[git] Esophageal Reflux (case)

CELLULAR PHYSIOLOGY

Eso ph agea l R ef lux

A 30-year-old man went to see his physician because of repeated episodes of substernal burning pain, which usually occurred shortly after eating. Because an antacid like Rolaids usually relieved the discomfort, he dismissed the problem as heartburn. However, the persistence of his symptoms and his family history of heart disease convinced him to get a checkup. Results of his physical examination were normal, and findings from the electrocardiogram, stress test, and chest x-ray examination were all normal. His physician assured him that his heart was normal and that his symptoms were caused by reflux of acid gastric contents into the esophagus, possibly caused by esophageal sphincter incompetence.

1. What are the physical factors that move materials along hollow organs? 2. What are the physical barriers to gastroesophageal reflux? 3. How might a retrograde pressure gradient be established from the stomach into the esophagus? 4. What are the muscle components of the esophagus and their functions? 5. Is the striated muscle of the esophagus skeletal or cardiac? Why? 6. The movement of a bolus of food down the esophagus is uniform with no major differences between the skeletal, mixed, or smooth muscle regions. How can this be explained, given the striking contrasts in shortening velocity and power output between smooth and skeletal muscle? 7. Tone in the lower esophageal sphincter (the circular layer of the distal 3 to 4 cm of the esophagus) varies, but it is not abolished by denervation and it is not caused by a train of smooth muscle action potentials. Tone persists if the sphincter is dissected and placed in an organ bath in vitro. What mechanisms may be involved in maintaining tone under these conditions? 8. What causes the lower esophageal sphincter to relax as food passes down the esophagus? 9. What would you expect the relative ATP consumption rates of the upper and lower esophageal sphincters to be when they are maintaining comparable levels of tone? 10. Heartburn is often intensified or triggered when an individual bends over or lies down, especially after eating. Explain. 11. Apart from the symptoms described by patients, can you think of some reasonable clinical tests to detect gastroesophageal reflux? 12. Why can some foods or drinks precipitate gastroesophageal reflux and heartburn whereas comparable volumes of others do not?

1. A pressure gradient and the absence of physical barriers allow materials to move along hollow organs.

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2. Barriers to esophageal reflux include a contracted lower esophageal sphincter and a diaphragmatic pinchcock where the esophagus passes through the diaphragm. 3. The pressures in the stomach depend on gastric smooth muscle contraction and the transmural pressure gradient from the abdominal cavity to the stomach lumen, but are always positive and typically 7 to 50 mm Hg. Because most of the esophagus is in the thoracic cavity, its mean pressure is negative and typically varies between -15 and +5 mm Hg during the respiratory cycle. Thus there is always a pressure gradient favoring reflux. This can be quite large with maximal inspiration or with contraction of the abdominal skeletal muscles that occurs in such reflexes as coughing, vomiting, and defecation. 4. The upper esophageal sphincter is a striated muscle that acts to exclude air during respiration. The proximal esophageal body contains an outer longitudinal and an inner circular striated muscle layer. There is a long transition region with two layers in which the fraction of smooth muscle increases. In humans the lower half of the esophagus contains circular and longitudinal layers of pure smooth muscle. The function of the esophageal body is to propel a bolus of food to the stomach by phasic contractions coordinated as peristalsis. The lower esophageal sphincter is smooth muscle that is distinguished from the adjacent circular body muscle more by its physiology than by its structure. The function of the lower esophageal sphincter is tonic contraction to form a barrier to prevent reflux of the gastric contents. 5. Even though it is not attached to bone and is found in the wall of a hollow organ, the striated muscle is skeletal. The function of the body muscle of the esophagus is more like skeletal muscle than cardiac; the body muscle is normally relaxed and may be recruited voluntarily in swallowing. 6. Both skeletal and particularly smooth muscles are very diverse. The smooth muscle of the esophagus resembles skeletal muscle with extensive innervation, generation of bursts of action potentials, and phasic contractions equivalent to a brief tetanus. However, it is not clear why primates, cats, and opossums have smooth muscle in their esophagus, whereas many other animals do not. It appears that the complex neural control mechanisms governing peristalsis in the esophagus can generate comparable mechanical responses from muscle cells that differ considerably in their contractile protein isoforms, structure, and crossbridge regulatory mechanisms. 7. Tone is dependent on Ca++-stimulated crossbridge phosphorylation. Because this is a steady-state contraction, the extracellular Ca++ pool and the sarcolemma regulate phosphorylation. Neurotransmitters or circulating hormones are clearly not obligatory for tone, which suggests that receptor-operated channels are not of major importance. The most likely explanation is a normally low membrane potential with elevated voltage-gated Ca++ channel conductance. 8. This must involve coordinated neural pathways and release of a neurotransmitter whose combination with a receptor produces a net reduction in cell Ca ++, inhibition of myosin kinase, and crossbridge dephosphorylation by myosin phosphatase. A major part of the relaxation reflects activity of vagal fibers that release VIP (vasoactive intestinal polypeptide) or NO (nitric oxide). A contributing factor is a decrease in excitatory nerve activity, such as in some cholinergic vagal fibers. 9. Because smooth muscles can maintain tone (an isometric contraction) with as much as 300-fold lower rates of ATP consumption, the smooth muscle in the lower esophageal sphincter would be expected to be far more economical than an equivalent mass of skeletal muscle in the upper esophageal sphincter.

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10. Anything that increases the pressure gradient from the stomach to the esophagus makes reflux more likely. Gravity is one such factor. Frequent reflux with heartburn is associated with lower than normal pressures in the lower esophagus, and thus the barrier that resists the pressure gradient is too low. 11. Radiologic assessment is one possibility. The patient would receive a radiopaque substance, such as a barium sulfate suspension with a meal. This substance would allow detection of reflux. Another approach would be measurement of esophageal pH via a catheter, because the reflux would contain gastric acid. Direct observation is also possible with an endoscope to detect wall damage or lower esophageal sphincter patency. Also, pressure-sensing balloon catheters can be used to measure lower esophageal sphincter tone. 12. Several factors are involved. Ingested fats and alcohol reduce lower esophageal sphincter tone in some individuals. The acid in cola drinks (pH ¡Ö 2.3) may cause pain in an injured esophageal mucosa, as may osmotic effects. Some food and drinks (including tea and coffee) are potent stimulators of gastric acid secretion or they increase the force of gastric contractions. Although such details may not be covered in a physiology text, they are understandable in terms of activating pain receptors, increasing the pressure gradient for reflux, or decreasing the barriers to reflux.

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