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
Understand water transportUnderstand the causes of diarrheaUnderstand secretory vs. osmotic diarrhea
Water transport; diarrhea
Grant’s Atlas, 1972
Black RE, et al., Lancet 375:1969 (2010)
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
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
Gary SchoolnikEnvironmental Degradation Begets Epidemics: Cholera in BangladeshMedicine Grand RoundsNovember 21, 2007url: http://lane.stanford.edu/biomed-resources/grandrounds/medgrandrounds-2007.html
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
What is the implication with respect to stool osmolarity?
What is the difference between the nephron and the intestine?
www.med.uiuc.edu
http://en.wikipedia.org/wiki/Thick_ascending_limb_of_loop_of_Henle
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.
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.
Why do we separate digestion into a lumenal and mucosal phase?
Why do we separate digestion into a lumenal and mucosal phase?◦Lumenal digestion of a disaccharide would
increase intestinal volume two-fold
Hypertonic Stool
Hypertonic Stool
• High stool osmolarity suggests a prolonged period of incubation before processing.
Sleisenger and Fordtran, Gastrointestinal Disease, 5th ed.
Hypotonic Stool
Hypotonic Stool
Suggest the addition of free water to the stool
Osmotic gap = 290mosm - (([Na+] + [K+] ) x 2)
Osmotic Gap
A gap of < 40mosm suggests a secretory diarrhea
How do we absorb water?
How do we absorb water?Beer = 4 mosm/liter
Proc. Natl. Acad. Sci. USA93:13367-13370 (1996)
SGLT1 and Water AbsorptionCo-transport of 2 Na+, 1 glucose, and 264
water molecules◦Blocking glucose transport with phlorizin will also
block water transport
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
WHO Oral Rehydration Solution
[Na+] = 90 mEq/L[K+] = 20 mEq/L[Cl-] = 80 mEq/LCitrate = 30 mEq/LGlucose = 20 gm/L (111 mM)
Alberts et al, Moleculare Biology of the Cell, 3rd ed.
CFTRFunctions as a chloride channel and also
regulates other transport pathwaysCan mediate water transport
Advantage of CFTR mutations?
Advantage of CFTR mutations?Knockout CFTR mice have been produced
Advantage of CFTR mutations?Knockout CFTR mice have been produced
◦Mice die of intestinal obstruction
Advantage of CFTR mutations?Knockout CFTR mice have been produced
◦Mice die of intestinal obstructionHomozygous mice are resistant to cholera toxin
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
Univ. of Kansas, Dept. of PathologyNormal Pancreas, H&E
Secretory DiarrheasE. coli heat stabile enterotoxinCholeraStaph. AureusB. CereusVasoactive intestinal peptide (VIPoma)
Secretory DiarrheasExcess secretionNutrient absorption intact
◦Therapy?
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)
Secretory Diarrhea due to a VIPoma?
(vasoactive intestinal peptide)
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
SomatostatinClinical Applications
◦ Inhibition of many G-protein mediated processes Secretory diarrhea Pancreatic secretions Gastrointestinal hemorrhage (variceal bleeding)
induces splanchnic vasoconstriction
Diarrhea-Acid/Base DisordersWhat disturbances in acid base balance will be
seen with significant diarrhea?
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-])
Distal Colonhigh resistance, high potential
difference, low permeability to ionsno nutrient dependent absorption
(e.g. Na+:glucose)responsive to mineralcorticoids
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
Metabolic Changes with DiarrheaHypokalemic, hyperchloremic, non-anion gap
metabolic acidosis
colonic limit is < 5L/d
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
Definitions of DiarrheaStool consistencyStool volumeFrequency (> 2/day)Stool volume > 250 g/day
Gastrointestinal Disease, ed: M.H. Sleisenger and J.S. Fordtran (1989), page 1034
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