48: Intestine I: Fluid & Electrolyte Transport Flashcards
Describe the functional anatomy of the small intestine, especially the importance of the absorptive surface area and the sites of intestinal absorption of important solutes.
The duodenum is about 1 foot long, and is demarcated from the jejunum by the ligament of Treitz.
The jejunum is 8 feet long, and is defined as the proximal 2/5 of the small intestine. Most absorption occurs in jejunum due to largest surface area by successive foldings of villi & microvilli.
The ileum is 12 feet long, and is defined as the distal 3/5 of the small intestine.
Intestinal absorptive cell. Transfer of materials occurs via two parallel pathways:
(1) transcellular pathway, across the brush border, then through the cytoplasm, and finally across the basolateral membrane
(2) across the shunt pathway or paracellular pathway: through the tight junction and the extracellular space. Tight junctions are quite permeable to H2O* and cations such as Na+ and K+, but have a low permeability to anions. Tight junction are a low resistance (high conductance) pathway. Jejunum < Ileum < Colon in order of tightness of tight junctions.
Jejunal absorption is responsible for more than half of the total fluid absorbed.
Water and most nutrient substances are absorbed from the duodenum and upper jejunum, being completely absorbed by the end of the jejunum. Two important exceptions are Vitamin B12, which requires combination with intrinsic factor, and ionized bile salts, which undergo enterohepatic circulation. Both of these substances are absorbed in the distal ileum.
Water is absorbed through the intestinal membrane entirely by passive diffusion. Water absorption by diffusion follows the usual law of osmosis, which is that water will flow from an area of lower concentration to an area of higher concentration of particles. In the case of the intestine, these particles consist of nutritional substances and the various ions absorbed by a variety of transport mechanisms.
The ileum absorbs some fluid and electrolytes, along with Vitamin B12 and takes up ionized bile salts by sodium-dependent cotransport. If the jejunum is removed surgically, the ileum can take over its function, i.e. it adapts. But if the distal ileum is removed, other parts of the gastrointestinal tract cannot adapt to absorb ionized bile salts and Vitamin B12 (cobalamin). Vitamin B12 deficiency causes pernicious anemia, a type of macrocytic anemia characterized by unusually large red blood cells. Intrinsic factor is a mucoprotein (55 kD) secreted by gastric parietal cells; it combines with Vitamin B12 in the stomach forming a complex that is absorbed in the distal ileum.
The absorption of B12 is greatly facilitated by its combination with a mucoprotein produced by the stomach (intrinsic factor). Because absorption of the B12–mucoprotein occurs in the terminal ileum, either gastrectomy or ileal resection can cause a B12 deficiency. Although fresh fruits and leafy green vegetables are excellent sources of vitamin C, they are inadequate sources of B12. Liver, meat, eggs, and milk are good sources of B12.
Describe the major secretory and absorptive stimuli of the small intestine.
Secretory stimuli:
Endogenous: acetylcholine, histamine, CCK, secretin, gastrin, gastric inhibitory polypeptide, motilin, vasoactive intestinal peptide.
Exogenous: vibrio cholera, E. coli, salmonella, bacterial enterotoxins, bile salts & fatty acids, laxatives.
Substances that promote secretion tend to inhibit absorption; substances that promote absorption tend to inhibit secretion.
Absorptive stimuli:
Endogenous: a-adrenergic agonists like epi & norepi, dopamine, enkephalin endogenous opiates like endorphins (also morphine), somatostatin, mineralocorticoids.
Exogenous: Nutrients like glucose, AA’s, peptides.
Explain the pathophysiology of celiac disease.
Certain malabsorptive disease states, such as nontropical sprue, also called celiac disease, are associated with a decrease in absorptive surface area due primarily to a reduction in the number and size of microvilli. Sprue is a type of malabsorption syndrome caused by sensitivity to gluten, the insoluble protein of wheat and other grains. Gluten in bread by some means destroys absorptive cells and decreases the number of villi. Since these patients cannot absorb all of the food that is digested, they get diarrhea and malnutrition; the associated dehydration can be fatal. Patients require a restricted diet of rice with no wheat.
Describe the mechanism of NaHCO3 absorption by the jejunal absorptive cell.
Nutrient-coupled Na+ absorption occurs in the villous cells of the jejunum and ileum and is the primary mechanism for postprandial Na+ absorption.
The jejunal enterocyte absorbs Na+ and HCO3-, along with glucose and amino acids. The pancreas secretes NaHCO3 which serves to neutralize acid from the stomach. The jejunal absorptive cell shown above avidly absorbs NaHCO3 to maintain fluid balance and thereby prevents diarrhea.
Na+ enters the jejunal enterocyte across the apical membrane by two mechanisms:
(1) by Na+/glucose and by Na+/amino acid cotransport, an important mechanism for absorption of Na+, glucose and amino acids in the jejunum; and
(2) by Na+/H+ antiport, a mechanism that serves to keep the internal pH of the enterocyte near neutral, and away from electrochemical equilibrium. Na+ entry is balanced by active efflux of Na+ across the basolateral membrane mediated by the Na+/K+ pump. The net transport of the above reactions is as follows:
1 Na+ + 1 HCO3- (Lumen) -> 1 Na+ + 1 HCO3- (Blood)
The membrane potential is +5 mV at rest on the serosal side and rises to about +15 mV during absorption after a meal due to the electrogenicity of the BASOLATERAL Na+/K+ pump.
Describe the mechanism of NaCl absorption by the ileal absorptive cell.
Net absorption of NaCl by the ileum. A lot of Na+ and Cl- is secreted by the liver and the pancreas, and is then reabsorbed by the ileal absorptive cell (and also in the colon).
Unlike what occurs in the jejunum, Na+ and Cl- enter the ileal absorptive cell via Na+/H+ antiport in parallel with Cl-/HCO3- exchange. The H+ and HCO3- that are extruded into the lumen are recycled back into the ileal cell after forming carbonic acid which equilibrates with CO2 and H2O.
A Cl- channel in the basolateral membrane allows Cl- to pass down its electrical gradient into the serosal fluid and into the blood.
Cyclic AMP inhibits NaCl absorption by the ileum.
ACh stimulates cAMP production, thereby decreasing NaCl absorption.
VIP (vasointestinal peptide, a neurotransmitter in the gut that increases pancreatic secretion) is normally of minor importance in stimulating cAMP production in the ileum, but in vipoma tumors, the amount of VIP is greatly increased, resulting in greatly decreased NaCl absorption, leading to increased osmolarity in the lumen, and osmotic diarrhea.
E. coli and Vibriocholera toxins also stimulate production of cAMP, causing diarrhea which is massive in the case of cholera infection.
Describe the mechanism of NaCl secretion by the crypt cell.
NaCl Secretion by crypt cells:
Crypt cells, immature enterocytes in the jejunum, ileum, and colon, function to secret NaCl into the lumen (not blood).
The apical membrane contains a CFTR Cl- channel permitting movement of Cl- from the crypt cell to the lumen across the apical membrane.
Na+, K+, and Cl- enter the crypt cell via a Na+/K+/2Cl- cotransporter in the basolateral membrane.
This transporter, which occurs also in the thick ascending limb of the Loop of Henley in the kidney, is lost during maturation of crypt cells into absorptive cells, and is sensitive to furosemide, bumetanide, and other loop diuretics.
The stoichiometry of 1 Na+ transported for 2 chloride ions is advantageous for chloride transport. The K+ is then lost through a K+ ion channel in the basolateral membrane.
Na+ and K+ also move down their electrical gradients via electrodiffusion from the serosal to the mucosal solution.
In the crypt cell, increased cAMP increases the conductance of the CFTR channel to Cl-. When the Cl- channels open, Cl- is driven out of the cell by the negative internal electrical potential.
Cholera toxin and VIP released from vipoma tumors increase cAMP and greatly increase secretion of NaCl (and also KCl), leading to diarrhea, dehydration, and possible death. VIP can result in even more diarrhea than cholera infection.
ACh INCREASES intracellular Ca via ITP, causing INCREASED conductance to K+. The resultant HYPERPOLARIZATION of the membrane potential drives Cl- OUT of the cell, thereby INCREASING secretion of NaCl.
Describe the processes of the jejunal absorption of iron and of calcium.
The body stores of Fe are regulated. When body stores of Fe are low, the number of brush border transporters increases, thereby ncreasing absorption of Fe++. When body stores of Fe are high, the number of brush border transporters decreases, thereby reducing transfer of Fe++ to the blood.
Duodenal absorption of iron. Heme iron is the major dietary source in red meat. We need about 1 mg of Fe every day, but ingest about 20 mg Fe/day. Most of the ingested Fe is in the Fe+++ form, which cannot be absorbed. The inorganic Fe++, about 5% of the total ingested Fe, is absorbed in preference to the Fe+++ form. Fe++ may be transported across the basolateral membrane or be stored in the absorptive enterocyte as ferritin. Fe++ is only absorbed as needed (e.g. after menstruation); the extra iron is stored as ferritin. DCT1 refers to divalent cation transporter.
Iron absorption occurs by two pathways.
- Heme iron. The most efficient pathway is iron absorbed as heme. This iron is then freed within the cell by heme oxygenase and bound to intracellular mobilferrin.
- Non-heme iron. Non-heme iron Fe2+ is absobed via cotransport with a proton. Fe2+ forms insoluble complexes with food, but is more soluble at acid pH. Fe2+ is thus released from food by gastric acid. Patients deficient in gastric acid secretion absorb less iron, resulting in iron deficiency anemia. Fe2+ spontaneously oxidizes to Fe3+, but ascorbate and citrate in the stomach help reduce Fe3+ to Fe2+. Fe3+ is unaccepted by the cell and is excreted.
Some iron is bound to ferritin and stored within the cell. Most ferritin-bound iron is lost when the cell exfoliates; a small amount as needed is transported across the serosal membrane and binds to plasma transferrin. Plasma transferrin carries Fe+++ to the bone marrow or liver.
Transferrins are iron-binding proteins with a stoichiometry of 2 Fe+++/TF. Plasma transferrin is a β1 –globulin.
Duodenal absorption of calcium. The concentration of calcium in the blood is around 2 mM, with about 1⁄2 of that bound to albumin. The overall transport of calcium is against its electrochemical gradient. A Ca-ATPase, activated by calmodulin, actively transports Ca++ from the cell into the serosal solution.
1,25(OH)2D3 stimulates the synthesis of calbindin, a Ca binding protein which is the membrane carrier for Ca++ across the brush border membrane. Soluble intracellular calbindn binds and buffers Ca++ within the cell. Intracellular Ca++ is also buffered by mitochondrial stores. Intracellular calcium cannot rise too much without initiating a variety of toxic reactions involving Ca-activated proteases (breaks down protein), phospholipases (hydrolyzes phospholipids), and transglutaminases (crosslinks the cytoskeleton).
Active Ca2+ uptake in the duodenum. The small intestine absorbs Ca2+ by two mechanisms.
The passive, paracellular absorption of Ca2+ occurs throughout the small intestine. This pathway predominates, but it is not under the control of vitamin D.
The second mechanism-the active, transcellular absorption of Ca2+-occurs only in the duodenum. Ca2+ enters the cell across the apical membrane through a channel. Inside the cell, the Ca2+ is buffered by binding proteins, such as calbindin, and is also taken up into intracellular organelles, such as the endoplasmic reticulum. The enterocyte then extrudes Ca2+ across the basolateral membrane through a Ca2+ pump and an Na-Ca exchanger. Thus, the net effect is Ca2+ absorption. The active form of vitamin D (1,25 dihydroxyvitamin D) stimulates all three steps of transcellular Ca2+ absorption.
Vitamin D increases the absorption of Calcium in the intestine by stimulating the synthesis of Calcium binding protein Calbindin in the intestine.
Under the influence of the ultraviolet component of sunlight, 7-dehydrocholesterol in the skin forms Vitamin D3 (also called cholecalciferol). In the liver Vitamin D3 is hydroxylated to 25(OH)D3, and then hydroxylated again in the kidney to form the ACTIVE form 1,25-Dihydroxycholecalciferol, or 1,25(OH)2D3, a reaction stimulated by parathyroid hormone (PTH).
Long term regulation of calcium. Increased absorption of Ca++ increases the plasma concentration of Ca++, which in turn decreases the secretion of parathyroid hormone, which inhibits formation of 1,25(OH)2D3, which decreases the synthesis of calbindin, which decreases absorption of Ca++.
Explain the pathophysiology of cholera.
Cholera toxin increases cAMP and greatly increase secretion of NaCl (and also KCl), leading to diarrhea, dehydration, and possible death.
Cholera toxin activates adenylyl cyclase (AC), increasing cyclic adenosine monophosphate (cAMP) production and opening Cl- channels in the apical membrane.
Oral rehydration treatment: Sodium/glucose co-transporter is activated on administration of an oral mixture of saline (NaCl) and glucose to rehydrate individuals suffering from dehydration with cholera.
