Download CASE 28

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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.
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Why would fatty foods aggravate the patient’s RUQ pain?
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What effect does cholecystokinin (CCK) have on gastric emptying?
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Why does CCK have some gastrin-like properties?
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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.
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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.
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CCK and gastric emptying: Delays gastric emptying to allow for a
longer period of time to digest the fatty meal.
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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.
2.
Understand the difference between the mechanisms of stimulation of
hormones (endocrines), paracrines, and neurocrines.
Know and understand the role of various gastrointestinal (GI) hormones (gastrin, CCK, secretin, glucose-dependent insulinotropic peptide [GIP]).
CLINICAL CASES
3.
4.
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Know and understand the role of various paracrines (somatostatin, histamine).
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,
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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 HCO3− secretion. The HCO3− 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
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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.
B.
C.
D.
E.
[28.2]
ACh, gastrin, histamine
ACh, CCK, nitric oxide
Nitric oxide, vasoactive intestinal polypeptide, histamine
Vasoactive intestinal polypeptide, gastrin, somatostatin
Nitric oxide, CCK, serotonin
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.
B.
C.
D.
E.
Gastrin
Secretin
Pancreatic bicarbonate
CCK
Somatostatin
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[28.3]
CASE FILES: PHYSIOLOGY
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.
B.
C.
D.
E.
CCK
Gastrin
Motilin
Secretin
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.
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PHYSIOLOGY PEARLS
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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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