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Food digestion is the breakdown of large food particles into smaller absorbable nutrients needed for energy production, growth, and cellular repair. It begins with ingestion and ends with defecation. Digestion takes place in the gastrointestinal tract in two principal forms: mechanical and chemical. Mechanical digestion is the physical degradation of large food particles into smaller pieces that digestive enzymes can access through chemical digestion. Chemical digestion is the enzymatic cleavage of proteins, carbohydrates, and fats into tiny amino acids, sugars, and fatty acids. Once food enters the mouth, it mixes with saliva and gets chewed through the process of mastication. Saliva is rich in mucus and salivary enzymes, and together, with the effects of mastication, it creates a mass called a food bolus. The food bolus then travels down the esophagus via wave-like muscular contractions, called peristalsis, before it reaches the stomach.
The stomach plays a critical role in the early stages of food digestion. Asides from squeezing and churning the food bolus, it also secretes a mixture of compounds, collectively known as "gastric juice." Gastric juice comprises water, mucus, hydrochloric acid, pepsin, and intrinsic factor. Of these five components, pepsin is the principal enzyme involved in protein digestion. It breaks down proteins into smaller peptides and amino acids that can be easily absorbed in the small intestine. Specific cells within the gastric lining, known as chief cells, release pepsin in an inactive form, or zymogen form, called pepsinogen. By doing so, the stomach prevents the auto-digestion of protective proteins in the lining of the digestive tract. Since chief cells release pepsin as a zymogen, activation by an acidic environment is necessary. Hydrochloric acid (HCl), another component of the gastric juice, plays a crucial role in creating the pH required for pepsin activity. Parietal cells produce HCl by secreting hydrogen and chloride ions. When pepsinogen and hydrochloric acid exist together in the gastric juice, pepsin takes its active form. Through the actions of pepsin and the squeezing properties of the stomach, the food bolus enters the intestines as a liquidy mixture of partially digested food particles, called chyme.
Issues of Concern
Pepsin depends on an acidic environment for protein digestion. Therefore, it is most effective at a pH of approximately 1.5 to 2. Low pH allows pepsinogen to cleave itself and form active pepsin. When it reaches the duodenum, though, it assumes an inactive form as the pH rises above 6. Nonetheless, protein digestion continues to take place throughout the small intestines via the effects of pancreatic enzymes: trypsin, chymotrypsin, elastase, and carboxypeptidase. As such, pepsin is not essential for life, and protein digestion can still take place in the absence of pepsin. It is worth mentioning that pepsin remains structurally stable until at least a pH of 8. Therefore, it can always be reactivated as long as pH remains below 8. This characteristic proves relevant in the pathophysiology of laryngopharyngeal reflux, as discussed later in the article.<1>
As mentioned earlier, the stomach provides pepsin with an ideal environment for protein digestion. Doing so helps with breaking down proteins into smaller nutrients, but at the same time, puts the stomach at risk of autodigestion. Therefore, a protective mechanism should exist to help maintain mucosal integrity. Fortunately, a mucus lining loaded with bicarbonate molecules helps protect against hydrochloric acid and creates a near-neutral pH environment that deactivates pepsin.<2>
Pepsin is an endopeptidase that breaks down dietary proteins reaching the stomach into amino acids. It functions by digesting peptide bonds, the predominant chemical bonds found in proteins. In response to various stimuli, small basophilic cells in the deeper layers of gastric glands, known as Chief cells, produce pepsinogen. Notably, acetylcholine, gastrin, and low pH directly stimulate chief cells to secrete pepsinogen. Acetylcholine is a neurotransmitter released from vagal parasympathetic nerve terminals in the "cephalic phase" of food digestion. Besides enhancing chief cell activity, it also stimulates parietal cells to produce hydrochloric acid (HCl) via their proton pumps. The low pH imposed by HCl breaks down pepsinogen into its active form, pepsin. Gastrin is another gastrointestinal hormone released by G cells in the stomach antrum and the duodenum. G cells secrete gastrin in response to many stimuli, including stomach distension, amino acids and peptides, high pH, and vagal stimulation. Similar to acetylcholine, gastrin also activates parietal cells to secrete hydrochloric acid (HCL) on top of its chief cell stimulatory effects. It does so both directly, and indirectly, through the action of histamine released by enterochromaffin-like (ECL) cells. Histamine is, in fact, the most potent activator of parietal cells. Somatostatin, on the other hand, is an inhibitory gastrointestinal hormone released by D cells in the duodenum and stomach antrum. It inhibits pepsinogen release from chief cells, thereby opposing the effects of gastrin, HCl, and acetylcholine.<3>
As mentioned earlier, the stomach protects itself from the digestive properties of pepsin by creating an adherent layer of bicarbonate-rich mucus lining. As such, pepsin should always remain in the stomach and should never regurgitate back to the upper tracts. As long as the lower esophageal sphincter functions accurately, pepsin resides withing the stomach and the duodenum, and the esophagus lining remains intact. However, a weak esophageal sphincter allows pepsin to reach not only the esophagus but also the upper airways. Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are two disease processes characterized by weak esophageal sphincters.<2>
The salivary pepsin test is a non-invasive, low-cost test that can detect the presence of pepsin in saliva, as the name implies. It has shown some promise as a useful diagnostic tool for LPR. However, further research should assess the sensitivity, specificity, and clinical utility of the test. On the contrary, the results are not that encouraging with GERD, and the test is no longer as helpful as previously thought.<4><5>
Pepsin plays a role in the pathophysiology of laryngopharyngeal reflux (LPR), a disease that originates from the digestive tract and significantly impacts the upper airway structures. Consider LPR in the differential diagnosis of a patient presenting with hoarseness, mild dysphagia, chronic cough, and non-productive throat clearing.
In an ideal digestive tract, pepsin is active only in the stomach, especially when the pH is between 1.5 and 2. This low pH occurs when the gastrointestinal (GI) tract senses a food bolus, properly releasing the three principal stimulants of proton pumps in parietal cells: gastrin, histamine, and acetylcholine.<6>
A weak lower esophageal sphincter (LES) allows gastric juice to travel retrogradely from the stomach up to the esophagus. If the upper esophageal sphincter (UES) fails as well, gastric juice might reach the larynx. In the larynx, hydrochloric acid and pepsin can damage critical structures, such as the vocal cords. It might even move past the larynx to affect the lungs themselves. In healthy people, the larynx contains dense neural tissue that prevents critical damage to structures in the larynx by inducing the cough reflex upon exposure to caustic stimuli. Unfortunately, patients with laryngopharyngeal reflux have altered neural sensitivity and cannot appropriately cough in response to acidic injury. Without an intact defense mechanism, acid and pepsin can readily enter the lower airways and damage the larynx. These structures are susceptible to gastric juice, and epithelial damage rapidly ensures, leading to hoarseness, dysphagia, and chronic cough.<7><8>
In a patient with a weak UES, an increase in intraabdominal pressure further reduces the sphincter"s function and predisposes to LPR symptoms. Thus, symptoms are more likely to occur in the upright position upon exertion, such as during exercise or when doing the Valsalva maneuver.<9>
Gastroesophageal reflux disease (GERD) is similar to LPR in that both disorders occur due to the reflux of the acidic contents from the stomach. However, two critical differences exist between GERD and LPR. The first is an anatomical difference as patients with GERD have weak LES while patients with LPR have weak LES and UES. The second is that pepsin plays a critical role in the pathophysiology of LPR while playing a minimal or unknown role in GERD.<10>
It may be helpful to think of GERD and LPR as two separate diseases on the same spectrum. A variety of food, including chocolate, peppermint, alcohol, fatty foods, and coffee, can impair the function of the upper and lower esophageal sphincters secondary to delayed gastric emptying. Avoidance of these foods plays a crucial role in decreasing the incidence of GERD and LPR.
Evaluating a patient with LPR should always begin with a thorough history to determine the presence of suggesting symptoms such as chronic cough, hoarseness, dysphagia, or throat clearing. Since gastroesophageal reflux disease shares many similarities with LPR, the next step is to rule out GERD. symptoms that worsen while upright and during periods of physical exertion are more suggestive of LPR. On the other hand, symptoms that get worse while lying down are more indicative of GERD. An example would be nocturnal asthma-like symptoms in GERD. Another symptom that suggests GERD rather than LPR is retrosternal burning chest pain (heartburn). A laryngoscope aids in the diagnosis of LPR by showing posterior laryngeal edema or vocal cord edema.<7><9>
Treatment of LPR relies on a combination of dietary modification and pharmacological interventions. Dietary modifications include avoidance of acidic food such as citrus fruits, tomatoes, and salad dressings. Other dietary changes involve avoiding foods that can weaken the esophageal sphincters, including caffeine, peppermint, alcohol, chocolate, and fatty foods. When these interventions prove ineffective, adding a pharmacological treatment might help. The goal of treatment is to inhibit acid release from parietal cells. Recall that histamine is the primary stimulant of proton pumps in parietal cells. Therefore, histamine-blockers such as ranitidine and cimetidine can successfully suppress acid release, thereby decreasing pepsin activity.<11> Proton pump inhibitors are another class of acid-suppressing agents that work by directly inhibiting acid release. Examples of PPIs are omeprazole and esomeprazole.
Parietal cells within the stomach lining secrete hydrochloric acid that lowers the pH of the stomach.
Acetylcholine, gastrin, and histamine stimulate the proton pump in parietal cells to release hydrogen ions and decrease pH.
A patient with weak upper and lower esophageal sphincters (UES and LES) can experience a retrograde flow of gastric juice, allowing pepsin to damage critical structures within the larynx.
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A weak UES and LES increase the risk of laryngopharyngeal reflux (LPR), a condition characterized by pepsin-mediated damage of structures within the larynx.