GI Physiology Resource 2
Problem Solving Exercises - Discussion
9 – 11 am, Tue Jan 24, 2012
E.S.Prakash, MBBS, MD
Division of Basic Medical Sciences
Mercer University School of Medicine
Prakash_es@mercer.edu
Follow-up Notes for this Resource will be available
at http://esprakash.wordpress.com/2012/01/ from Thu
Jan 26, as well as at Mercer Blackboard.
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.
Primary objectives:
• To provide formative assessment;
• To provide examples of application of knowledge of
physiologic mechanisms to clinical practice, and thereby
to motivate learning
• TOPICS
Physiology and pathophysiologic aspects of:
Liver and biliary system; Digestion and Absorption of
Nutrients; Functions of Bile and Pancreatic Juice;
Intestinal Motility; Electrolyte and Water Transport by
the Intestine; Functions of the Colon
Pathophysiologic mechanisms
implicated in cholelithiasis
• 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 in the biliary system due to any cause: 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.
• S. Bilirubin (total), S. albumin, and prothrombin time were WNL.
• Alkaline phosphatase - moderate elevation
• -glutamyltransferase - mild elevation
• What is the likely pathophysiologic basis of this presentation?
• Issue – Transport of bile acids and bile salts by the hepatocyte
Uptake of bile acids, bile salts, bilirubin and other organic
species at the basolateral (sinusoidal membrane) of hepatocyte
Transporter
Function
Na+ -Taurocholate Cotransporter Polypeptide
(NTCP)
Uptake of conjugated and
unconjugated bile acids; note
unconjugated BA also enter by
nonionic diffusion
Organic Anion Transporting Polypeptide (OATP);
Na+ independent mechanism; anions exchanged
for chloride from hepatocyte
Uptake of bile salts, bile acids,
organic dyes, steroid hormone
conjugates, drugs, toxins and
xenobiotics
Organic Cation Transporter (OCT 1 and 2)
Uptake of organic cations incl.
aromatic and aliphatic amines,
drugs, antibiotics, choline,
thiamine and nicotinamide
Secretion of bile salts, bilirubin, and other organic species at
the canalicular membrane of hepatocyte
Transporter
Function
Multidrug associated Protein (MRP-2);
ATP dependent
Secretion of conjugated bilirubin; defective
in Dubin Johnson syndrome; note secretion
is the rate limiting step in bilirubin
metabolism by hepatocyte
ABC transporter (ABCG5 / ABCG8)
Cholesterol secretion into bile
Multidrug Resistance Protein 1 (MDR 1) Excretion of organic cations and
xenobiotics
Multidrug Resistance Protein 3 (MDR 3) Flippase allowing extraction of lecithin by
bile salts into micelles in bile
Bile Salt Export Pump (BSEP)
Secretion of Na & K salts of taurocholate
and glycocholate. Loss of fx mutations
result in a progressive decline in bile
secretion and flow (intrahepatic
cholestasis)
Question 20
• Describe the pathogenesis of ascites in an
individual with cirrhosis of the liver.
PATHOGENESIS OF
ASCITES IN CIRRHOSIS
Splanchnic arteriolar
dilation
portal venules and hepatic sinusoids
↑ Portal vein
pressure
↑ formation of lymph in
the liver
Hypoalbuminemia
↑ Resistance to blood flow through
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)
Question 1
• How would you distinguish jaundice primarily
due to cholestasis from that primarily due to
hepatocellular disease?
Hepatocellular vs. Cholestatic jaundice
Note - Mixed patterns occur frequently
MARKER
PREDOMINANTLY
HEPATOCELLULAR
PATTERN
PREDOMINANTLY
CHOLESTATIC
PATTERN
S. Total Bilirubin
Raised
Raised
S. conjugated Bilirubin
Raised
Raised
Yes
Yes
S. Alanine aminotransferase


S. Aspartate
aminotransferase




Urobilinogen in urine
Raised
Absent
Color of Stools
Normal
Pale
Urine bilirubin
S. Alkaline phosphatase
• Fourfold or greater elevation in alkaline phosphatase
occurs especially in cholestatic liver disease.
• The presence of elevation of serum 5 nucleotidase or
γ-glutamyltransferase in combination with an
elevated alkaline phosphatase strongly points to the
liver as the source of these enzymes.
Question 2
• Based on your knowledge of the anatomy and
physiology of the digestive system, predict the
consequences of resection of the terminal ileum on
digestion and absorption of nutrients explaining the
underlying mechanisms.
Deficiency of
Consequences
Vitamin B12
Macrocytic anemia (may take years to
develop)
Bile salts
Bile acid diarrhea: Bile acid induced
secretion of Na and Cl in colonic epithelial
cells (diarrhea);
Steatorrhea: due to an eventual reduction
in total bile salt pool and fat malabsorption
Deficiency of fat soluble vitamins
(A, D, E and K)
Question 3
• A 50 year old man has undergone a cholecystectomy
as part of management of acute cholecystitis. How
would you expect cholecystectomy to impact on
digestion and absorption of nutrients?
• A mechanism for storage of bile is lost
• Bile flow less precisely regulated
• More bile flows into the duodenum during the interdigestive
phase
• A large amount of bile cannot flow quickly in response to CCK
• Advise avoiding fatty meal
Question 4
• You are examining a 50 year old male who underwent
bowel surgery the previous morning. The patient is
conscious, alert, and complains of a bloating sensation in
the abdomen but reports no pain in the abdomen. He
says he has not passed flatus since he has been awake.
Percussion of the abdomen elicits a tympanitic resonant
note, bowel sounds are consistently absent throughout
the abdomen, and x-ray reveals distention of the small
bowel and colon by pockets of gas and fluid.
• What pattern of motility in the intestines is this
consistent with?
There are different ways of thinking and organizing
our ideas about GI motility
1.
2.
3.
Digestive versus interdigestive motility
Propulsive movements versus mixing movements
Anatomical: motility in the stomach versus that in the
duodenum versus that in the proximal colon. BER
frequency varies from region to region.
SMALL INTESTINAL MOTILITY IN
THE DIGESTIVE PHASE
INTESTINAL MOTILITY IN THE
DIGESTIVE PHASE
Segmentation contractions –
Migrating Motor Complex (MMC) from
allow greater exposure of mucosa mid-stomach to ileum; once every 90
to chyme and foster absorption
min; house keeping functions.
Followed by peristalsis
PROPULSIVE MOVEMENTS
Peristalsis (digestive phase)
Migrating Motor Complex
(interdigestive phase)
Mass action contractions
(simultaneous contraction of
large confluent areas of colon –
say entire transverse and
descending colon; occur only in
the colon; 2-3 times per day;
induce the desire to defecate
MOVEMENTS THAT PRIMARILY
CAUSE MIXING OF CHYME
AND FOSTER ABSORPTION OF
NUTRIENTS
Segmentation contractions (in
small intestine)
Haustral shuttling (in large
intestine)
In this Question
• Abdominal distention + no abdominal pain + tympanitic
resonant note + individual has not passed flatus as yet + bowel
sounds absent + x-ray shows intestines distended by pockets of
gas and fluid
•
•
•
•
•
Paralytic ileus (postoperative ileus in this case)
Mechanism:
Ileus is a reflex response to injury to peritoneum and
abdominal viscera; sympathetically mediated
Hypokalemia is a risk factor for ileus
Recovery occurs within 2-3 days in the absence of complicating
factors
Until then decompress the lumen with a nasogastric tube; and
nil per oral
Question 5
• How would you distinguish whether diarrhea in an
individual is primarily due to increased secretion of
electrolytes and water, or due to abnormally large
amounts of an ingested and unabsorbed osmole in
the intestinal lumen?
SECRETORY DIARRHEA
Diarrhea due to an
abnormally elevated
secretion of Na and Cl and
consequently water by
epithelial cells in crypts.
OSMOTIC DIARRHEA
Diarrhea primarily due to the
presence in the lumen of large
amounts of an unabsorbed
osmole (other than Na and Cl)
Does not cease with fasting Ceases with fasting or when
the offending osmole is not
ingested
Stool osmotic gap: normal
Measured osmolality of stool
is 50 mOsm / Kg H20 than the
expected (or calculated)
osmolality of stool.
Question 6
• Based on your knowledge of the cellular mechanisms
of secretion of Na and Cl and water by intestinal
epithelial cells, propose a pharmacologic strategy for
controlling secretory diarrhea.
• In the Small Intestine: Note distinction between the
functions of villus cells vs. those in crypts.
• In the Large Intestine: There are no villi; note the
distinction between surface epithelial cells and cells
in crypts.
• Crypt cells – predominantly secretion of Na and Cl
• Villus cells; surface epithelial cells – primarily
reabsorption of electrolytes
Mechanism of Na and Cl secretion
by intestinal crypt cells
for details, see the next 2 slides
ClTight
junctions
Na+
H2O
GI
Lumen
__
CFTR
++ PKA
enterocyte
cAMP
Na-K-2Cl
Basolateral m.
Na+
H2O
Intestinal capillary
+++
Description for the schematic on the previous
slide; note the following:
1. Tight junctions linking apical membranes of enterocytes;
2. PKA activates CFTR (cystic fibrosis transmembrane
regulator - a chloride ion channel in the apical
membrane of crypt cells);
3. Chloride enters enterocytes from interstitium by NaK-2Cl symporter;
Continued..
4. Chloride passes down a transepithelial gradient through
chloride ion channels (CFTR) in the luminal membrane and
into the GI lumen;
5. This makes lumen in the crypts about 10 mV negative
(transepithelial potential difference) with respect to
interstitial fluid;
6. Na+ leaks via tight junctions (they aren’t really as “tight”)
because the lumen is negative with respect to interstitial
fluid.
7. Water enters lumen from interstitial fluid (driven by the
NaCl rich luminal content in the crypt lumen; i.e. driven by
osmotic gradient)
Question 7
• Your patient is a 60 year old woman with clinical evidence of
malabsorption – a chronic history of bulky, malodorous, greasy
stool, and documented steatorrhea.
• Prothrombin time is elevated (INR – 2).
• Results of the D-xylose test are normal.
• There is no histologic evidence of villous atrophy in the
duodenum.
• The patient is not on any medication.
• He has not undergone any surgeries in the past.
• What further investigations will allow us to identify the
mechanism of malabsorption?
• Since D-xylose does not require digestion before absorption in
the small intestine, a ‘normal D-xylose test’ makes extensive
mucosal disease of the small intestine test less likely.
Evaluating bile sufficiency; sufficiency of bile salts and
conjugated bile acids in bile
• Do clinical and radiologic data provide evidence suggestive of
extrahepatic cholestasis?
• Is there evidence for cholestasis such as a combination of 3-4
fold  ALP,  γ-glutamyltranspeptidase; conjugated
hyperbilirubinemia; lack or  of urobilinogen in urine?
Causes
Mechanisms
Extensive liver cell disease
Decreased synthesis of bile acids
and bile salts
Specific defects in hepatocyte
excretion of bile acids and salts
Intrahepatic cholestasis; biliary
cirrhosis
Excessive deconjugation of bile
salts and bile acids in the jejunum
Bacterial overgrowth in small
bowel; jejunal diverticulosis
Disease or resection of terminal
ileum
Diminished bile salt pool in the
long run
Evaluating exocrine function of the pancreas
Test
Description
Secretin Test
Hormone(s) given IV; pancreatic juice – volume,
HCO3 & or trypsin output assessed by duodenal
intubation; sensitive to mild, moderate or severe
exocrine pancreatic dysfunction.
CCK Test
Secretin – CCK Test
Lundh test meal
Measurement of duodenal trypsin after oral
ingestion of a liquid test meal.
Fecal fat
Insensitive for detecting mild-moderate exocrine
dysfunction
Fecal chymotrypsin
Fecal elastase
N-benzoyl tyrosyl p- Oral ingestion of NBT-PABA with a meal followed
aminobenzoic acid by measurements of PABA in serum or urine;
cleavage of NBT-PABA requires chymotrypsin
Question 8
• Does severe (NYHA class IV) heart failure
predispose to invasive infections of the
intestine? Explain.
Decreased cardiac output
Decreased blood pressure
(perfusion pressure)
Decreased mesenteric blood flow; also sympathetic
activation in heart failure reduces splanchnic blood
flow
If splanchnic autoregulation overwhelmed
Then Mucosal hypoxia
Contd.
Villus necrosis (tips of villi are most
susceptible to hypoxia)
Entry of luminal pathogens & toxins into blood
stream
Septicemia
Teaching point:
• Importance of splanchnic blood flow illustrated
• Importance of defense function of intestinal mucosal
barrier illustrated
31
Question 9
• A 65 year old man presents with a history of loose stools
since the past 2 years. Other symptoms included
flushing, weight loss and severe weakness.
• Until then, his bowel habits have been essentially
normal. He denies taking laxatives.
• He has been previously hospitalized at least on three
occasions over the past 4 months for management of
acute renal failure.
Question 9 (contd.)
• Further findings of note were:
–
–
–
–
–
diarrhea did not cease with fasting;
plasma [K+] = 2.8 mM (normal 3.5-5.5 mM);
basal acid output = 1 mmol/h (normal avg. 3 mmol/h)
osmotic gap in stool was normal.
colonoscopy did not reveal any abnormality.
• Further investigations revealed the presence of a
tumor in the pancreas. Additionally there were
metastases in the liver.
• What is the most likely etiology of the diarrhea?
Propose a pharmacologic strategy for alleviating it.
• VIP secreting tumor (VIPOma; Verner –
Morrison Syndrome; pancreatic cholera)
Effects of VIP (in large doses)
• Increases blood flow to the intestine
• Increases secretion of Na, Cl and water by the
intestine (watery diarrhea)
• Relaxes intestinal smooth muscle
• Peripheral vasodilation (flushing)
• Inhibition of gastric acid secretion (achlorhydria)
Question 10
• An 65 year old man has had to undergo near-total
colectomy as part of management of colorectal
cancer. Based on our knowledge of the functions of
the small intestine and large intestine, what would
would you expect the short-term and long-term
consequences of extensive resection of the large
intestine to be?
Functions of the colon
• Length of colon: approx 3.5 ft (in living humans,
measured by intubation); contrast – small intestine is
about 9.5 ft long.
• In the healthy adult, the colon is presented with about 2
liters of fluid per day; its capacity for absorption of Na,
Cl and H2O is greater than this [about 4 L/day]…
• Normal water output in stool?
• Normally, there is net secretion of K and HCO3 in the
colon.
• Undigested or unabsorbed carbohydrate escaping into
colon are metabolized to short-chain fatty acids (SCFA) by
colonic bacteria;
• Examples – acetate, propionate, butyrate
• These are absorbed by colonic epithelial cells
• SCFA somehow are said to increase Na and Cl absorption
by colonic epithelial cells.
• This may be affected when colonic bacteria are altered
by antibiotic therapy, and may be one mechanism of
antibiotic associated diarrhea.
• Intestinal adaptations following colectomy
– If fluid balance and electrolyte balance is maintained,
– volume of ileal discharge decreases over time.