The stomach plays a critical role in the early stages of food digestion. Specifically, the stomach lining secretes a mixture of compounds, collectively known as "gastric juice." Gastric juice comprises water, mucus, hydrochloric acid, pepsin, and intrinsic factor. Of these 5 components, pepsin is the principal enzyme involved in digestion of protein. However, pepsin is released in its inactive form, or zymogen form, known as pepsinogen. By secreting pepsin in its inactive form, the stomach prevents digestion of protective proteins in the lining of the digestive tract. Specific cells within the gastric lining, known as the chief cells, release pepsin when stimulated by gastrin, another gastrointestinal hormone, and acetylcholine, a neurotransmitter. As chief cells release pepsinogen, activation by an acidic environment is necessary. Hydrochloric acid, another component of the gastric juice, plays a crucial role in creating the acidic environment required for pepsin activity. Cells that are known as parietal cells release hydrogen ions through a proton pump. Parietal cells also release chloride ions to form hydrochloric acid. Similar to chief cells, gastrin and acetylcholine also stimulate parietal cells to release hydrochloric acid. The most potent activator of the parietal cells, however, is histamine. When both pepsinogen and hydrochloric acid are present in the gastric juice, pepsin takes its active form.
Pepsin is an endopeptidase and can digest peptide bonds, the predominant chemical bond found in proteins. Pepsin’s main role is to digest proteins found in food. Because of pepsin’s dependence on an acidic environment for it to digest protein, pepsin is most active around a pH of 1.5 to 2. Pepsin assumes its inactive form at pH above 4.
Pepsin plays a role in the pathophysiology of laryngopharyngeal reflux (LPR), a disease that originates from the digestive tract and significantly impacts the structures of the upper airway. Consider LPR in differential diagnosis in the patient who presents with dysphonia/hoarseness, mild dysphagia, chronic cough, and nonproductive throat clearing.
In an ideal digestive tract, pepsin is active only in the stomach, specifically when the pH of the stomach is between 1.5 and 2, a pH where active pepsin can digest proteins found in food. This low pH only occurs when the gastrointestinal (GI) tract senses a food bolus, properly releasing the 3 main stimulants of the proton pump in parietal cells: gastrin, histamine, and acetylcholine.
Gastric juice may travel retrograde due to a weak lower esophageal sphincter (LES). Gastric juice can continue to travel through a weak upper esophageal sphincter where it can reach the level of the larynx. When gastric juice reaches the level of the larynx, it has the potential to damage critical structures in the larynx, such as the vocal cords and structures below the larynx, such as the lungs. In healthy patients, the larynx contains dense neural tissue that can respond to caustic materials such as gastric juice by coughing, which opposes the direction of the gastric juice, preventing critical damage to structures in the larynx. However, in patients with laryngopharyngeal reflux, the larynx cannot appropriately respond to acidic injury by coughing due to decreased neural sensitivity. Without a cough mechanism, acid and pepsin can damage the larynx and enter the lower airway with no opposing mechanism. These structures are sensitive to the combination of acid and pepsin because pepsin is most active when in the presence of an acidic environment. Any exposure to these substances can cause epithelial damage to the structure of the larynx. Therefore, patients with LPR present with hoarseness (due to vocal cord damage), dysphagia, and chronic cough.
The next step in assessing a patient with possible LPR is to determine how gastric juice travels in the wrong direction (upward through the esophageal sphincters rather than through the pyloric sphincter and into the small intestine). Recall that many patients with LPR may have a weak upper esophageal sphincter (UES). Weakness in this sphincter can cause acid to travel backward and out of the esophagus and damage the larynx. As a clinician, it is important to explain causes for a weak UES. When discussing the causes of a weak UES with a patient, it is important to understand how increases in intraabdominal pressure can cause UES opening. Thus, symptoms of LPR are more likely to occur in an upright position while exerting, such as doing the Valsalva maneuver or physical exercise, both of which increase intraabdominal pressure.
Gastroesophageal reflux disease (GERD) is like LPR in that both diseases occur due to a weak lower esophageal sphincter. There are two key differences in GERD and LPR. The first is an anatomical difference. Symptoms of GERD are due to a weak LES while symptoms of LPR are due to both a weak UES and LES. It may be helpful to think of GERD and LPR as two separate diseases on the same spectrum. While a weak UES is due to an increase in intraabdominal pressure, certain foods and beverages can cause both a weak UES and LES secondary to delayed gastric emptying. These include chocolate, peppermint, alcohol, fatty foods, and coffee. Avoidance of these foods can play a key role in decreasing the incidence of GERD. Another key difference in these two diseases is that pepsin plays a critical role in the pathophysiology of LPR while playing a minimal or unknown role in GERD.
Diagnose LPR if a patient complains of a chronic cough, hoarseness, dysphagia, and/or throat clearing and laryngoscope show posterior laryngeal edema or true vocal cord edema.
Rule out GERD based on symptoms. If symptoms worsen while upright and during periods of physical exertion, then the patient may have LPR due to an increase in intraabdominal pressure causing weakness in the UES. However, if worse when lying down, then consider GERD. An example would be nocturnal asthma-like symptoms when in a recumbent position. Another symptom that suggests GERD rather than LPR is retrosternal burning chest pain (heartburn).
Treat patients with dietary modification and pharmacological intervention. Dietary modification includes avoidance of acidic foods. Common acidic foods (pH less than 4.6) are citrus fruits, tomatoes, and salad dressings. Other dietary modifications are avoidance of foods that can weaken the esophageal sphincters. These foods include caffeine, peppermint, alcohol, chocolate, and fatty foods. Along with dietary modifications, pharmacological treatment may be beneficial. The goal of treatment is to inhibit acid release from parietal cells. Recall that histamine is a major stimulant (along with gastrin and acetylcholine) of the proton pump in parietal cells. Histamine-blockers such as ranitidine and cimetidine can successfully suppress acid release, therefore decreasing pepsin activity. Another class of drugs is the proton-pump inhibitors (PPIs), which directly inhibit acid release. Examples of PPIs are omeprazole and esomeprazole.
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