W ATER T RANSPORT AND D IARRHEA Anson Lowe September 25, 2015 Medicine/Gastroenterology.
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Transcript of W ATER T RANSPORT AND D IARRHEA Anson Lowe September 25, 2015 Medicine/Gastroenterology.
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WATER TRANSPORT AND DIARRHEA
Anson Lowe
September 25, 2015Medicine/Gastroenterology
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Understand water transportUnderstand the causes of diarrheaUnderstand secretory vs. osmotic diarrhea
Water transport; diarrhea
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Grant’s Atlas, 1972
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Black RE, et al., Lancet 375:1969 (2010)
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Childhood Deaths11 million per year
◦1 in 5 die before their fifth birthday70% are secondary to pneumonia, diarrhea,
measles, malaria, and malnutrition2 million die of diarrhea diseases, 90% of
whom could have been saved by the appropriate treatment
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Cholera Death Rates
Estimated 1 million cases / year
100,000 - 130,000 deaths / year
Case fatality rates:
South Africa = 0.22%
Other parts of Africa = up to 30%
WHO
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Gary SchoolnikEnvironmental Degradation Begets Epidemics: Cholera in BangladeshMedicine Grand RoundsNovember 21, 2007url: http://lane.stanford.edu/biomed-resources/grandrounds/medgrandrounds-2007.html
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Jejunum ileum Colontransepithelial P.D. -3mv -6mv -20mvmucosal resistance low med highpassive NaCl movement high low minimal[Na+] equilibrium conc. 133 mEq/l 75 30
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What is the implication with respect to stool osmolarity?
What is the difference between the nephron and the intestine?
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www.med.uiuc.edu
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http://en.wikipedia.org/wiki/Thick_ascending_limb_of_loop_of_Henle
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Absorption of most solutes from the intestinal lumen is secondary active transport. The major driving force is Na+:K+-ATPase.
Unlike the kidney, the intestine does not possess a diluting segment. Thus the intestinal fluid is always isotonic with respect to plasma.
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Stool OsmolarityIn contrast to the kidney, the GI tract cannot
dilute or concentrate its contentsStool contents is always isotonicSerum osmolarity is tightly regulated at
~290 mosm.
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Why do we separate digestion into a lumenal and mucosal phase?
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Why do we separate digestion into a lumenal and mucosal phase?◦Lumenal digestion of a disaccharide would
increase intestinal volume two-fold
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Hypertonic Stool
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Hypertonic Stool
• High stool osmolarity suggests a prolonged period of incubation before processing.
Sleisenger and Fordtran, Gastrointestinal Disease, 5th ed.
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Hypotonic Stool
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Hypotonic Stool
Suggest the addition of free water to the stool
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Osmotic gap = 290mosm - (([Na+] + [K+] ) x 2)
Osmotic Gap
A gap of < 40mosm suggests a secretory diarrhea
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How do we absorb water?
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How do we absorb water?Beer = 4 mosm/liter
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Proc. Natl. Acad. Sci. USA93:13367-13370 (1996)
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SGLT1 and Water AbsorptionCo-transport of 2 Na+, 1 glucose, and 264
water molecules◦Blocking glucose transport with phlorizin will also
block water transport
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SGLT1 and Water AbsorptionAlso able to transport water in response to an
osmotic gradientProduces an osmotic gradient that can be used
by other water channels such as the aquaporins
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WHO Oral Rehydration Solution
[Na+] = 90 mEq/L[K+] = 20 mEq/L[Cl-] = 80 mEq/LCitrate = 30 mEq/LGlucose = 20 gm/L (111 mM)
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Alberts et al, Moleculare Biology of the Cell, 3rd ed.
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CFTRFunctions as a chloride channel and also
regulates other transport pathwaysCan mediate water transport
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Advantage of CFTR mutations?
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Advantage of CFTR mutations?Knockout CFTR mice have been produced
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Advantage of CFTR mutations?Knockout CFTR mice have been produced
◦Mice die of intestinal obstruction
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Advantage of CFTR mutations?Knockout CFTR mice have been produced
◦Mice die of intestinal obstructionHomozygous mice are resistant to cholera toxin
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Advantage of CFTR mutations?Knockout CFTR mice have been produced
◦Mice die of intestinal obstructionHomozygous mice are resistant to cholera toxinHeterozygote mice are partially resistant to
cholera toxin
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Univ. of Kansas, Dept. of PathologyNormal Pancreas, H&E
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Secretory DiarrheasE. coli heat stabile enterotoxinCholeraStaph. AureusB. CereusVasoactive intestinal peptide (VIPoma)
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Secretory DiarrheasExcess secretionNutrient absorption intact
◦Therapy?
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Secretory DiarrheasExcess secretionNutrient absorption intact
◦Oral rehydration formula [Na+] = 90 mEq/L [K+] = 20 mEq/L [Cl-] = 80 mEq/L Citrate = 30 mEq/L Glucose = 20 gm/L (111 mM)
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Secretory Diarrhea due to a VIPoma?
(vasoactive intestinal peptide)
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Somatostatin
Source: ◦ Neurons of CNS and PNS◦ Endocrine cells of the pancreas (D cells) and stomach
Actions in the GI tract◦ Inhibition of transport◦ Inhibition of secretion◦ Splanchnic vasoconstriction
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SomatostatinClinical Applications
◦ Inhibition of many G-protein mediated processes Secretory diarrhea Pancreatic secretions Gastrointestinal hemorrhage (variceal bleeding)
induces splanchnic vasoconstriction
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Diarrhea-Acid/Base DisordersWhat disturbances in acid base balance will be
seen with significant diarrhea?
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Diarrhea-Acid/Base Disorders What disturbances in acid base balance will be
seen with significant diarrhea?◦ Non-anion gap metabolic acidosis
Anion gap = ([Na] + [K]) - ([Cl] + [HCO3-])
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Distal Colonhigh resistance, high potential
difference, low permeability to ionsno nutrient dependent absorption
(e.g. Na+:glucose)responsive to mineralcorticoids
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Jejunum ileum Colontransepithelial P.D. -3mv -6mv -20mvmucosal resistance low med highpassive NaCl movement high low minimal[Na+] equilibrium conc. 133 mEq/l~ 75 ~30
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Metabolic Changes with DiarrheaHypokalemic, hyperchloremic, non-anion gap
metabolic acidosis
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colonic limit is < 5L/d
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Stool Characteristics
• consistency of the stool (semi-solid or watery)• stool volume• presence of blood or pus in the stool• nocturnal diarrhea• relationship to meals
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Definitions of DiarrheaStool consistencyStool volumeFrequency (> 2/day)Stool volume > 250 g/day
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Gastrointestinal Disease, ed: M.H. Sleisenger and J.S. Fordtran (1989), page 1034
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Stool fecal volume > 250 g/day
fecal fat, fecal electrolytes
> 6g fat/day, osmotic< 6g fat /day
D-xylose test (check mucosal integrity)
small intestinal biopsysmall intestinal X-ray
CT scanERCPtrial of pancreatic enzymes
VIP5HIAAhistaminecalcitoninthyroid functionlaxative screen
abnormalyesosmotic
nosecretory
stool pHlaxative screen
osmotic gap (? secretory or osmotic)
normal