Burning epigastric pain exacerbated by fasting and improved with meals is a symptom complex associated with peptic ulcer disease (PUD). An ulcer is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation. Ulcers occur within the stomach and/or duodenum and are often chronic in nature. Acid peptic disorders are very common in the United States, with 4 million individuals (new cases and recurrences) affected per year. Lifetime prevalence of PUD in the United States is ˜12% in men and 10% in women. Moreover, an estimated 15,000 deaths per year occur as a consequence of complicated PUD. The financial impact of these common disorders has been substantial, with an estimated burden on direct and indirect health care costs of ˜$10 billion per year in the United States.
Despite the constant attack on the gastroduodenal mucosa by a host of noxious agents (acid, pepsin, bile acids, pancreatic enzymes, drugs, and bacteria), integrity is maintained by an intricate system that provides mucosal defense and repair.
The gastric epithelial lining consists of rugae that contain microscopic gastric pits, each branching into four or five gastric glands made up of highly specialized epithelial cells. The makeup of gastric glands varies with their anatomic location. Glands within the gastric cardia comprise <5% of the gastric gland area and contain mucous and endocrine cells. The 75% of gastric glands are found within the oxyntic mucosa and contain mucous neck, parietal, chief, endocrine, enterochromaffin, and enterochromaffin-like (ECL) cells (Fig. 293-1). Pyloric glands contain mucous and endocrine cells (including gastrin cells) and are found in the antrum.
Diagrammatic representation of the oxyntic gastric gland. (Adapted from S Ito, RJ Winchester: Cell Biol 16:541, 1963. © The Rockefeller University Press.)
The parietal cell, also known as the oxyntic cell, is usually found in the neck, or isthmus, or in the oxyntic gland. The resting, or unstimulated, parietal cell has prominent cytoplasmic tubulovesicles and intracellular canaliculi containing short microvilli along its apical surface (Fig. 293-2). H+,K+-adenosine triphosphatase (ATPase) is expressed in the tubulovesicle membrane; upon cell stimulation, this membrane, along with apical membranes, transforms into a dense network of apical intracellular canaliculi containing long microvilli. Acid secretion, a process requiring high energy, occurs at the apical canalicular surface. Numerous mitochondria (30–40% of total cell volume) generate the energy required for secretion.
Gastric parietal cell undergoing transformation after secretagogue-mediated stimulation. cAMP, cyclic adenosine monophosphate. (Adapted from SJ Hersey, G Sachs: Physiol Rev 75:155, 1995.)
Gastroduodenal Mucosal Defense
The gastric epithelium is under constant assault by a series of endogenous noxious factors, including hydrochloric acid (HCl), pepsinogen/pepsin, and bile salts. In addition, a steady flow of exogenous substances such as medications, alcohol, and bacteria encounter the gastric mucosa. A highly intricate biologic system is in place to provide defense from mucosal injury and to repair any injury that may occur.
The mucosal defense system can be envisioned as a three-level barrier, composed of preepithelial, epithelial, and subepithelial elements (Fig. 293-3). The first line of defense is a mucus-bicarbonate-phospholipid layer, which serves as a physicochemical barrier to multiple molecules, including hydrogen ions. Mucus is secreted in a regulated fashion by gastroduodenal surface epithelial cells. It consists primarily of water (95%) and a mixture of phospholipids and glycoproteins (mucin). The mucous gel functions as a nonstirred water layer impeding diffusion of ions and molecules such as pepsin. Bicarbonate, secreted in a regulated manner by surface epithelial cells of the gastroduodenal mucosa into the mucous gel, forms a pH gradient ranging from 1 to 2 at the gastric luminal surface and reaching 6 to 7 along the epithelial cell surface.
Components involved in providing gastroduodenal mucosal defense and repair. CCK, cholecystokinin; CRF, corticotropin-releasing factor; EGF, epidermal growth factor; HCl, hydrochloride; IGF, insulin-like growth factor; TGFα, transforming growth factor α; TRF, thyrotropin releasing factor. (Modified and updated from Tarnawski A. Cellular and molecular mechanisms of mucosal defense and repair. In: Yoshikawa T, Arakawa T. Bioregulation and Its Disorders in the Gastrointestinal Tract. Tokyo, Japan: Blackwell Science, 1998:3–17.)
Surface epithelial cells provide the next line of defense through several factors, including mucus production, epithelial cell ionic transporters that maintain intracellular pH and bicarbonate production, and intracellular tight junctions. Surface epithelial cells generate heat shock proteins that prevent protein denaturation and protect cells from certain factors such as increased temperature, cytotoxic agents, or oxidative stress. Epithelial cells also generate trefoil factor family peptides and cathelicidins, which also play a role in surface cell protection and regeneration. If the preepithelial barrier were breached, gastric epithelial cells bordering a site of injury can migrate to restore a damaged region (restitution). This process occurs independent of cell division and requires uninterrupted blood flow and an alkaline pH in the surrounding environment. Several growth factors, including epidermal growth factor (EGF), transforming growth factor (TGF) α, and basic fibroblast growth factor (FGF), modulate the process of restitution. Larger defects that are not effectively repaired by restitution require cell proliferation. Epithelial cell regeneration is regulated by prostaglandins and growth factors such as EGF and TGF-α. In tandem with epithelial cell renewal, formation of new vessels (angiogenesis) within the injured microvascular bed occurs. Both FGF and vascular endothelial growth factor (VEGF) are important in regulating angiogenesis in the gastric mucosa.
An elaborate microvascular system within the gastric submucosal layer is the key component of the subepithelial defense/repair system, providing HCO3–, which neutralizes the acid generated by the parietal cell. Moreover, this microcirculatory bed provides an adequate supply of micronutrients and oxygen while removing toxic metabolic ...