulation), and paracrine (released from neighboring cells and diffuses to the effector cells). The secretory, digestive, absorptive, and motility processes of the GI tract and their regulation can be divided into stages: cephalic, gastric, and intestinal. The cephalic phase begins before any food is ingested, is reinforced during the act of chewing, and ends shortly after the meal is finished. The gastric phase begins when food arrives in the stomach and continues as long as nutrients remain in the stomach. The intestinal phase begins with the first emptying of contents from the stomach. It is the longest and perhaps the most important phase, lasting as long as nutrients and undigested residue are present in the intestinal lumen. Although regulatory events are more numerous during digestion of a meal, they also are important during the time when no digestion and absorption of nutrients are taking place: the interdigestive state. Regulation during the cephalic phase is mostly neurocrine. Reflexes initiated by the sight and smell of food as well as the presence of material in the mouth bring about the release of acetylcholine (ACh) at the salivary glands,
236 CASE FILES: PHYSIOLOGY at acid-secreting (parietal) and pepsin-secreting (chief) cells in the body of the stomach, and at enzyme-secreting (acinar) cells of the pancreas. Vagal neural pathways also initiate the release from antral G cells of the hormone gastrin, which reaches parietal cells through the circulation. Thus, salivary (large volume), gastric acid and pepsin (small volumes), and pancreatic enzyme (small volume) secretions are stimulated during this phase. The voluntary act of swallowing initiates a neural reflex that elicits a peristaltic contraction of the pharynx and esophagus that propels material into the stomach to begin the gastric phase. During this phase, nerves intrinsic to the stomach as well as vagal reflexes respond to mechanical stimulation of the gastric mucosa and release ACh near parietal and chief cells and gastrinreleasing peptide (GRP) near antral G cells. Gastrin also is released in response to stimulation by products of digestion, especially small peptides and amines. ACh and gastrin do stimulate parietal cells directly, but more important, they act on enterochromaffin-like (ECL) cells to release histamine, which in turn stimulates the parietal cells. The gastric phase accounts for 60% to 70% of the acid secretory response to a meal. Neural reflexes also bring about receptive relaxation of the orad region of the stomach to accommodate the ingested food, and they modulate electrical events of the muscle that constitutes the body and antrum to regulate gastric contractions that accomplish mixing and emptying. Pancreatic secretion, which begins during the cephalic phase, also is enhanced by local reflexes elicited during the gastric phase, though not to a great extent. Not all events of the gastric phase are stimulatory. When acid secretion is sufficient to lower the ph of the antral contents to 3 or so, somatostatin is released from cells close to antral G cells and acts in a paracrine manner to inhibit gastrin secretion. The emptying of gastric contents into the duodenum initiates and perpetuates the intestinal phase. Products of digestion as well as acid stimulate intestinal mucosal receptors to initiate neural reflexes and the secretion of many hormones, including secretin, CCK, GIP, and glucagon-like peptide (GLP, or enteroglucagon). When the contents emptied from the stomach lower duodenal ph to about 4.5 or less, S cells release secretin, which circulates to the pancreas to stimulate HCO 3 secretion. The HCO 3 neutralizes the acid to allow for more optimal activity of the pancreatic enzymes. Protein and lipid breakdown products in the contents induce I cells to release CCK, which acts as an endocrine to induce pancreatic enzyme secretion, contraction of the gallbladder, and relaxation of the sphincter of Oddi (perhaps through a neural reflex as well). The enzymes and bile secreted effect the digestion and absorption of protein, fat, and carbohydrate moieties. CCK also induces relaxation of smooth muscle of the orad stomach to lead to slow gastric emptying. The release and absorption of glucose induce the release of both GIP and GLP, which act in an endocrine fashion to enhance the release of insulin, another hormone, from the endocrine pancreas. Neural reflexes, and perhaps CCK and other hormones, regulate contractions of the intestine to induce mixing of contents (segmenting contractions). The contractions also effect the slow aboral
CLINICAL CASES 237 progression of contents toward the colon. In the colon, neural reflexes, and perhaps endocrine influences, control segmenting contractions (haustral contractions) that aid in the absorption of electrolytes and water and peristaltic contractions (mass movements) that ultimately lead to the evacuation of feces. If the interval between ingestion of foodstuffs is long enough (roughly 6 hours or more), the GI tract enters an interdigestive state. The activity characteristic of this state, described in Case 29, is regulated by both endocrine and neurocrine pathways. The hormone motilin is released periodically during the interdigestive state and appears to initiate the increasing and burst of contractile activity in the stomach and duodenum. The migration of the intense contractile activity aborally along the intestine is coordinated by enteric nerves. In addition to the neurocrines, endocrines, and paracrines mentioned above, there are many others whose roles in the GI tract are not as clear. Vasoactive intestinal polypeptide, although a peptide, normally acts mainly as a neurocrine. It is found in nerve endings and, when released, induces relaxation of GI smooth muscle. However, there are tumors that secrete VIP into the blood, where it acts as an endocrine to induce voluminous pancreatic secretion. Peptides such as leptin, ghrelin, and peptide YY are being evaluated for their possible roles in regulating appetite and satiety. Serotonin, which is found in many enteric nerves and in enterochromaffin cells, plays a major role in regulating motility and the secretory and absorptive functions of the GI tract. Finally, both nitric oxide and carbon monoxide (CO) are two neurocrines/paracrines that appear to be responsible for the inhibition of GI smooth muscle that occurs in many physiologic reflexes and pathologic states. COMPREHENSION QUESTIONS [28.1] During the chewing of a bolus of food, but before swallowing, salivary secretion, gastric secretion, and pancreatic secretion are stimulated by which of the following neurocrine, endocrine, and paracrine mediators? A. ACh, gastrin, histamine B. ACh, CCK, nitric oxide C. Nitric oxide, vasoactive intestinal polypeptide, histamine D. Vasoactive intestinal polypeptide, gastrin, somatostatin E. Nitric oxide, CCK, serotonin [28.2] A 31-year-old woman takes antacids with and after a meal so that gastric ph does not decrease below ph 6, for peptic ulcer disease. This agent will cause a greater than normal secretion of which of the following? A. Gastrin B. Secretin C. Pancreatic bicarbonate D. CCK E. Somatostatin
238 CASE FILES: PHYSIOLOGY [28.3] Motility recordings in a patient with signs of bacterial overgrowth of the small intestine indicate an abnormal pattern of motility in the fasting state that is characterized by a lack of the normal periodic bursts of gastric and intestinal contractions. This patient is likely to demonstrate abnormal secretion of which of the following hormones? A. CCK B. Gastrin C. Motilin D. Secretin E. Vasoactive intestinal polypeptide Answers [28.1] A. During the cephalic phase of digestion, the presence of food in the mouth induces local and vagal neural reflexes, culminating in the release of the neurocrine ACh at the salivary glands, gastric parietal cells, antral gastrin cells, and pancreatic acinar cells. This results in secretion of saliva, gastric acid, gastrin, and pancreatic enzymes. The hormone gastrin in turn stimulates gastric parietal cells directly and also induces gastric enterochromaffin cells to release histamine, which also stimulates gastric parietal cells in a paracrine manner. [28.2] A. The ingestion of a meal results in local and vagal reflexes, resulting in the secretion of gastric acid by neurocrine, endocrine, and paracrine pathways. The major endocrine involved is gastrin released from G cells in the antrum. Normally, as gastric acid lowers gastric ph to around 3, somatostatin is secreted by cells located next to the G cells to inhibit further gastrin release. If ph is not allowed to fall, this does not occur and gastrin secretion continues. Normally, gastric contents emptying from the stomach lower intraduodenal ph to levels that result in the secretion of secretin (around 4.5 and less). If gastric acid is buffered, this does not occur, and so both secretin and pancreatic bicarbonate secretion are decreased. [28.3] C. The motility pattern that is disorganized is the migrating motor complex (MMC), which is highly propulsive. Data indicate that the phase of intense contractions in the stomach and duodenum is associated with and perhaps initiated by the hormone motilin.
CLINICAL CASES 239 PHYSIOLOGY PEARLS ACh is the major excitatory neurocrine; and NO and VIP are the major inhibitory neurocrines. Serotonin is an important neurocrine modulator. Gastrin, secretin, GIP, CCK, and motilin are the major GI hormones (endocrines). Histamine and somatostatin are the major paracrines. The cephalic phase of digestion is mediated primarily by neural (vagal) reflexes and consists of salivary secretion, gastric acid and pepsin secretion, pancreatic secretion, and gastrin secretion. The gastric phase of digestion is mediated by neural (vagal and enteric) reflexes and gastrin. The intestinal phase of digestion is mediated by neural (vagal and enteric) reflexes and the hormones secretin, CCK, and GIP. The interdigestive state is characterized by MMCs initiated by motilin and regulated by local nerves. VIP and NO are major neurocrines that are important for relaxation of GI smooth muscle, especially sphincteric smooth muscle. REFERENCES Johnson LR. Gastrointestinal physiology. In: Johnson LR, ed. Essential Medical Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press; 2003:465-558. Johnson LR. Regulation: Peptides of the gastrointestinal tract. In: Johnson LR, ed. Gastrointestinal Physiology, 7th ed. Philadelphia, PA: Mosby: 2007:1-11. Kutchai HC. Digestive system. In: Levy MN, Koeppen BM, and Stanton BA, eds. Berne & Levy, Principles of Physiology 4th ed. Philadelphia, PA: Mosby: 2006:429-494.
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