Transcript GI Physiology Resource 1 Jan 17, 2011

GI Physiology Resource 1
Problem Solving Exercises - Discussion
9 am Jan 17, 2012
E.S.Prakash, MBBS, MD
Division of Basic Medical Sciences
Mercer University School of Medicine
[email protected]
URLs last accessed Jan 16 2012.
External links may be under access control.
License: This is an open access article distributed under the terms of the Creative
Commons Attribution License http://creativecommons.org/licenses/by-nc/3.0/
which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work, is properly cited. External links within the article are
provided for convenience and may be under access control.
Question 1
• How has the contribution of the cephalic
phase to gastric acid output been
investigated in experimental animals?
• See Figures in Wood J. Physiology, 2004
http://physiologyonline.physiology.org/content/19/6/326
• http://physiologyonline.physiology.org/content/19/6/326/F3.l
arge.jpg
• http://physiologyonline.physiology.org/content/19/6/326/F2.
expansion.html
Question 2
• A 35 year old man
• C: Progressive difficulty in swallowing over the
last 12 months.
• HPC: Initially he had difficulty swallowing solid
food but since the last month the ability to
swallow liquids had diminished as well, and
swallowing was associated with chest pain.
• Upper GI series: dilated esophagus with a bird
beak like narrowing of the lower end of the
esophagus.
• Upper GI endoscopy: no mucosal abnormality
in the esophagus.
• Discuss the pathophysiologic mechanisms of
the symptomatology.
• What are the available therapeutic
strategies?
The basic efferent arm in the ENS that
mediates peristalsis
• Barium swallow:
http://www.nature.com/gimo/contents/pt1/fig_tab/gimo80_F1.html
• Esophageal motility study:
http://www.nature.com/gimo/contents/pt1/fig_tab/gimo80_F2.html
• Radiograph in diffuse esophageal
spasm:http://www.nature.com/gimo/contents/pt1/fig_tab/gimo22_F
12.html
• Related illustration (does not apply to the Case in Q 2 - Aspiration
(secondary to a defect in pharyngeal phase of
swallowing)http://www.nature.com/gimo/contents/pt1/images/gimo
19-v3.mov
• What is the defining abnormality in achalasia?
• Absence of deglutitive inhibition of the LES
• And absence of propulsive peristalsis in the
esophagus
Therapeutic modalities:
• Calcium channel blockers
• Endoscopic dilation of LES
• Botulinum toxin injections into LES
• Surgical division of the LES
Question 3
• By the end of the third trimester of pregnancy, 50-80% of
pregnant women have had new or exacerbation of preexisting
heartburn.
• What are the likely mechanisms contributing to this
observation?
• See the Figure at this link below.
http://accessmedicine.com/popup.aspx?aID=5242548
Intra-esophageal
pressure;
salivation;
esophageal
clearance
Crura of
diaphragm;
phrenoesophageal
ligament
Pressure in
lumen of LES
Intragastric
pressure; gastric
emptying
Tone and competence
of PS
Factors affecting LES tone and pressure
INCREASE LES PREESURE
(AND DECREASE
LIKELIHOOD OF GER)
DECREASE LES PREESURE
(AND INCREASE LIKELIHOOD
OF GER)
Muscarinic receptor
agonist;
Alpha-adrenergic agonist;
Dopamine 2 receptor
antagonist;
Gastrin; Motilin; MMC
Protein meal
Botulinum toxin;
Calcium channel blocker;
Dopamine;
Gastric distention;
Secretin, CCK,
Progesterone
Fat meal, Chocolate, Smoking
GER – Gastroesophageal Reflux
• Normal LES pressure: 20 mm Hg
• Transient relaxation of LES (TLESR) occurs at
the frequency of MMC; i.e. LES relaxation
unrelated to swallowing and esophageal
peristalsis.
• Function of TLESR?
• What is the mechanism of belching?
– Stimulus – proximal gastric distention
– Response – TLESR
– Integrated in – medulla (blocked by cerv.
Vagotomy)
– Also blocked by – NOS inhibitors
• The sphincter effects of smooth muscle in LES
is augmented by contraction of crural fibres of
diaphragm
• GER cannot happen unless the LES is
incompetent.
Question 4:
• Epidemiologic studies indicate a significant
association between obesity and
gastroesophageal reflux disease (GERD).
• What mechanistic evidence supports the
possibility of a cause and effect relationship
between obesity and GERD?
Theories proposed include:
• Fat, chocolate reduce LES tone
• Slower gastric emptying with fat meal
• Hiatal hernia – in a study cited in the paper below, as many as
50% of morbidly obese patients selected for bariatric surgery
had hiatal
herniahttp://www.nature.com/ajg/journal/v103/n8/pdf/ajg2
008412a.pdf
• Adipokines from adipose tissue may have an effect on the LES
• Gastric motor abnormalities have been documented to be
more frequent in obesity (especially morbid obesity)
abnormalities included especially diminished gastric
compliance and raised intragastric pressure
• Ref: Obesity reviews (2002) 3, 9–15
Question 5
• 50 year old man with recurrent heartburn.
• HPC: He has been taking antacids and H2 receptor blockers on
and off with some improvement.
• He inquires about surgical options and indicates being willing
to undergo surgery if the likelihood of permanent symptom
control would be highly likely.
• How can one establish if his symptoms are indeed
attributable due to gastroesophageal reflux?
• What other physiologic information would help decide if
anti-reflux surgery would be helpful or not?
• Why is the esophagus prone to injury by acid
and pepsin?
• What is the mechanism of water brash?
• Diagnosis of GERD in practice is almost always
presumptive.
• What is the principle of management of
GERD?
• Establishing a diagnosis by ambulatory pH
monitoring of the esophagus
• Before anti-reflux surgery, check:
– Pathologic reflux is highly likely to be the cause of
the symptomatology
– Defective salivation is not the cause of GERD
– Defective esophageal peristalsis is not the cause of
GERD
Question 6
• Do tests of gastric acid secretion have a role in
establishing a diagnosis of peptic ulcer
disease? Explain.
• There is considerable interindividual
variability in BAO and MAO.
• Typically DU is characterized by an increase in
BAO and MAO.
• Depending on location, GU may be associated
with normal, low or elevated BAO.
Indications for gastric acid secretory testing:
• Evaluation of hypergastrinemia (allows
distinction between gastrinoma and
pernicious anemia)
• Checking BAO for completeness of vagotomy
such as in an individual with ulcers following
vagotomy
Question 7
• A 55 year old man with a history of recurrent episodes of
heartburn, epigastric pain and duodenal ulcer was
investigated and found to have a gastrin-secreting tumor in the
pancreas.
• His basal acid output (BAO) was determined to be 20
mmol/hour (normally 2-3 mmol/hour).
• The patient also had a history of steatorrhea (fatty, bulky,
malodorous stool; fat excretion > 6 g on a 24 hour stool
collection).
• What is the most likely reason for the excretion of large
amount of fat in stool?
• How would you manage this patient if he was not willing to
undergo surgery?
Question 8
• What would be the effect of resection of upper
small intestine on meal stimulated gastric acid
output?
Question 9
• How does H. pylori infection of the antral mucosa
perturb gastric acid secretion – does it result in
hypochlorhydria or hyperchlorhydria? Explain.
• Acute infections – hypochlorhydria
• Chronic infections – hyper or hypochlorhydria
• Hyperchlorhydria occurs with ulcers limited to antrum
and with gastric metaplasia of the duodenum
• Host response is an important factor..
• N methyl histamine (a H3 receptor agonist) from H pylori
postulated to inhibit somatostatin release from D cells
and thereby increase gastrin release and cause
hyperchlorhydria.
•
•
•
•
Hypochlorhydria with a chronic atrophic pangastritis
Large fraction of patients may develop this.
Often asymptomatic
Mechanisms:
– Molecular mimicry: H. pylori antigens and H-K ATPase
• The hypochlorhydria may reverse with successful
eradication of H. pylori
• Hypochlorhydria suggested to offer some protection
against development of GERD and Barrett’s
esophagus.
• Details in Sleisenger and Fordtran’s Gastrointestinal
Disease, pp. 830 (available via Mercer Med Library)
Question 10
• The pain of an uncomplicated duodenal ulcer is
frequently relieved by food. Why may this be so?
Question 11
• Defecation following meals is the rule in children’. Why
may this be so?
Question 12
• Truncal vagotomy surgery for intractable peptic ulcer disease
is typically accompanied by a gastrojejunostomy.
• What purpose does the gastrojejunostomy serve?
• What would be expected to happen to BAO and MAO
following truncal vagotomy?
• What is the line of section of vagi in a truncal vagotomy?
See Figure at
http://emedicine.medscape.com/article/181753overview#aw2aab6b2b2aa
Question 13
• A 50 year old man underwent truncal vagotomy, antrectomy
and a gastrojejunostomy for chronic duodenal ulcer
complicated by gastric outlet obstruction 4 months ago.
• He presented with complaints of nausea, vomiting and
epigastric discomfort following a meal.
• These symptoms have been there since the last 2-3 months.
• He had also undergone cholecystectomy 10 years ago.
• On examination, he was in no apparent distress; vital signs –
WNL. CVS, RS – WNL.
• Per abdomen: soft, nontender, no organomegaly, no free
fluid, no abnormal masses.
• Upper GI endoscopy revealed swelling, redness, erosions and
bile staining of the gastric mucosa.
• Discuss the mechanisms likely contributing to the
symptomatology and the clinical signs.
Dumping Syndrome:
Mechanisms postulated:
• Early Phase symptoms (within 30-45 min of a meal)
– Impairment of receptive relaxation
– Loss of the antral pump effect
– Loss of regulation of gastric emptying (pyloric sphincter gone)
– Rapid delivery of hyperosmolar chyme into the jejunum (this
induces hypovolemia)
• Late Phase symptoms (2 hr after a meal):
– Rapid absorption of glucose into blood, insulin
secretion and reactive hypoglycemia 2 hr following a
meal
Question 14
• A 60 year old male presented with a history of fatigability on
exertion and weakness of the lower limbs since the past 4
months.
• He had undergone Roux-en-Y-bypass surgery 10 years ago for
managing severe obesity.
http://video.about.com/weightloss/Roux-en-Y-GastricBypass.htm
•
•
•
•
•
•
•
•
•
•
•
OE: pale but in no distress.
BP: 140/90 mmHg; pulse: 94/min; respiration: 16/min.
CVS, RS, abdomen and genitourinary exam – WNL.
GIT: the tongue was smooth
Neuro:
a mild impairment in cognition was noted,
Romberg’s sign was present
ankle reflexes were absent on both sides.
The plantar response was initially flexor and then extensor.
No other abnormality was noted.
Investigations: Blood [Hb]: 10 g/dL
• Peripheral smear showed macrocytosis and vitamin B12 levels
in serum were considerably diminished.
• Serum ferritin level was lower than normal.
• Could the surgery he underwent 10 years ago have
predisposed him to the symptom complex now observed?
Explain.
• We need to explain why this individual has developed:
– Vitamin B12 deficiency
– Iron deficiency
Question 15
• A 50 year old man with a longstanding history of type I
diabetes presented with complaints of vague discomfort in
the epigastric region.
• Symptoms started 6 months ago and included mild nausea
and vomiting within couple of hours of a meal. These
symptoms first occurred 6 months ago.
• He also frequently experienced lightheadedness and shaking
tremors about an hour after a meal.
• There was no history of chest pain, abdominal pain.
• Medications included insulin injections taken before meals.
•
•
•
•
•
He did not smoke or drink alcohol.
He had not undergone any surgeries in the past.
The vomitus consisted of undigested, chewed food.
OE: BP: 140/94 mmHg, HR – 82/min. CVS, RS – WNL.
PA: The abdomen was soft, nontender, and there was no
organomegaly, masses or free fluid.
• Serology for H. pylori was negative.
• Omeprazole 20 mg od for three weeks did not produce any
improvement in symptoms.
• Administration of a test meal with radioisotope indicated
retention of greater than 40% of the meal in the stomach
four hours following ingestion.
• He was prescribed metoclopramide but these had to be
stopped within 2 months because of tardive dyskinesia.
• Dyspeptic symptoms showed significant improvement with
erythromycin.
• Discuss the pathophysiologic basis of this presentation and
the therapeutic strategy.
• Gastroparesis – delayed emptying of a
standard test meal.
Causes:
• Longstanding diabetes
• Following truncal vagotomy and other gastric
surgeries
• Gastric outlet obstruction due to a chronic DU;
rarely due to hypertrophic and hypertonic
pyloric sphincter
• Chronic ischemia of the stomach
• There is evidence that chronic hyperglycemia
and end products of products of advanced
glycosylation (AGE) lead to:
– Loss of interstitial cells of Cajal
– Antral hypomotility
– Isolated pyloric contractions
– Acute or chronic gastric dilation may occur in
some instances. See
– http://www.nejm.org/doi/full/10.1056/NEJMicm0
55086
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2
190544/
•
•
•
•
•
Therapeutic strategies depend on cause and
severity of the gastroparesis
Metoclopramide (D2 receptor antagonist)
Domperidone
Erythromycine (motilin receptor agonist)
Gastrostomy
Corrective surgery (in the case of gastric outlet
obstruction)
Question 16
• Comment on this equilibrium phase diagram (URL below) of
cholesterol – phospholipid and mixed bile salt system (37°C,
0.15M NaCl, pH 7, total lipid concentration 7.5 g/dL) and
explain its relevance to the pathogenesis of gallstones
• http://www.bmj.com/highwire/filestream/428390/field_high
wire_fragment_image_l/0/F2.medium.gif
Risk Factors for Gallstones
Incidence increases with age
More common in females
Diets rich in fat
Rapid weight loss
Infection of the biliary tract
Oral contraceptive use
Total parenteral nutrition
Prolonged fasting
Terminal ileal resection
Excessive hemolysis
Excessive hemolysis (for Ca bilirubinate stones)
Pathophysiologic mechanisms:
• Lithogenic bile: lower in bile salts and lecithin and
richer in cholesterol.
– Defects in bile acid secretion in bile;
– decrease in bile salt pool due to any cause;
– E.coli secretes beta-glucuronidase that deconjugates bilirubin
diglucuronide and bilirubin is insoluble and precipitates as
calcium bilirubinate
• Stasis of Bile: Total parenteral nutrition; prolonged
fasting, denervation of gall bladder; obstruction in
the biliary tract.
• Excessive secretion of gall bladder mucins? Biliary
sludge – a mix of cholesterol crystals, mucin, and
calcium bilirubinate.
Question 17
• A 32 year old pregnant woman in the third trimester of her
pregnancy presents with a history of bothersome itching since the
past 2 weeks.
• To begin with, itching was prominent in the palms and soles but it
was now generalized.
• Past history is notable for cholecystectomy done 3 years ago.
• She is not on any medication.
• She is not jaundiced.
• Physical examination is unremarkable.
• Vital signs – WNL.
• She reported fetal movements and fetal heart rate was within
normal limits.
• What is the likely pathophysiologic basis of this presentation?
• Issue – Transport of bile acids and bile salts by
the hepatocyte
• Figure Link:
• http://tinyurl.com/6rcz6fg
Question 18
• Bilirubin is conjugated by liver cells to bilirubin mono-and
diglucuronide and secreted in bile.
• In conjugated hyperbilirubinemia, there is a
predominance of conjugated bilirubin in the blood
stream.
• How does conjugated bilirubin enter the blood stream?
MRP2 (MOAT) extrudes conjugated bilirubin into the
canaliculus; MRP3 is not normally expressed in the sinusoidal
membrane but expressed in Dubin Johnson syndrome
See Figure 1 at
http://advan.physiology.org/content/31/4/370.ful
l
Advances in Physiol Educ 2007
Question 19
• What acid-base abnormality would you expect vomiting
from gastric outlet obstruction or pyloric stenosis to
produce? What are the pathophysiologic considerations
in the management of this acid-base abnormality?
Question 20
• Describe the various mechanisms that contribute to the
occurrence of ascites in an individual with cirrhosis of the
liver.
• See this figure:
• http://accessmedicine.com/popup.aspx?aID=5245482
↑ Resistance to blood flow through portal venules and hepatic
sinusoids
Hepatic arteriolar dilation
↑ formation of lymph in
the liver
Hypoalbuminemia
↑ Portal vein
pressure
Retrograde transmission
to splanchnic capillaries
Dilation of
portosystemic
collaterals
Ascites
↓ in effective arterial blood volume,
cardiac output
↓ Renal blood flow
Reflex ↑ renal
sympathetic nerve
activity
Activation of renal renin-angiotensin-aldosterone axis and renal retention
of Na, Cl and H2O (secondary hyperaldosteronism)