Case Based Learning
You will work on this case in 8 groups of 7 students per group. The group should discuss all the questions (10 min) and then each member of the group should pick one of the 7 questions to research during the during the next 30 minutes of the first session and submit their answer using this form. During the last 10 minutes of the first session, the 7 students who researched each question will form a new group (e.g., 7 students who worked on question 1) and take 10 minutes to discuss their individual answers and make plans for coming up with a group consensus answer to be presented during the second session for the case. During the second session, one or more students from each group will present the answer to their group’s question for 5 minutes followed by 2 minutes for questions from the class.
Pre-study
Learning Objectives
Describe the process and rate-determining factors of passive transport of nonpolar substances; e.g., O2 and CO2, across cell membranes (Fick’s Law of Passive Diffusion).
Contrast the features of primary versus secondary active transport across cell membranes and give examples of these transporters in the intestine.
Describe the mechanism of water reabsorption in the intestine.
Explain the importance of the intestinal sodium glucose co-transporter in the treatment of cholera.
Explain how cholera toxin causes loss of body fluids and dehydration.
Describe the specific transport processes affected by cholera toxin in the small intestine.
Explain the arterial blood gases and acid-base status of this patient.
25 y/o female with diarrhea - case study
A 25 year old female was transported from her rural village to the emergency room at Bujumbura Hospital in Burundi after she developed severe diarrhea, vomiting, and lethargy for 2 days.
A physician from Medicine Sans Frontiers found her to be afebrile and tachycardic with blood pressure of 85/45 mm Hg. Tissue turgor was markedly reduced and she had dry mucous membranes and sunken eyes. Respiratory rate was 20/min. An ECG revealed sinus tachycardia with prolonged QT interval. Arterial blood gas analysis showed a pH of 7.15; PO2 of 100 mm Hg; and PCO2 of 30 mm Hg. Blood chemistry showed hematocrit of 45%, Na+ of 140 mEq/L, K+ of 2.5 mEq/L (3.5 – 5.0), Cl- of 100 mEq/L, creatinine of 0.32 mmol/L (0.04 – 0.12), bicarbonate of 10 mEq/L (22-26). End tidal PCO2 was 30 mm Hg (38-42). Gram negative bacilli (Vibrio cholerae) were isolated from a stool sample.
She was initially treated with tetracycline and oral administration of a solution with 3.5 g NaCl, 2.5g NaHCO3, 1.5g KCl per L which was not effective in rehydrating the patient. She was later switched to oral rehydration with World Health Organization (WHO) solution (3.5 g NaCl, 2.5g NaHCO3, 1.5g KCl and 20g glucose per L). Her end-tidal PCO2 was 40 mm Hg and plasma bicarbonate was 24 mEq/L. Tissue turgor was normal and biochemistry showed K+ of 4 mEq/L, Na+ of 135 mEq/L, Cl- of 104 mEq/L, and creatinine of 0.1 mmol/L.
She was treated with high dose aspirin (300 mg/kg) to relieve a headache. This dose proved to be toxic and she developed rapid and deep breathing.
Please submit your answers to the following using this form.
Describe the process and rate-determining factors of passive transport of nonpolar substances; e.g., O2 and CO2, across cell membranes (Fick’s Law of Passive Diffusion).
2. Contrast the features of primary versus secondary active transport across cell membranes and give examples of these transporters in the intestine.
Cholera toxin inhibits all the Na transporters except the Na-glucose cotransporter. Apical = lumen; basolateral = blood side
Big Picture - Glucose transport in enterocytes (line intestine)
3. Describe the mechanism of water reabsorption in the intestine.
4. Explain why the initial rehydration treatment did not work but the second WHO rehydration solution did work.
This picture is of Dr Robert K. Crane and his sketch on a piece of napkin for coupled cotransport that he proposed at the international meetings in Prague in 1960. The sketch shows brush-border membrane supposedly of the intestinal epithelium showing the digestive surface and the diffusion barrier. During digestion the dietary glucose liberated from sucrose at the digestive surface is transported across the plasma membrane by a sodium-glucose carrier complex. Glucose transport is driven by the inward Na+ gradient maintained by the Na+ pump. Strophanthidin inhibits the Na+ pump causing the Na+ gradient to dissipate and remove the driving force for uphill glucose transport. Phlorizin inhibits cotransport. The model remains valid to this day, apart from some minor details such as the site of phlorizin inhibition (extracellular) and the location of the Na+/K+ pump.
5. Describe the rationale for the composition of the World Health Organization oral rehydration fluid.
5. Explain how cholera toxin causes loss of body fluids and dehydration.
Cholera toxin has binding and enzymatically active subunits that activate the adenylate cyclase system of cells in the intestinal mucosa leading to increased levels of intracellular cAMP (11). The effect is dependent on a specific receptor, a monosialoganglioside (GM1), present on the luminal surface of epithelial cells. The A1 subunit of the toxin, once it enters the cell, enzymatically transfers ADP-ribose from NAD to the αS-subunit of a stimulatory G protein (GS). When ADP-ribose is bound, the intrinsic GTPase activity of the αS-subunit is inhibited and the GTP-coupled form is permanently activated. Once activated, the αS-subunit of the GS attaches to the catalytic subunit of adenylate cyclase and leads to its continuous activation producing abnormally high levels of cAMP.
6. Describe the specific transport processes affected by cholera toxin in the small intestine.
Intestinal crypt cells, the primary secretory cells found in the small intestinal mucosa, respond to numerous secretagogues including acetylcholine, prostaglandins, and vasoactive intestinal peptide and the second messengers Ca2+ and cAMP to lead to chloride secretion through CFTRs located on the apical (luminal) side of the cells (see Fig. 1). In the presence of cholera toxin, chloride transport into the intestinal lumen through CFTRs located on the luminal surface of intestinal crypt cells is continuously activated by intracellular cAMP causing osmotic diarrhea drawing water into the lumen and leading to the characteristic large volumes of watery diarrhea
This model of NaCl transport across ductal cells in sweat glands of normal and CF individuals demonstrates the differences in salt reabsorption there that leads to the elevated sweat NaCl in CF patients. Na+ ions utilize ENaCs to enter the cells from the luminal side and Na+-K+-ATPases to leave the cells on the blood side. Cl− ions predominantly utilize CFTRs to enter the cells from the luminal side and other Cl− transporters to leave the cells on the blood side. In CF, the lack of functional CFTRs on the luminal side of the cell compromises the movement of cationic Na+ ions and its accompanying anionic Cl− ions leading to less reabsorption of salt out of the lumen. Salt concentrations in CF sweat can be up to 3–5 times normal. (Modeled after Figure 1 in Ref. 27.)
7. Explain the arterial blood gases and acid-base status of this patient.
