W ATER T RANSPORT AND D IARRHEA Anson Lowe September 25, 2015 Medicine/Gastroenterology

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