InternalMed_Harrison

InternalMed_Harrison. to the development of copy with mucosal biopsies, which are necessary tion. In terms of endoscopic appearance, infectious esophagitis is diffuse and tends to involve the proximal esophagus far more frequently than does reflux esophagitis. The ulcerations seen in peptic esophagitis are usually solitary and distal, whereas infectious ulcerations are punctate and diffuse. Eosinophilic esophagitis characteristically exhibits multiple esophageal rings, linear furrows, or white punctate exudate. Esophageal ulcerations from pill esophagitis are usually singular and deep at points of luminal narrowing, especially near the carina, with sparing of the distal esophagus.


InternalMed_Harrison

InternalMed_Harrison. The complications of GERD are related to chronic esophagitis (bleeding and stricture) and the relationship between GERD and esophageal adenocarcinoma. However, both esophagitis and peptic strictures have become increasingly rare in the era of potent antisecretory medications. Conversely, the most severe histologic consequence of GERD is Barrett’s metaplasia with the associated risk of esophageal adenocarcinoma, and the incidence of these lesions has increased, not decreased, in the era of potent acid suppression. Barrett’s metaplasia, endoscopically recognized by tongues of reddish mucosa extending proximally from the gastroesophageal junction (Fig. 347-9) or histopathologically by the finding of specialized columnar metaplasia, is associated with a substantially increased risk for development of esophageal adenocarcinoma.


InternalMed_Harrison

InternalMed_Harrison. Barrett’s metaplasia can progress to adenocarcinoma through the intermediate stages of lowand high-grade dysplasia (Fig. 347-10). Owing to this risk, areas of Barrett’s and especially any included areas of mucosal irregularity should be extensively biopsied. The rate of cancer development is estimated at 0.1–0.3% per year, but vagaries in definitional criteria and of the extent of Barrett’s metaplasia requisite to establish the diagnosis have contributed to variability and inconsistency in this risk assessment. The group at greatest risk is obese white males in their sixth decade of life. However, despite common practice, the utility of endoscopic screening and surveillance programs intended FIGURE 347-10 Histopathology of Barrett’s metaplasia and Barrett’s with high-grade dysplasia. H&E, hematoxylin and eosin.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 347-10 Histopathology of Barrett’s metaplasia and Barrett’s with high-grade dysplasia. H&E, hematoxylin and eosin. to control the adenocarcinoma risk has not been established. Also of note, no high-level evidence confirms that aggressive antisecretory therapy or antireflux surgery causes regression of Barrett’s esophagus or prevents adenocarcinoma.


InternalMed_Harrison

InternalMed_Harrison. Although the management of Barrett’s esophagus remains controversial, the finding of dysplasia in Barrett’s, particularly high-grade dysplasia, mandates further intervention. In addition to the high rate of progression to adenocarcinoma, there is also a high prevalence of unrecognized coexisting cancer with high-grade dysplasia. Nonetheless, treatment remains controversial. Esophagectomy, intensive endoscopic surveillance, and mucosal ablation have all been advocated. Currently, esophagectomy is the gold standard treatment for high-grade dysplasia in an otherwise healthy patient with minimal surgical risk. However, esophagectomy has a mortality ranging from 3–10%, along with substantial morbidity. That, along with increasing evidence of the effectiveness of endoscopic therapy with purpose-built radiofrequency ablation devices, has led many to favor this therapy as a preferable management strategy.


InternalMed_Harrison

InternalMed_Harrison. Lifestyle modifications are routinely advocated as GERD therapy. Broadly speaking, these fall into three categories: (1) avoidance of foods that reduce LES pressure, making them “refluxogenic” (these commonly include fatty foods, alcohol, spearmint, peppermint, tomato-based foods, and possibly coffee and tea); (2) avoidance of acidic foods that are inherently irritating; and (3) adoption of behaviors to minimize reflux and/or heartburn. In general, minimal evidence supports the efficacy of these measures. However, clinical experience dictates that subsets of patients are benefitted by specific recommendations, based on their unique history and symptom profile. A patient with sleep disturbance from nighttime heartburn is likely to benefit from elevation of the head of the bed and avoidance of eating before retiring, but those recommendations are superfluous for a patient without nighttime symptoms. The most broadly applicable recommendation is for weight reduction. Even though the


InternalMed_Harrison

InternalMed_Harrison. of eating before retiring, but those recommendations are superfluous for a patient without nighttime symptoms. The most broadly applicable recommendation is for weight reduction. Even though the benefit with respect to reflux cannot be assured, the strong epidemiologic relationship between body mass index and GERD and the secondary health gains of weight reduction are beyond dispute.


InternalMed_Harrison

InternalMed_Harrison. The dominant pharmacologic approach to GERD management is with inhibitors of gastric acid secretion, and abundant data support the effectiveness of this approach. Pharmacologically reducing the acidity of gastric juice does not prevent reflux, but it ameliorates reflux symptoms and allows esophagitis to heal. The hierarchy of effectiveness among pharmaceuticals parallels their antisecretory potency. Proton pump inhibitors (PPIs) are more efficacious than histamine2 receptor antagonists (H2RAs), and both are superior to placebo. No major differences exist among PPIs, and only modest gain is achieved by increased dosage.


InternalMed_Harrison

InternalMed_Harrison. Paradoxically, the perceived frequency and severity of heartburn correlate poorly with the presence or severity of esophagitis. When GERD treatments are assessed in terms of resolving heartburn, both efficacy and differences among pharmaceuticals are less clear-cut than with the objective of healing esophagitis. Although the same overall hierarchy of effectiveness exists, observed efficacy rates are lower and vary widely, likely reflecting patient heterogeneity.


InternalMed_Harrison

InternalMed_Harrison. Reflux symptoms tend to be chronic, irrespective of esophagitis. Thus, a common management strategy is indefinite treatment with PPIs or H2RAs as necessary for symptom control. The side effects of PPI therapy are generally minimal. Vitamin B12 and iron absorption may be compromised and susceptibility to enteric infections, particularly Clostridium difficile colitis, increased with treatment. Population studies have also suggested a slight increased risk of bone fracture with chronic PPI use suggesting an impairment of calcium absorption, but prospective studies have failed to corroborate this. Nonetheless, as with any medication, PPI dosage should be minimized to that necessary for the clinical indication.


InternalMed_Harrison

InternalMed_Harrison. Laparoscopic Nissen fundoplication, wherein the proximal stomach is wrapped around the distal esophagus to create an antireflux barrier, is a surgical alternative to the management of chronic GERD. Just as with PPI therapy, evidence on the utility of fundoplication is strongest for treating esophagitis, and controlled trials suggest similar efficacy to PPI therapy. However, the benefits of fundoplication must be weighed against potential deleterious effects, including surgical morbidity and mortality, postoperative dysphagia, failure or breakdown requiring reoperation, an inability to belch, and increased bloating, flatulence, and bowel symptoms after surgery.


InternalMed_Harrison

InternalMed_Harrison. Eosinophilic esophagitis (EoE) is increasingly recognized in adults and children around the world. Current prevalence estimates identified 4–6 cases per 10,000 with a predilection for white males. The increasing prevalence of EoE is attributable to a combination of an increasing incidence and a growing recognition of the condition. There is also an incompletely understood, but important, overlap between EoE and GERD that confuses diagnosis of the disease.


InternalMed_Harrison

InternalMed_Harrison. EoE is diagnosed based on the combination of typical esophageal symptoms and esophageal mucosal biopsies demonstrating squamous epithelial eosinophil-predominant inflammation. Alternative etiologies of esophageal eosinophilia include GERD, drug hypersensitivity, connective tissue disorders, hypereosinophilic syndrome, and infection. Current evidence indicates that EoE is an immunologic disorder induced by antigen sensitization in susceptible individuals. Dietary factors play an important role in both the pathogenesis and treatment of EoE. Aeroallergens may also contribute, but the evidence is weaker. The natural history of EoE is unclear, but an increased risk of esophageal stricture development paralleling the duration of untreated disease has been noted. Diseases of the Esophagus FIGURE 347-11 Endoscopic features of (A) eosinophilic esophagitis (EoE), (B) Candida esophagitis, (C) giant ulcer associated with HIV, (D) and a Schatzki ring.


InternalMed_Harrison

InternalMed_Harrison. EoE should be strongly considered in children and adults with dysphagia and esophageal food impactions. In preadolescent children, symptom presentations of EoE include chest or abdominal pain, nausea, vomiting, and food aversion. Other symptoms in adults may include atypical chest pain and heartburn, particularly heartburn that is refractory to PPI therapy. An atopic history of food allergy, asthma, eczema, or allergic rhinitis is present in the majority of patients. Peripheral blood eosinophilia is demonstrable in up to 50% of patients, but the specificity of this finding is problematic in the setting of concomitant atopy. The characteristic endoscopic esophageal findings are loss of vascular markings (edema), multiple esophageal rings, longitudinally oriented furrows, and punctate exudate (Fig. 347-11). Histologic confirmation is made with the demonstration of esophageal mucosal eosinophilia (greatest density ±15 eosinophils per high-power field) (Fig. 347-12). Complications of EoE


InternalMed_Harrison

InternalMed_Harrison. (Fig. 347-11). Histologic confirmation is made with the demonstration of esophageal mucosal eosinophilia (greatest density ±15 eosinophils per high-power field) (Fig. 347-12). Complications of EoE include esophageal stricture, narrow-caliber esophagus, food impaction, and esophageal perforation.


InternalMed_Harrison

InternalMed_Harrison. The goals of EoE management are symptom control and the prevention of complications. Once esophageal eosinophilia is demonstrated, patients typically undergo a trial of PPI therapy as a practical means of excluding a contribution of GERD to the esophageal mucosal inflammation. PPI-responsive esophageal eosinophilia, characterized by elimination of mucosal eosinophilia, occurs in 30–50% of cases of suspected EoE. Patients with persistent symptoms and eosinophilic inflammation following PPI therapy are subsequently considered for EoE treatments such as elimination diets or swallowed topical glucocorticoids. Elemental formula diets are a highly effective therapy that have primarily been studied in children but are limited by palatability. Notably, allergy testing by means of either serum IgE or skin prick testing has demonstrated poor sensitivity and specificity in the identification of foods that incite the esophageal inflammatory response. Allergy testing combining skin prick and atopy


InternalMed_Harrison

InternalMed_Harrison. or skin prick testing has demonstrated poor sensitivity and specificity in the identification of foods that incite the esophageal inflammatory response. Allergy testing combining skin prick and atopy patch testing has been effective in children with EoE, but additional validation is needed. Empiric elimination of common food allergies (milk, wheat, egg, soy, nuts, and seafood) followed by systematic reintroduction has been an effective diet therapy in both children and adults with EoE. The intent of the elimination diet approach is the identification of a single food trigger or a small number of food triggers. Swallowed, topical glucocorticoids (fluticasone propionate or budesonide) are highly effective, but recurrence of disease is common following the cessation of therapy. Systemic glucocorticoids are reserved for severely afflicted patients refractory to less morbid treatments. Esophageal dilation is very effective at relieving dysphagia in patients with fibrostenosis. Dilation


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InternalMed_Harrison. are reserved for severely afflicted patients refractory to less morbid treatments. Esophageal dilation is very effective at relieving dysphagia in patients with fibrostenosis. Dilation should be approached conservatively because of the risk of deep, esophageal mural laceration or perforation in the stiff-walled esophagus that is characteristic of the disease.


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InternalMed_Harrison. FIGURE 347-12 Histopathology of eosinophilic esophagitis (EoE) showing infiltration of the esophageal squamous epithelium with eosinophils. Additional features of basal cell hyperplasia and lamina propria fibrosis are present. Eosinophilic inflammation can also be seen with gastroesophageal reflux disease.


InternalMed_Harrison

InternalMed_Harrison. With the increased use of immunosuppression for organ transplantation as well as chronic inflammatory diseases and chemotherapy along with the AIDS epidemic, infections with Candida species, herpesvirus, and cytomegalovirus (CMV) have become relatively common. Although rare, infectious esophagitis also occurs among the nonimmunocompromised, with herpes simplex and Candida albicans being the most common pathogens. Among AIDS patients, infectious esophagitis becomes more common as the CD4 count declines; cases are rare with a CD4 count >200 and common when <100. HIV itself may also be associated with a self-limited syndrome of acute esophageal ulceration with oral ulcers and a maculopapular skin rash at the time of seroconversion. Additionally, some patients with advanced disease have deep, persistent esophageal ulcers treated with oral glucocorticoids or thalidomide. However, with the widespread use of protease inhibitors, a reduction in these HIV complications has been noted.


InternalMed_Harrison

InternalMed_Harrison. Regardless of the infectious agent, odynophagia is a characteristic symptom of infectious esophagitis; dysphagia, chest pain, and hemorrhage are also common. Odynophagia is uncommon with reflux esophagitis, so its presence should always raise suspicion of an alternative etiology.


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InternalMed_Harrison. 1910 CANDIDA ESOPHAGITIS Candida is normally found in the throat, but can become pathogenic and produce esophagitis in a compromised host; C. albicans is most common. Candida esophagitis also occurs with esophageal stasis secondary to esophageal motor disorders and diverticula. Patients complain of odynophagia and dysphagia. If oral thrush is present, empirical therapy is appropriate, but co-infection is common, and persistent symptoms should lead to prompt endoscopy with biopsy, which is the most useful diagnostic evaluation. Candida esophagitis has a characteristic appearance of white plaques with friability. Rarely, Candida esophagitis is complicated by bleeding, perforation, stricture, or systemic invasion. Oral fluconazole (200–400 mg on the first day, followed by 100–200 mg daily) for 14–21 days is the preferred treatment. Patients refractory to fluconazole may respond to itraconazole, voriconazole, or posaconazole. Alternatively, poorly responsive patients or those who cannot


InternalMed_Harrison

InternalMed_Harrison. for 14–21 days is the preferred treatment. Patients refractory to fluconazole may respond to itraconazole, voriconazole, or posaconazole. Alternatively, poorly responsive patients or those who cannot swallow medications can be treated with an intravenous echinocandin (caspofungin 50 mg daily for 7–21 days).


InternalMed_Harrison

InternalMed_Harrison. Herpes simplex virus type 1 or 2 may cause esophagitis. Vesicles on the nose and lips may coexist and are suggestive of a herpetic etiology. Varicella-zoster virus can also cause esophagitis in children with chickenpox or adults with zoster. The characteristic endoscopic findings are vesicles and small, punched-out ulcerations. Because herpes simplex infections are limited to squamous epithelium, biopsies from the ulcer margins are most likely to reveal the characteristic ground-glass nuclei, eosinophilic Cowdry’s type A inclusion bodies, and giant cells. Culture or polymerase chain reaction (PCR) assays are helpful to identify acyclovir-resistant strains. Acyclovir (200 mg orally five times a day for 7–10 days) can be used for immunocompetent hosts, although the disease is typically self-limited after a 1to 2-week period in such patients. Immunocompromised patients are treated with acyclovir (400 mg orally five times a day for 14–21 days), famciclovir (500 mg orally three times a


InternalMed_Harrison

InternalMed_Harrison. after a 1to 2-week period in such patients. Immunocompromised patients are treated with acyclovir (400 mg orally five times a day for 14–21 days), famciclovir (500 mg orally three times a day), or valacyclovir (1 g orally three times a day). In patients with severe odynophagia, intravenous acyclovir, 5 mg/kg every 8 h for 7–14 days, reduces this morbidity.


InternalMed_Harrison

InternalMed_Harrison. CMV esophagitis occurs primarily in immunocompromised patients, particularly organ transplant recipients. CMV is usually activated from a latent stage. Endoscopically, CMV lesions appear as serpiginous ulcers in an otherwise normal mucosa, particularly in the distal esophagus. Biopsies from the ulcer bases have the greatest diagnostic yield for finding the pathognomonic large nuclear or cytoplasmic inclusion bodies. Immunohistology with monoclonal antibodies to CMV and in situ hybridization tests are useful for early diagnosis. Data on therapy for CMV esophagitis are limited. Treatment studies of CMV gastrointestinal disease have demonstrated effectiveness of both ganciclovir (5 mg/kg every 12 h intravenously) and foscarnet (90 mg/kg every 12 h intravenously). Valganciclovir (900 mg two times a day), an oral formulation of ganciclovir, can also be used. Therapy is continued until healing, which may take 3–6 weeks. Maintenance therapy may be needed for patients with relapsing disease.


InternalMed_Harrison

InternalMed_Harrison. Most cases of esophageal perforation are from instrumentation of the esophagus or trauma. Alternatively, forceful vomiting or retching can lead to spontaneous rupture at the gastroesophageal junction (Boerhaave’s syndrome). More rarely, corrosive esophagitis or neoplasms lead to perforation. Instrument perforation from endoscopy or nasogastric tube placement typically occurs in the hypopharynx or at the gastroesophageal junction. Perforation may also occur at the site of a stricture in the setting of endoscopic food disimpaction or esophageal dilation. Esophageal perforation causes pleuritic retrosternal pain that can be associated with pneumomediastinum and subcutaneous emphysema. Mediastinitis is a major complication of esophageal perforation, and prompt recognition is key to optimizing outcome. CT of the chest is most sensitive in detecting mediastinal air. Esophageal perforation is confirmed by a contrast swallow, usually Gastrografin followed by thin barium. Treatment includes


InternalMed_Harrison

InternalMed_Harrison. outcome. CT of the chest is most sensitive in detecting mediastinal air. Esophageal perforation is confirmed by a contrast swallow, usually Gastrografin followed by thin barium. Treatment includes nasogastric suction and parenteral broad-spectrum antibiotics with prompt surgical drainage and repair in noncontained leaks. Conservative therapy with NPO status and antibiotics without surgery may be appropriate in cases of contained perforation that are detected early. Endoscopic clipping or stent placement may be indicated in nonoperated iatrogenic perforations or nonoperable cases such as perforated tumors.


InternalMed_Harrison

InternalMed_Harrison. Vomiting, retching, or vigorous coughing can cause a nontransmural tear at the gastroesophageal junction that is a common cause of upper gastrointestinal bleeding. Most patients present with hematemesis. Antecedent vomiting is anticipated but not always evident. Bleeding usually abates spontaneously, but protracted bleeding may respond to local epinephrine or cauterization therapy, endoscopic clipping, or angiographic embolization. Surgery is rarely needed.


InternalMed_Harrison

InternalMed_Harrison. Radiation esophagitis can complicate treatment for thoracic cancers, especially breast and lung, with the risk proportional to radiation dosage. Radiosensitizing drugs such as doxorubicin, bleomycin, cyclophosphamide, and cisplatin also increase the risk. Dysphagia and odynophagia may last weeks to months after therapy. The esophageal mucosa becomes erythematous, edematous, and friable. Submucosal fibrosis and degenerative tissue changes and stricturing may occur years after the radiation exposure. Radiation exposure in excess of 5000 cGy has been associated with increased risk of esophageal stricture. Treatment for acute radiation esophagitis is supportive. Chronic strictures are managed with esophageal dilation.


InternalMed_Harrison

InternalMed_Harrison. Caustic esophageal injury from ingestion of alkali or, less commonly, acid can be accidental or from attempted suicide. Absence of oral injury does not exclude possible esophageal involvement. Thus, early endoscopic evaluation is recommended to assess and grade the injury to the esophageal mucosa. Severe corrosive injury may lead to esophageal perforation, bleeding, stricture, and death. Glucocorticoids have not been shown to improve the clinical outcome of acute corrosive esophagitis and are not recommended. Healing of more severe grades of caustic injury is commonly associated with severe stricture formation and often requires repeated dilatation.


InternalMed_Harrison

InternalMed_Harrison. Pill-induced esophagitis occurs when a swallowed pill fails to traverses the entire esophagus and lodges within the lumen. Generally, this is attributed to poor “pill taking habits”: inadequate liquid with the pill or lying down immediately after taking a pill. The most common location for the pill to lodge is in the mid-esophagus near the crossing of the aorta or carina. Extrinsic compression from these structures halts the movement of the pill or capsule. Since initially reported in 1970, more than 1000 cases of pill esophagitis have been reported, suggesting that this is not an unusual occurrence. A wide variety of medications are implicated with the most common being doxycycline, tetracycline, quinidine, phenytoin, potassium chloride, ferrous sulfate, nonsteroidal anti-inflammatory drugs (NSAIDs), and bisphosphonates. However, virtually any pill can result in pill esophagitis if taken carelessly.


InternalMed_Harrison

InternalMed_Harrison. Typical symptoms of pill esophagitis are the sudden onset of chest pain and odynophagia. Characteristically, the pain will develop over a period of hours or will awaken the individual from sleep. A classic history in the setting of ingestion of recognized pill offenders obviates the need for diagnostic testing in most patients. When endoscopy is performed, localized ulceration or inflammation is evident. Histologically, acute inflammation is typical. Chest CT imaging will sometimes reveal esophageal thickening consistent with transmural inflammation. Although the condition usually resolves within days to weeks, symptoms may persist for months and stricture can develop in severe cases. No specific therapy is known to hasten the healing process, but antisecretory medications are frequently prescribed to remove concomitant reflux as an aggravating factor. When healing results in stricture formation, dilation is indicated.


InternalMed_Harrison

InternalMed_Harrison. Food or foreign bodies may lodge in the esophagus causing complete obstruction, which in turn can cause an inability to handle secretions (foaming at the mouth) and severe chest pain. Food impaction may occur due to stricture, carcinoma, Schatzki ring, eosinophilic esophagitis, or simply inattentive eating. If it does not spontaneously resolve, impacted food can be dislodged endoscopically. Use of meat tenderizer enzymes to facilitate passage of a meat bolus is discouraged because of potential esophageal injury. Glucagon (1 mg IV) is sometimes tried before endoscopic dislodgement. After emergent treatment, patients should be evaluated for potential causes of the impaction with treatment rendered as indicated.


InternalMed_Harrison

InternalMed_Harrison. Scleroderma esophagus (hypotensive LES and absent esophageal peristalsis) was initially described as a manifestation of scleroderma or other collagen vascular diseases and thought to be specific for these disorders. However, this nomenclature subsequently proved unfortunate and has been discarded because an estimated half of qualifying patients do not have an identifiable systemic disease, and reflux disease is often the only identifiable association. When scleroderma esophagus occurs as a manifestation of a collagen vascular disease, the histopathologic findings are of infiltration and destruction of the esophageal muscularis propria with collagen deposition and fibrosis. The pathogenesis of absent peristalsis and LES hypo-tension in the absence of a collagen vascular disease is unknown. Regardless of the underlying cause, the manometric abnormalities predispose patients to severe GERD due to inadequate LES barrier function combined with poor esophageal clearance of refluxed acid.


InternalMed_Harrison

InternalMed_Harrison. Regardless of the underlying cause, the manometric abnormalities predispose patients to severe GERD due to inadequate LES barrier function combined with poor esophageal clearance of refluxed acid. Dysphagia may also be manifest but is generally mild and alleviated by eating in an upright position and using liquids to facilitate solid emptying.


InternalMed_Harrison

InternalMed_Harrison. A host of dermatologic disorders (pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, Behçet’s syndrome, and epidermolysis bullosa) can affect the oropharynx and esophagus, particularly the proximal esophagus with blisters, bullae, webs, and strictures. Glucocorticoid treatment is usually effective. Erosive lichen planus, Stevens-Johnson syndrome, and graft-versus-host disease can also involve the esophagus. Esophageal dilatation may be necessary to treat strictures.


InternalMed_Harrison

InternalMed_Harrison. 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. PUD significantly affects quality of life by impairing overall patient well-1911 being and contributing substantially to work absenteeism. 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 ~$6 billion per year in the United States, with $3 billion spent on hospitalizations, $2 billion on


InternalMed_Harrison

InternalMed_Harrison. has been substantial, with an estimated burden on direct and indirect health care costs of ~$6 billion per year in the United States, with $3 billion spent on hospitalizations, $2 billion on physician office visits, and $1 billion in decreased productivity and days lost from work.


InternalMed_Harrison

InternalMed_Harrison. 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. Gastric Anatomy 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. 348-1). Pyloric glands contain mucous and endocrine cells (including gastrin cells) and are found in the antrum.


InternalMed_Harrison

InternalMed_Harrison. 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. 348-2). 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 FIGURE 348-1 Diagrammatic representation of the oxyntic gastric gland. (Adapted from S Ito, RJ Winchester: J Cell Biol 16:541, 1963. doi:10.1083/jcb.16.3.541. © 1963 Ito and Winchester.) HCl H+,K+–ATPase KCl


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InternalMed_Harrison. HCl H+,K+–ATPase KCl FIGURE 348-2 Gastric parietal cell undergoing transformation after secretagogue-mediated stimulation. cAMP, cyclic adenosine mono-phosphate. (Adapted from SJ Hersey, G Sachs: Physiol Rev 75:155, 1995.) process requiring high energy, occurs at the apical canalicular surface. Numerous mitochondria (30–40% of total cell volume) generate the energy required for secretion. 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.


InternalMed_Harrison

InternalMed_Harrison. The mucosal defense system can be envisioned as a three-level barrier, composed of preepithelial, epithelial, and subepithelial elements (Fig. 348-3). The first line of defense is a mucus-bicarbonatephospholipid 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 by-products.


InternalMed_Harrison

InternalMed_Harrison. Prostaglandins play a central role in gastric epithelial defense/ repair (Fig. 348-4). The gastric mucosa contains abundant levels of prostaglandins that regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution. Prostaglandins are derived from esterified arachidonic acid, which is formed from phospholipids (cell membrane) by the action of phospholipase A2. A key enzyme that controls the rate-limiting step in prostaglandin synthesis is cyclooxygenase (COX), which is present in two isoforms (COX-1, COX-2), each having distinct characteristics regarding structure, tissue distribution, and expression. COX-1 is expressed in a host of tissues, including the stomach, platelets, kidneys, and endothelial cells. This isoform is expressed in a constitutive manner and plays an important role in maintaining the integrity of renal function, platelet aggregation, and gastrointestinal


InternalMed_Harrison

InternalMed_Harrison. and endothelial cells. This isoform is expressed in a constitutive manner and plays an important role in maintaining the integrity of renal function, platelet aggregation, and gastrointestinal (GI) mucosal integrity. In contrast, the expression of COX-2 is inducible by inflammatory stimuli, and it is expressed in macrophages, leukocytes, fibroblasts, and synovial cells. The beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on tissue inflammation are due to inhibition of COX-2; the toxicity of these drugs (e.g., GI mucosal ulceration and renal dysfunction) is related to inhibition of the COX-1 isoform. The highly COX-2–selective NSAIDs have the potential to provide the beneficial effect of decreasing tissue inflammation while minimizing toxicity in the GI tract. Selective COX-2 inhibitors have had adverse effects on the cardiovascular system, leading to increased risk of myocardial infarction. Therefore, the


InternalMed_Harrison

InternalMed_Harrison. U.S. Food and Drug Administration (FDA) has removed two of these agents (valdecoxib and rofecoxib) from the market (see below). Nitric oxide (NO) is important in the maintenance of gastric mucosal integrity. The key enzyme NO synthase is constitutively expressed in the mucosa and contributes to cytoprotection by stimulating gastric mucus, increasing mucosal blood flow, and maintaining epithelial cell barrier function. The central nervous system (CNS) and hormonal factors also play a role in regulating mucosal defense through multiple pathways (Fig. 348-3).


InternalMed_Harrison

InternalMed_Harrison. Physiology of Gastric Secretion Hydrochloric acid and pepsinogen are the two principal gastric secretory products capable of inducing mucosal injury. Gastric acid and pepsinogen play a physiologic role in protein digestion; absorption of iron, calcium, magnesium, and vitamin B12; and killing ingested bacteria. Acid secretion should be viewed as occurring under basal and stimulated conditions. Basal acid production occurs in a circadian pattern, with highest levels occurring during the night and lowest levels during the morning hours. Cholinergic input via the vagus nerve and histaminergic input from local gastric sources are the principal contributors to basal acid secretion. Stimulated gastric acid secretion occurs primarily in three phases based on the site where the signal originates (cephalic, gastric, and intestinal). Sight, smell, and taste of food are the components of the cephalic phase, which stimulates gastric secretion via the vagus nerve. The gastric phase is activated


InternalMed_Harrison

InternalMed_Harrison. (cephalic, gastric, and intestinal). Sight, smell, and taste of food are the components of the cephalic phase, which stimulates gastric secretion via the vagus nerve. The gastric phase is activated once food enters the stomach. This component of secretion is driven by nutrients (amino acids and amines) that directly stimulate the G cell to release gastrin, which in turn activates the parietal cell via direct and indirect mechanisms. Distention of the stomach wall also leads to gastrin release and acid production. The last phase of gastric acid secretion is initiated as food enters the intestine and is mediated by luminal distention and nutrient assimilation. A series of pathways that inhibit gastric acid production are also set into motion during these phases. The GI hormone somatostatin is released from endocrine cells found in the gastric mucosa (D cells) in response to HCl. Somatostatin can inhibit acid production by both direct (parietal cell) and indirect mechanisms (decreased


InternalMed_Harrison

InternalMed_Harrison. is released from endocrine cells found in the gastric mucosa (D cells) in response to HCl. Somatostatin can inhibit acid production by both direct (parietal cell) and indirect mechanisms (decreased histamine release from ECL cells and gastrin release from G cells). Additional neural (central and peripheral) and humoral (amylin, atrial natriuretic peptide [ANP], cholecystokinin, ghrelin, interleukin 11 [IL-11], obestatin, secretin, and serotonin) factors play a role in counterbalancing acid secretion. Under physiologic circumstances, these phases occur simultaneously. Ghrelin, the appetite-regulating hormone expressed in Gr cells in the


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InternalMed_Harrison. FIGURE 348-3 Components involved in providing gastroduodenal mucosal defense and repair. CCK, cholecystokinin; CRF, corticotropinreleasing 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.) stomach, may increase gastric acid secretion through stimulation of histamine release from ECL cells, but this remains to be confirmed.


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InternalMed_Harrison. The acid-secreting parietal cell is located in the oxyntic gland, adjacent to other cellular elements (ECL cell, D cell) important in the gastric secretory process (Fig. 348-5). This unique cell also secretes intrinsic factor (IF) and IL-11. The parietal cell expresses receptors for several stimulants of acid secretion, including histamine (H2), gastrin (cholecystokinin B/gastrin receptor), and acetylcholine (muscarinic, M3). Binding of histamine to the H2 receptor leads to activation of adenylate cyclase and an increase in cyclic adenosine monophosphate (AMP). Activation of the gastrin and muscarinic receptors results in activation of the protein kinase C/phosphoinositide signaling pathway. Each of these signaling pathways in turn regulates a series of downstream kinase cascades that control the acid-secreting pump, H+,K+-ATPase. The discovery that different ligands and their corresponding receptors lead to activation of different signaling pathways explains the potentiation of acid


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InternalMed_Harrison. the acid-secreting pump, H+,K+-ATPase. The discovery that different ligands and their corresponding receptors lead to activation of different signaling pathways explains the potentiation of acid secretion that occurs when histamine and gastrin or acetylcholine are combined. More importantly, this observation explains why blocking one receptor type (H2) decreases acid secretion stimulated by agents that activate a different pathway (gastrin, acetylcholine). Parietal cells also express receptors for ligands that inhibit acid production (prostaglandins, somatostatin, and EGF). Histamine also stimulates gastric acid secretion indirectly by activating the histamine H3 receptor on D-cells, which inhibits somatostatin release.


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InternalMed_Harrison. The enzyme H+,K+-ATPase is responsible for generating the large concentration of H+. It is a membrane-bound protein that consists of two subunits, α and β. The active catalytic site is found within the α subunit; the function of the β subunit is unclear. This enzyme uses the 1914 Membrane phospholipids Arachidonic acid Phospholipase A2 Stomach Kidney Platelets Endothelium TXA2, PGI2, PGE2 Gastrointestinal mucosal integrity Platelet aggregation Renal function PGI2, PGE2 Inflammation Mitogenesis Bone formation Other functions? Macrophages Leukocytes Fibroblasts Endothelium COX-1 housekeeping COX-2 inflammation


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InternalMed_Harrison. Gastric ulcers In contrast to DUs, GUs can represent a malignancy and should be biopsied upon discovery. Benign GUs are most often found distal to the junction between the antrum and the acid secretory mucosa. Benign GUs are quite rare in the gastric fundus and are histologically similar to DUs. Benign GUs associated with H. pylori are also associated with antral gastritis. In contrast, NSAID-related GUs are not accompanied by chronic active gastritis but may instead have evidence of a chemical gastropathy, typified by foveolar hyperplasia, edema of the lamina propria, and epithelial regeneration in the absence of H. pylori. Extension of smooth-muscle fibers into the upper portions of the mucosa, where they are not typically found, may also occur.


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InternalMed_Harrison. Pathophysiology • DuoDenal ulcers H. pylori and NSAID-induced injury account for the majority of DUs. Many acid secretory abnormalities have been described in DU patients. Of these, average basal and nocturnal gastric acid secretion appears to be increased in DU patients as compared to controls; however, the level of overlap between DU patients and control subjects is substantial. The reason for this altered secretory process is unclear, but H. pylori infection may contribute. Bicarbonate secretion is significantly decreased in the duodenal bulb of patients with an active DU as compared to control subjects. H. pylori infection may also play a role in this process (see below).


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InternalMed_Harrison. H. pylori infection may also play a role in this process (see below). Gastric ulcers As in DUs, the majority of GUs can be attributed to either H. pylori or NSAID-induced mucosal damage. GUs that occur in the prepyloric area or those in the body associated with a DU or a duodenal scar are similar in pathogenesis to DUs. Gastric acid output (basal and stimulated) tends to be normal or decreased in GU patients. When GUs develop in the presence of minimal acid levels, impairment of mucosal defense factors may be present. GUs have been classified based on their location: Type I occur in the gastric body and tend to be associated with low gastric acid production; type II occur in the antrum and gastric acid can vary from low to normal; type III occur within 3 cm of the pylorus and are commonly accompanied by DUs and normal or high gastric acid production; and type IV are found in the cardia and are associated with low gastric acid production.


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InternalMed_Harrison. H.pylori anD aciD peptic DisorDers Gastric infection with the bacterium H. pylori accounts for the majority of PUD (Chap. 188). This organism also plays a role in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma. Although the entire genome of H. pylori has been sequenced, it is still not clear how this organism, which resides in the stomach, causes ulceration in the duodenum, or whether its eradication will lead to a decrease in gastric cancer.


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InternalMed_Harrison. the bacterium The bacterium, initially named Campylobacter pyloridis, is a gram-negative microaerophilic rod found most commonly in the deeper portions of the mucous gel coating the gastric mucosa or between the mucous layer and the gastric epithelium. It may attach to gastric epithelium but under normal circumstances does not appear to invade cells. It is strategically designed to live within the aggressive environment of the stomach. It is S-shaped (~0.5–3 μm in size) and contains multiple sheathed flagella. Initially, H. pylori resides in the antrum but, over time, migrates toward the more proximal segments of the stomach. The organism is capable of transforming into a coccoid form, which represents a dormant state that may facilitate survival in adverse conditions. The genome of H. pylori (1.65 million base pairs) encodes ~1500 proteins. Among this multitude of proteins there are factors that are essential determinants of H. pylori–mediated pathogenesis and colonization such as


InternalMed_Harrison

InternalMed_Harrison. pylori (1.65 million base pairs) encodes ~1500 proteins. Among this multitude of proteins there are factors that are essential determinants of H. pylori–mediated pathogenesis and colonization such as the outer membrane protein (Hop proteins), urease, and the vacuolating cytotoxin (Vac A). Moreover, the majority of H. pylori strains contain a genomic fragment that encodes the cag pathogenicity island (cag-PAI). Several of the genes that make up cag-PAI encode components of a type IV secretion island that translocates Cag A into host cells. Once in the cell, Cag A activates a series of cellular events important in cell growth and cytokine production. H. pylori also has extensive genetic diversity that in turn enhances its ability to promote disease. The first step in infection by H. pylori is dependent on the bacteria’s motility and its ability to produce urease. Urease produces ammonia from urea, an essential 1915 step in alkalinizing the surrounding pH. Additional bacterial factors


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InternalMed_Harrison. is dependent on the bacteria’s motility and its ability to produce urease. Urease produces ammonia from urea, an essential 1915 step in alkalinizing the surrounding pH. Additional bacterial factors include catalase, lipase, adhesins, platelet-activating factor, and pic B (induces cytokines). Multiple strains of H. pylori exist and are characterized by their ability to express several of these factors (Cag A, Vac A, etc.). It is possible that the different diseases related to H. pylori infection can be attributed to different strains of the organism with distinct pathogenic features.


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InternalMed_Harrison. epidemiology The prevalence of H. pylori varies throughout the world and depends largely on the overall standard of living in the region. In developing parts of the world, 80% of the population may be infected by the age of 20, whereas the prevalence is 20–50% in industrialized countries. In contrast, in the United States this organism is rare in childhood. The overall prevalence of H. pylori in the United States is ~30%, with individuals born before 1950 having a higher rate of infection than those born later. About 10% of Americans <30 years of age are colonized with the bacteria. The rate of infection with H. pylori in industrialized countries has decreased substantially in recent decades.


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InternalMed_Harrison. The steady increase in the prevalence of H. pylori noted with increasing age is due primarily to a cohort effect, reflecting higher transmission during a period in which the earlier cohorts were children. It has been calculated through mathematical models that improved sanitation during the latter half of the nineteenth century dramatically decreased transmission of H. pylori. Moreover, with the present rate of intervention, the organism will be ultimately eliminated from the United States. Two factors that predispose to higher colonization rates include poor socioeconomic status and less education. These factors, not race, are responsible for the rate of H. pylori infection in blacks and Hispanic Americans being double the rate seen in whites of comparable age. Other risk factors for H. pylori infection are (1) birth or residence in a developing country, (2) domestic crowding, (3) unsanitary living conditions, (4) unclean food or water, and (5) exposure to gastric contents of an


InternalMed_Harrison

InternalMed_Harrison. H. pylori infection are (1) birth or residence in a developing country, (2) domestic crowding, (3) unsanitary living conditions, (4) unclean food or water, and (5) exposure to gastric contents of an infected individual.


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InternalMed_Harrison. Transmission of H. pylori occurs from person to person, following an oral-oral or fecal-oral route. The risk of H. pylori infection is declining in developing countries. The rate of infection in the United States has fallen by >50% when compared to 30 years ago. pathophysiology H. pylori infection is virtually always associated with a chronic active gastritis, but only 10–15% of infected individuals develop frank peptic ulceration. The basis for this difference is unknown, but is likely due to a combination of host and bacterial factors some of which are outlined below. Initial studies suggested that >90% of all DUs were associated with H. pylori, but H. pylori is present in only 30–60% of individuals with GUs and 50–70% of patients with DUs. The pathophysiology of ulcers not associated with H. pylori or NSAID ingestion (or the rare Zollinger-Ellison syndrome [ZES]) is becoming more relevant as the incidence of H. pylori is dropping, particularly in the Western world (see below).


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InternalMed_Harrison. The particular end result of H. pylori infection (gastritis, PUD, gastric MALT lymphoma, gastric cancer) is determined by a complex interplay between bacterial and host factors (Fig. 348-6). 1. Bacterial factors: H. pylori is able to facilitate gastric residence, induce mucosal injury, and avoid host defense. Different strains of


InternalMed_Harrison

InternalMed_Harrison. H. pylori produce different virulence factors. A specific region of the bacterial genome, the pathogenicity island (cag-PAI), encodes the virulence factors Cag A and pic B. Vac A also contributes to pathogenicity, although it is not encoded within the pathogenicity island. These virulence factors, in conjunction with additional bacterial constituents, can cause mucosal damage, in part through their ability to target the host immune cells. For example, Vac A targets human CD4 T cells, inhibiting their proliferation and in addition can disrupt normal function of B cells, CD8 T cells, macrophages, and mast cells. Multiple studies have demonstrated that H. pylori strains that are cag-PAI positive are associated with a higher risk of PUD, premalignant gastric lesions, and gastric cancer than are strains that lack the cag-PAI. In addition, H. pylori may directly inhibit parietal cell H+,K+-ATPase activity through a


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InternalMed_Harrison. Bacterial factors Structure Adhesins Porins Enzymes (urease, vac A, cag A, etc.) Host factors Duration Location Inflammatory response Genetics?? FIGURE 348-6 Outline of the bacterial and host factors important in determining H. pylori–induced gastrointestinal disease. MALT, mucosal-associated lymphoid tissue.


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InternalMed_Harrison. FIGURE 348-6 Outline of the bacterial and host factors important in determining H. pylori–induced gastrointestinal disease. MALT, mucosal-associated lymphoid tissue. Cag A–dependent mechanism, leading in part to the low acid production observed after acute infection with the organism. Urease, which allows the bacteria to reside in the acidic stomach, generates NH3, which can damage epithelial cells. The bacteria produce surface factors that are chemotactic for neutrophils and monocytes, which in turn contribute to epithelial cell injury (see below). H. pylori makes proteases and phospholipases that break down the glycoprotein lipid complex of the mucous gel, thus reducing the efficacy of this first line of mucosal defense. H. pylori expresses adhesins (OMPs like BabA), which facilitate attachment of the bacteria to gastric epithelial cells. Although lipopolysaccharide (LPS) of gram-negative bacteria often plays an important role in the infection,


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InternalMed_Harrison. H. pylori LPS has low immunologic activity compared to that of other organisms. It may promote a smoldering chronic inflammation.


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InternalMed_Harrison. 2. Host factors: Studies in twins suggest that there may be genetic predisposition to acquire H. pylori. The inflammatory response to H. pylori includes recruitment of neutrophils, lymphocytes (T and B), macrophages, and plasma cells. The pathogen leads to local injury by binding to class II major histocompatibility complex (MHC) molecules expressed on gastric epithelial cells, leading to cell death (apoptosis). Moreover, bacterial strains that encode cag-PAI can introduce Cag A into the host cells, leading to further cell injury and activation of cellular pathways involved in cytokine production and repression of tumor-suppressor genes. Elevated concentrations of multiple cytokines are found in the gastric epithelium of H. pylori–infected individuals, including interleukin (IL) 1α/β, IL-2, IL-6, IL-8, tumor necrosis factor (TNF) α, and interferon (IFN) γ. H. pylori infection also leads to both a mucosal and a systemic humoral response, which does not lead to eradication of the


InternalMed_Harrison

InternalMed_Harrison. IL-2, IL-6, IL-8, tumor necrosis factor (TNF) α, and interferon (IFN) γ. H. pylori infection also leads to both a mucosal and a systemic humoral response, which does not lead to eradication of the bacteria but further compounds epithelial cell injury. Additional mechanisms by which H. pylori may cause epithelial cell injury include (1) activated neutrophil-mediated production of reactive oxygen or nitrogen species and enhanced epithelial cell turnover and (2) apoptosis related to interaction with T cells (T helper 1, or TH1, cells) and IFN-γ. Finally, the human stomach can be colonized by a host of commensal organisms that may affect the likelihood of


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InternalMed_Harrison. H. pylori–mediated mucosal injury. The reason for H. pylori–mediated duodenal ulceration remains unclear. Studies suggest that H. pylori associated with duodenal ulceration may be more virulent. In addition, certain specific bacterial factors such as the DU-promoting gene A (dupA), may be associated with the development of DUs. Another potential contributing factor is that gastric metaplasia in the duodenum of DU patients, which may be due to high acid exposure (see below), permits H. pylori to bind to it and produce local injury secondary to the host response. Another hypothesis is that H. pylori antral infection could lead to increased


InternalMed_Harrison

InternalMed_Harrison. Vagus Acetylcholine Histamine Histamine H, K ATPase Tubulovesicles Somatostatin Somatostatin ECL cell Gastrin ECL cell D cell Canaliculus Blood vessel Gastrin D cell G cell ANTRUMSomatostatin + + – – + + + – FIGURE 348-7 Summary of potential mechanisms by which H. pylori may lead to gastric secretory abnormalities. D, somatostatin cell; ECL, enterochromaffin-like cell; G, G cell. (Adapted from J Calam et al: Gastroenterology 113:543, 1997.) acid production, increased duodenal acid, and mucosal injury. Basal and stimulated (meal, gastrin-releasing peptide [GRP]) gastrin release are increased in H. pylori–infected individuals, and somatostatinsecreting D cells may be decreased. H. pylori infection might induce increased acid secretion through both direct and indirect actions of H. pylori and proinflammatory cytokines (IL-8, TNF, and IL-1) on G, D, and parietal cells (Fig. 348-7). GUs, in contrast, are associated with


InternalMed_Harrison

InternalMed_Harrison. H. pylori and proinflammatory cytokines (IL-8, TNF, and IL-1) on G, D, and parietal cells (Fig. 348-7). GUs, in contrast, are associated with H. pylori–induced pangastritis and normal or low gastric acid secretion. H. pylori infection has also been associated with decreased duodenal mucosal bicarbonate production. Data supporting and contradicting each of these interesting theories have been demonstrated. Thus, the mechanism by which H. pylori infection of the stomach leads to duodenal ulceration remains to be established. In summary, the final effect of H. pylori on the GI tract is variable and determined by microbial and host factors. The type and distribution of gastritis correlate with the ultimate gastric and duodenal pathology observed. Specifically, the presence of antral-predominant gastritis is associated with DU formation; gastritis involving primarily the corpus predisposes to the development of GUs, gastric atrophy, and ultimately gastric carcinoma (Fig. 348-8).


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InternalMed_Harrison. nsaiD-inDuceD Disease epidemiology NSAIDs represent a group of the most commonly used medications in the United States. More than 30 billion over-thecounter tablets and over 100 million prescriptions are sold yearly in the United States alone. In fact, after the introduction of COX-2 inhibitors in the year 2000, the number of prescriptions written for NSAIDs was >111 million at a cost of $4.8 billion. Side effects and complications due to NSAIDs are considered the most common drug-related toxicities in the United States. The spectrum of NSAID-induced morbidity ranges from nausea and dyspepsia (prevalence reported as high as 50–60%) to a serious GI complication such as endoscopy-documented peptic ulceration (15–30% of individuals taking NSAIDs regularly) complicated by bleeding or perforation in as many as 1.5% of users per year. It is estimated that NSAID-induced GI bleeding accounts for 60,000–120,000 hospital admissions per year, and deaths related to NSAID-induced toxicity may be


InternalMed_Harrison

InternalMed_Harrison. in as many as 1.5% of users per year. It is estimated that NSAID-induced GI bleeding accounts for 60,000–120,000 hospital admissions per year, and deaths related to NSAID-induced toxicity may be as high as 16,000 per year in the United States. Approximately 4–5% of patients develop symptomatic ulcers within 1 year. Unfortunately, dyspeptic symptoms do not correlate with NSAID-induced pathology. Over 80% of patients with serious NSAID-related complications did not have preceding dyspepsia.


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InternalMed_Harrison. High level of acid production Duodenal ulcer Normal gastric H. pylori H. pylori H.pylori Low level of acid production Gastric cancer FIGURE 348-8 Natural history of H. pylori infection. MALT, mucosalassociated lymphoid tissue. (Used with permission from S Suerbaum, P Michetti: N Engl J Med 347:1175, 2002.)


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InternalMed_Harrison. In view of the lack of warning signs, it is important to identify patients who are at increased risk for morbidity and mortality related to NSAID usage. Even 75 mg/d of aspirin may lead to serious GI ulceration; thus, no dose of NSAID is completely safe. In fact, the incidence of mucosal injury (ulcers and erosions) in patients taking low-dose aspirin (75–325 mg) has been estimated to range from as low as 8% to as high as 60%. It appears that H. pylori infection increases the risk of PUD-associated GI bleeding in chronic users of low-dose aspirin. Established risk factors include advanced age, history of ulcer, concomitant use of glucocorticoids, high-dose NSAIDs, multiple NSAIDs, concomitant use of anticoagulants, clopidogrel, and serious or multisystem disease. Possible risk factors include concomitant infection with H. pylori, cigarette smoking, and alcohol consumption.


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InternalMed_Harrison. pathophysiology Prostaglandins play a critical role in maintaining gastroduodenal mucosal integrity and repair. It therefore follows that interruption of prostaglandin synthesis can impair mucosal defense and repair, thus facilitating mucosal injury via a systemic mechanism. Animal studies have demonstrated that neutrophil adherence to the gastric microcirculation plays an essential role in the initiation of NSAID-induced mucosal injury. A summary of the pathogenetic pathways by which systemically administered NSAIDs may lead to mucosal injury is shown in Fig. 348-9. Single nucleotide polymorphisms (SNPs) have been found in several genes, including those encoding certain subtypes of cytochrome P450 (see below), interleukin-1β (IL-1β), angiotensinogen (AGT), and an organic ion transporting polypeptide (SLCO1B1), but these findings need confirmation in larger scale studies.


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InternalMed_Harrison. Injury to the mucosa also occurs as a result of the topical encounter with NSAIDs. Aspirin and many NSAIDs are weak acids that remain in a nonionized lipophilic form when found within the acid environment of the stomach. Under these conditions, NSAIDs migrate across lipid membranes of epithelial cells, leading to cell injury once trapped intracellularly in an ionized form. Topical NSAIDs can also alter the surface mucous layer, permitting back diffusion of H+ and pepsin, leading to further epithelial cell damage. Moreover, enteric-coated or buffered preparations are also associated with risk of peptic ulceration.


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InternalMed_Harrison. The interplay between H. pylori and NSAIDs in the pathogenesis of PUD is complex. Meta-analysis supports the conclusion that each of these aggressive factors is independent and synergistic risk factors for PUD and its complications such as GI bleeding. For example, eradication of H. pylori reduces the likelihood of GI complications in high-risk individuals to levels observed in individuals with average risk of NSAID-induced complications.


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InternalMed_Harrison. Endothelial effects • Stasis IschemiaULCER EROSIONS HEALING (spontaneous or therapeutic) Epithelial effects (due to prostaglandin depletion) • ˜HCl secretion • °Mucin secretion • °HCO3 – secretion • °Surface active phospholipid secretion • °Epithelial cell proliferation • Direct toxicity “ion trapping” Acid FIGURE 348-9 Mechanisms by which nonsteroidal anti-inflammatory drugs may induce mucosal injury. (Adapted from J Scheiman et al: J Clin Outcomes Management 3:23, 1996. Copyright 2003 Turner White Communications, Inc., www.turner-white.com. Used with permission.) patHoGenetic factors unrelateD to H. pylori anD nsaiDs in aciD peptic Disease Cigarette smoking has been implicated in the pathogenesis of PUD. Not only have smokers been found to have ulcers more frequently than do nonsmokers, but smoking appears to decrease healing rates, impair response to therapy, and increase ulcer-related complications such as perforation. The mechanism responsible for increased ulcer diathesis in


InternalMed_Harrison

InternalMed_Harrison. but smoking appears to decrease healing rates, impair response to therapy, and increase ulcer-related complications such as perforation. The mechanism responsible for increased ulcer diathesis in smokers is unknown. Theories have included altered gastric emptying, decreased proximal duodenal bicarbonate production, increased risk for H. pylori infection, and cigarette-induced generation of noxious mucosal free radicals. Genetic predisposition may play a role in ulcer development. First-degree relatives of DU patients are three times as likely to develop an ulcer; however, the potential role of H. pylori infection in contacts is a major consideration. Increased frequencies of blood group O and of the nonsecretor status have also been implicated as genetic risk factors for peptic diathesis. However, H. pylori preferentially binds to group O antigens. Additional genetic factors have been postulated to predispose certain individuals to developing PUD and/or upper GI bleeding.


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InternalMed_Harrison. diathesis. However, H. pylori preferentially binds to group O antigens. Additional genetic factors have been postulated to predispose certain individuals to developing PUD and/or upper GI bleeding. Specifically, genes encoding the NSAID-metabolizing enzymes cytochrome P450 2C9 and 2C8 (CYP2C9 and CYP2C8) are potential susceptibility genes for NSAID-induced PUD, but unfortunately, the studies have not been consistent in demonstrating this association. In a United Kingdom study, the CYP2C19*17 gain-of-function polymorphism was associated with PUD in a Caucasian cohort, irrespective of ulcer etiology. These findings need to be confirmed in broader studies. Psychological stress has been thought to contribute to PUD, but studies examining the role of psychological factors in its pathogenesis have generated conflicting results. Although PUD is associated with certain personality traits (neuroticism), these same traits are also present in individuals with nonulcer dyspepsia (NUD) and other


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InternalMed_Harrison. have generated conflicting results. Although PUD is associated with certain personality traits (neuroticism), these same traits are also present in individuals with nonulcer dyspepsia (NUD) and other functional and organic disorders.


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InternalMed_Harrison. Diet has also been thought to play a role in peptic diseases. Certain foods and beverages can cause dyspepsia, but no convincing studies indicate an association between ulcer formation and a specific diet. Specific chronic disorders have been shown to have a strong association with PUD: (1) advanced age, (2) chronic pulmonary disease, (3) chronic renal failure, (4) cirrhosis, (5) nephrolithiasis, (6) α1antitrypsin deficiency, and (7) systemic mastocytosis. Disorders with a possible association are (1) hyperparathyroidism, (2) coronary artery disease, (3) polycythemia vera, (4) chronic pancreatitis, (5) former alcohol use, (6) obesity, (7) African-American race, and (8) three or more doctor visits in a year. Multiple factors play a role in the pathogenesis of PUD. The two predominant causes are H. pylori infection and NSAID ingestion. PUD CAuSES of ulCERS noT CAuSED By HELICOBACTER PYLORI AnD nSAiDs Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease


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InternalMed_Harrison. CAuSES of ulCERS noT CAuSED By HELICOBACTER PYLORI AnD nSAiDs Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease Bisphosphonates Chemotherapy Clopidogrel Crack cocaine Glucocorticoids (when combined with NSAIDs) Mycophenolate mofetil Potassium chloride Duodenal obstruction (e.g., annular pancreas) Idiopathic hypersecretory state Abbreviations: Hp, H. pylori; NSAIDs, nonsteroidal anti-inflammatory drugs. not related to H. pylori or NSAIDs is increasing. Other less common causes of PUD are shown in Table 348-1. These etiologic agents should be considered as the incidence of H. pylori is decreasing. Independent of the inciting or injurious agent, peptic ulcers develop as a result of an imbalance between mucosal protection/repair and aggressive factors. Gastric acid plays an important role in mucosal injury.


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InternalMed_Harrison. CLINICAL FEATURES History Abdominal pain is common to many GI disorders, including DU and GU, but has a poor predictive value for the presence of either DU or GU. Up to 10% of patients with NSAID-induced mucosal disease can present with a complication (bleeding, perforation, and obstruction) without antecedent symptoms. Despite this poor correlation, a careful history and physical examination are essential components of the approach to a patient suspected of having peptic ulcers.


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InternalMed_Harrison. Epigastric pain described as a burning or gnawing discomfort can be present in both DU and GU. The discomfort is also described as an ill-defined, aching sensation or as hunger pain. The typical pain pattern in DU occurs 90 minutes to 3 hours after a meal and is frequently relieved by antacids or food. Pain that awakes the patient from sleep (between midnight and 3 A.M.) is the most discriminating symptom, with two-thirds of DU patients describing this complaint. Unfortunately, this symptom is also present in one-third of patients with NUD (see below). Elderly patients are less likely to have abdominal pain as a manifestation of PUD and may instead present with a complication such as ulcer bleeding or perforation. The pain pattern in GU patients may be different from that in DU patients, where discomfort may actually be precipitated by food. Nausea and weight loss occur more commonly in GU patients. Endoscopy detects ulcers in <30% of patients who have dyspepsia.


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InternalMed_Harrison. The mechanism for development of abdominal pain in ulcer patients is unknown. Several possible explanations include acid-induced activation of chemical receptors in the duodenum, enhanced duodenal sensitivity to bile acids and pepsin, or altered gastroduodenal motility. Variation in the intensity or distribution of the abdominal pain, as well as the onset of associated symptoms such as nausea and/or vomiting, may be indicative of an ulcer complication. Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (pancreas). Sudden onset of severe, generalized abdominal pain may indicate perforation. Pain worsening with meals, nausea, and vomiting of undigested food suggest gastric outlet obstruction. Tarry stools or coffee-ground emesis indicate bleeding.


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InternalMed_Harrison. Physical examination Epigastric tenderness is the most frequent finding in patients with GU or DU. Pain may be found to the right of the midline in 20% of patients. Unfortunately, the predictive value of this finding is rather low. Physical examination is critically important for discovering evidence of ulcer complication. Tachycardia and orthostasis suggest dehydration secondary to vomiting or active GI blood loss. A severely tender, board-like abdomen suggests a perforation. Presence of a succussion splash indicates retained fluid in the stomach, suggesting gastric outlet obstruction.


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InternalMed_Harrison. PUD-Related Complications • Gastrointestinal bleeDinG GI bleeding is the most common complication observed in PUD. Bleeding is estimated to occur in 19.4–57 per 100,000 individuals in a general population or in approximately 15% of patients. Bleeding and complications of ulcer disease occur more often in individuals >60 years of age. The 30-day mortality rate is as high as 5–10%. The higher incidence in the elderly is likely due to the increased use of NSAIDs in this group. In addition, up to 80% of the mortality in PUD-related bleeding is due to nonbleeding causes such as multiorgan failure (24%), pulmonary complications (24%), and malignancy (34%). Up to 20% of patients with ulcer-related hemorrhage bleed without any preceding warning signs or symptoms.


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InternalMed_Harrison. Up to 20% of patients with ulcer-related hemorrhage bleed without any preceding warning signs or symptoms. perforation The second most common ulcer-related complication is perforation, being reported in as many as 6–7% of PUD patients with an estimated 30-day mortality of over 20%. As in the case of bleeding, the incidence of perforation in the elderly appears to be increasing secondary to increased use of NSAIDs. Penetration is a form of perforation in which the ulcer bed tunnels into an adjacent organ. DUs tend to penetrate posteriorly into the pancreas, leading to pancreatitis, whereas GUs tend to penetrate into the left hepatic lobe. Gastrocolic fistulas associated with GUs have also been described.


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InternalMed_Harrison. Gastric outlet obstruction Gastric outlet obstruction is the least common ulcer-related complication, occurring in 1–2% of patients. A patient may have relative obstruction secondary to ulcer-related inflammation and edema in the peripyloric region. This process often resolves with ulcer healing. A fixed, mechanical obstruction secondary to scar formation in the peripyloric areas is also possible. The latter requires endoscopic (balloon dilation) or surgical intervention. Signs and symptoms relative to mechanical obstruction may develop insidiously. New onset of early satiety, nausea, vomiting, increase of postprandial abdominal pain, and weight loss should make gastric outlet obstruction a possible diagnosis.


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InternalMed_Harrison. Differential Diagnosis The list of GI and non-GI disorders that can mimic ulceration of the stomach or duodenum is quite extensive. The most commonly encountered diagnosis among patients seen for upper abdominal discomfort is NUD. NUD, also known as functional dyspepsia or essential dyspepsia, refers to a group of heterogeneous disorders typified by upper abdominal pain without the presence of an ulcer. Dyspepsia has been reported to occur in up to 30% of the U.S. population. Up to 60% of patients seeking medical care for dyspepsia have a negative diagnostic evaluation. The etiology of NUD is not established, and the potential role of H. pylori in NUD remains controversial. Several additional disease processes that may present with “ulcerlike” symptoms include proximal GI tumors, gastroesophageal reflux, vascular disease, pancreaticobiliary disease (biliary colic, chronic pancreatitis), and gastroduodenal Crohn’s disease.


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InternalMed_Harrison. Diagnostic Evaluation In view of the poor predictive value of abdominal pain for the presence of a gastroduodenal ulcer and the multiple disease processes that can mimic this disease, the clinician is often confronted with having to establish the presence of an ulcer. Documentation of an ulcer requires either a radiographic (barium study) or an endoscopic procedure. However, a large percentage of patients with symptoms suggestive of an ulcer have NUD; testing for H. pylori and antibiotic therapy (see below) is appropriate for individuals who are otherwise healthy and <45 years of age, before embarking on a diagnostic evaluation (Chap. 54). FIGURE 348-10 Barium study demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.


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InternalMed_Harrison. Barium studies of the proximal GI tract are still occasionally used as a first test for documenting an ulcer. The sensitivity of older single-contrast barium meals for detecting a DU is as high as 80%, with a double-contrast study providing detection rates as high as 90%. Sensitivity for detection is decreased in small ulcers (<0.5 cm), with presence of previous scarring, or in postoperative patients. A DU appears as a well-demarcated crater, most often seen in the bulb (Fig. 348-10A). A GU may represent benign or malignant disease. Typically, a benign GU also appears as a discrete crater with radiating mucosal folds originating from the ulcer margin (Fig. 348-10B). Ulcers >3 cm in size or those associated with a mass are more often malignant. Unfortunately, up to 8% of GUs that appear to be benign by radiographic appearance are malignant by endoscopy or surgery. Radiographic studies that show a GU must be followed by endoscopy and biopsy.


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InternalMed_Harrison. Endoscopy provides the most sensitive and specific approach for examining the upper GI tract (Fig. 34811). In addition to permitting direct visualization of the mucosa, endoscopy facilitates photographic documentation of a mucosal defect and tissue biopsy to rule out malignancy (GU) or H. pylori. Endoscopic examination is particularly helpful in identifying lesions too small to detect by radiographic examination, for evaluation of atypical radiographic abnormalities, or to determine if an ulcer is a source of blood loss. Although the methods for diagnosing H. pylori are outlined in Chap. 181, a brief summary will be included here (Table 348-2). Several biopsy urease tests have been developed (PyloriTek, CLOtest, Hpfast, Pronto Dry) that have a sensitivity and specificity of >90–95%. Several noninvasive methods for detecting this organism have been developed. Three types of studies routinely used include serologic testing, the 13Cor 14C-urea breath test, and the fecal


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InternalMed_Harrison. H. pylori (Hp) antigen test. A urinary Hp antigen test, as well as a refined monoclonal antibody stool antigen test, appears promising. Occasionally, specialized testing such as serum gastrin and gastric acid analysis or sham feeding may be needed in individuals with complicated or refractory PUD (see “Zollinger-Ellison Syndrome [ZES],” below). Screening for aspirin or NSAIDs (blood or urine) may also be necessary in refractory H. pylori–negative PUD patients. Before the discovery of H. pylori, the therapy of PUD was centered on the old dictum by Schwartz of “no acid, no ulcer.” Although acid secretion is still important in the pathogenesis of PUD, eradication of H. pylori and therapy/prevention of NSAID-induced disease is the mainstay of treatment. A summary of commonly used drugs for treatment of acid peptic disorders is shown in Table 348-3.


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InternalMed_Harrison. ACID-NEUTRALIZING/INHIBITORY DRUGS Antacids Before we understood the important role of histamine in stimulating parietal cell activity, neutralization of secreted acid with antacids constituted the main form of therapy for peptic FIGURE 348-11 Endoscopy demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer. TABlE 348-2 TESTS foR DETECTion of H. PYLORI Sensitivity/ Test Specificity, % Comments Rapid urease 80–95/95–100 Simple, false negative with recent use of PPIs, antibiotics, or bismuth compounds Culture —/— Time-consuming, expensive, dependent on experience; allows determination of antibiotic susceptibility Serology >80/>90 Inexpensive, convenient; not useful for early follow-up Urea breath test >90/>90 Simple, rapid; useful for early follow-up; false negatives with recent therapy (see rapid urease test); exposure to low-dose radiation with 14C test Stool antigen >90/>90 Inexpensive, convenient Abbreviation: PPIs, proton pump inhibitors.


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InternalMed_Harrison. Stool antigen >90/>90 Inexpensive, convenient Abbreviation: PPIs, proton pump inhibitors. ulcers. They are now rarely, if ever, used as the primary therapeutic agent but instead are often used by patients for symptomatic relief of dyspepsia. The most commonly used agents are mixtures of aluminum hydroxide and magnesium hydroxide. Aluminum hydroxide can produce constipation and phosphate depletion; magnesium hydroxide may cause loose stools. Many of the commonly used antacids (e.g., Maalox, Mylanta) have a combination of both aluminum and magnesium hydroxide in order to avoid these side effects. The magnesium-containing preparation should not be used in chronic renal failure patients because of possible hypermagnesemia, and aluminum may cause chronic neurotoxicity in these patients.


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InternalMed_Harrison. Calcium carbonate and sodium bicarbonate are potent antacids with varying levels of potential problems. The long-term use of calcium carbonate (converts to calcium chloride in the stomach) can lead to milk-alkali syndrome (hypercalcemia, hyperphosphatemia with possible renal calcinosis and progression to renal insufficiency). Sodium bicarbonate may induce systemic alkalosis. H2 Receptor Antagonists Four of these agents are presently available (cimetidine, ranitidine, famotidine, and nizatidine), and their structures share homology with histamine. Although each has different potency, all will significantly inhibit basal and stimulated acid secretion to comparable levels when used at therapeutic doses. Moreover, similar ulcer-healing rates are achieved with each drug when used at the correct dosage. Presently, this class of drug is often used for treatment of active ulcers (4–6 weeks) in combination with antibiotics directed at eradicating H. pylori (see below).


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InternalMed_Harrison. Cimetidine was the first H2 receptor antagonist used for the treatment of acid peptic disorders. The initial recommended dosing profile for cimetidine was 300 mg qid. Subsequent studies have documented the efficacy of using 800 mg at bedtime for treatment of active ulcer, with healing rates approaching 80% at 4 weeks. Cimetidine may have weak antiandrogenic side effects resulting in reversible gynecomastia and impotence, primarily in patients receiving high doses for prolonged periods of time (months to years, as in ZES). In view of cimetidine’s ability to inhibit cytochrome P450, careful monitoring of drugs such as warfarin, phenytoin, and theophylline is indicated with long-term usage. Other rare reversible adverse effects reported with cimetidine include confusion and elevated levels of serum aminotransferases, creatinine, and serum prolactin. Ranitidine, famotidine, and nizatidine are more potent H2 receptor antagonists than cimetidine. Each can be used once a day at bedtime for


InternalMed_Harrison

InternalMed_Harrison. of serum aminotransferases, creatinine, and serum prolactin. Ranitidine, famotidine, and nizatidine are more potent H2 receptor antagonists than cimetidine. Each can be used once a day at bedtime for ulcer prevention, which was commonly done before the discovery of H. pylori and the development of proton pump inhibitors (PPIs). Patients may develop tolerance to H2 blockers, a rare event with PPIs (see below). Comparable nighttime dosing regimens are ranitidine 300 mg, famotidine 40 mg, and nizatidine 300 mg.


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InternalMed_Harrison. Additional rare, reversible systemic toxicities reported with H2 receptor antagonists include pancytopenia, neutropenia, anemia, and thrombocytopenia, with a prevalence rate varying from 0.01– 0.2%. Cimetidine and ranitidine (to a lesser extent) can bind to hepatic cytochrome P450; famotidine and nizatidine do not.


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InternalMed_Harrison. Proton Pump (H+,K+-ATPase) Inhibitors Omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole are substituted benzimidazole derivatives that covalently bind and irreversibly inhibit H+,K+-ATPase. Esomeprazole, one of the newest members of this drug class, is the S-enantiomer of omeprazole, which is a racemic mixture of both Sand R-optical isomers. The R-isomer of lansoprazole, dexlansoprazole, is the most recent PPI approved for clinical use. Its reported advantage is a dual delayed-release system, aimed at improving treatment of gastroesophageal reflux disease (GERD). These are the most potent acid inhibitory agents available. Omeprazole and lansoprazole are the PPIs that have been used for the longest time. Both are acid-labile and are administered as enteric-coated granules in a sustained-release capsule that dissolves within the small intestine at a pH of 6. Lansoprazole is available in an orally disintegrating tablet that can be taken with or without water, an


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InternalMed_Harrison. in a sustained-release capsule that dissolves within the small intestine at a pH of 6. Lansoprazole is available in an orally disintegrating tablet that can be taken with or without water, an advantage for individuals who have significant dysphagia. Absorption kinetics are similar to the capsule. In addition, a lansoprazole-naproxen combination preparation that has been made available is targeted at decreasing NSAID-related GI injury (see below). Omeprazole is available as nonenteric-coated granules mixed with sodium bicarbonate in a powder form that can be administered orally or via gastric tube. The sodium bicarbonate has two purposes: to protect the omeprazole from acid degradation and to promote rapid gastric alkalinization and subsequent proton pump activation, which facilitates rapid action of the PPI. Pantoprazole and rabeprazole are available as enteric-coated tablets. Pantoprazole is also available as a parenteral formulation for intravenous use. These agents are lipophilic


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InternalMed_Harrison. action of the PPI. Pantoprazole and rabeprazole are available as enteric-coated tablets. Pantoprazole is also available as a parenteral formulation for intravenous use. These agents are lipophilic compounds; upon entering the parietal cell, they are protonated and trapped within the acid environment of the tubulovesicular and canalicular system. These agents potently inhibit all phases of gastric acid secretion. Onset of action is rapid, with a maximum acid inhibitory effect between 2 and 6 h after administration and duration of inhibition lasting up to 72–96 h. With repeated daily dosing, progressive acid inhibitory effects are observed, with basal and secretagogue-stimulated acid production being inhibited by >95% after 1 week of therapy. The half-life of PPIs is ~18 h; thus, it can take between 2 and 5 days for gastric acid secretion to return to normal levels once these drugs have been discontinued. Because the pumps need to be activated for these agents to be effective, their


InternalMed_Harrison

InternalMed_Harrison. take between 2 and 5 days for gastric acid secretion to return to normal levels once these drugs have been discontinued. Because the pumps need to be activated for these agents to be effective, their efficacy is maximized if they are administered before a meal (except for the immediate-release formulation of omeprazole) (e.g., in the morning before breakfast). Mild to moderate hypergastrinemia has been observed in patients taking these drugs. Carcinoid tumors developed in some animals given the drugs preclinically; however, extensive experience has failed to demonstrate gastric carcinoid tumor development in humans. Serum gastrin levels return to normal levels within 1–2 weeks after drug cessation. Rebound gastric acid hypersecretion has been described in H. pylori–negative individuals after discontinuation of PPIs. It occurs even after relatively short-term usage (2 months) and may last for up to 2 months after the PPI has been discontinued. The mechanism involves gastrininduced


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InternalMed_Harrison. after discontinuation of PPIs. It occurs even after relatively short-term usage (2 months) and may last for up to 2 months after the PPI has been discontinued. The mechanism involves gastrininduced hyperplasia and hypertrophy of histamine-secreting ECL cells. The clinical relevance of this observation is that individuals may have worsening symptoms of GERD or dyspepsia upon stopping the PPI. Gradual tapering of the PPI and switching to an H2 receptor antagonist may prevent this from occurring. H. pylori– induced inflammation and concomitant decrease in acid production may explain why this does not occur in H. pylori–positive patients. IF production is also inhibited, but vitamin B12-deficiency anemia is uncommon, probably because of the large stores of the vitamin. As with any agent that leads to significant hypochlorhydria, PPIs may interfere with absorption of drugs such as ketoconazole, ampicillin, iron, and digoxin. Hepatic cytochrome P450 can be inhibited by the earlier PPIs


InternalMed_Harrison

InternalMed_Harrison. leads to significant hypochlorhydria, PPIs may interfere with absorption of drugs such as ketoconazole, ampicillin, iron, and digoxin. Hepatic cytochrome P450 can be inhibited by the earlier PPIs (omeprazole, lansoprazole). Rabeprazole, pantoprazole, and esomeprazole do not appear to interact significantly with drugs metabolized by the cytochrome P450 system. The overall clinical significance of this observation is not definitely established. Caution should be taken when using theophylline, warfarin, diazepam, atazanavir, and phenytoin concomitantly with PPIs. Long-term acid suppression, especially with PPIs, has been associated with a higher incidence of community-acquired pneumonia as well as community and hospital acquired Clostridium difficile–associated disease. These observations require confirmation but should alert the practitioner to take caution when recommending these agents for long-term use, especially in elderly patients at risk for developing pneumonia or C. difficile


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InternalMed_Harrison. confirmation but should alert the practitioner to take caution when recommending these agents for long-term use, especially in elderly patients at risk for developing pneumonia or C. difficile infection. A population-based study revealed that long-term use of PPIs was associated with the development of hip fractures in older women. The absolute risk of fracture remained low despite an observed increase associated with the dose and duration of acid suppression. The mechanism for this observation is not clear, and this finding must be confirmed before making broad recommendations regarding the discontinuation of these agents in patients who benefit from them. Long-term use of PPIs has also been implicated in the development of iron and magnesium deficiency, but here again, the studies are limited and inconclusive. PPIs may exert a negative effect on the antiplatelet effect of clopidogrel. Although the evidence is mixed and inconclusive, a small increase in mortality and readmission rate


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InternalMed_Harrison. and inconclusive. PPIs may exert a negative effect on the antiplatelet effect of clopidogrel. Although the evidence is mixed and inconclusive, a small increase in mortality and readmission rate for coronary events was seen in patients receiving a PPI while on clopidogrel in earlier studies. Subsequently, three meta-analyses reported an inverse correlation between clopidogrel and PPI use; therefore, the influence of this drug interaction on mortality is not clearly established. The mechanism involves the competition of the PPI and clopidogrel with the same cytochrome P450 (CYP2C19). Whether this is a class effect of PPIs is unclear; there appears to be at least a theoretical advantage of pantoprazole over the other PPIs, but this has not been confirmed. This drug interaction is particularly relevant in light of the common use of aspirin and clopidogrel for prevention of coronary events and the efficacy of PPIs in preventing GI bleeding in these patients. The FDA has made several


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InternalMed_Harrison. relevant in light of the common use of aspirin and clopidogrel for prevention of coronary events and the efficacy of PPIs in preventing GI bleeding in these patients. The FDA has made several recommendations while awaiting further evidence to clarify the impact of PPI therapy on clopidogrel use. Health care providers should continue to prescribe clopidogrel to patients who require it and 1921 should reevaluate the need for starting or continuing treatment with a PPI. From a practical standpoint, additional recommendations to consider include the following: Patients taking clopidogrel with aspirin, especially with other GI risk factors for bleeding, should receive GI protective therapy. Although high-dose H2 blockers have been considered an option, these do not appear to be as effective as PPIs. If PPIs are to be given, some have recommended that there be a 12-h separation between administration of the PPI and clopidogrel to minimize competition of the two agents with the involved cyto


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InternalMed_Harrison. PPIs. If PPIs are to be given, some have recommended that there be a 12-h separation between administration of the PPI and clopidogrel to minimize competition of the two agents with the involved cyto chrome P450. One option is to give the PPI 30 min before breakfast and the clopidogrel at bedtime. Insufficient data are available to firmly recommend one PPI over another. Patients 65 years of age or older have a higher risk for some of the long-term side effects of PPIs highlighted above, in part due to the higher prevalence of concomitant chronic diseases. It is therefore important to carefully select individuals, especially among the elderly, who need long-term PPI therapy and discontinue it in those individuals who do not need it.


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InternalMed_Harrison. Two new formulations of acid inhibitory agents are being developed. Tenatoprazole is a PPI containing an imidazopyridine ring instead of a benzimidazole ring, which promotes irreversible proton pump inhibition. This agent has a longer half-life than the other PPIs and may be beneficial for inhibiting nocturnal acid secretion, which has significant relevance in GERD. A second new class of agents is the potassium-competitive acid pump antagonists (P-CABs). These compounds inhibit gastric acid secretion via potassium competitive binding of the H+,K+-ATPase.


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InternalMed_Harrison. CYTOPROTECTIVE AGENTS Sucralfate Sucralfate is a complex sucrose salt in which the hydroxyl groups have been substituted by aluminum hydroxide and sulfate. This compound is insoluble in water and becomes a viscous paste within the stomach and duodenum, binding primarily to sites of active ulceration. Sucralfate may act by several mechanisms: serving as a physicochemical barrier, promoting a trophic action by binding growth factors such as EGF, enhancing prostaglandin synthesis, stimulating mucus and bicarbonate secretion, and enhancing mucosal defense and repair. Toxicity from this drug is rare, with constipation being most common (2–3%). It should be avoided in patients with chronic renal insufficiency to prevent aluminum-induced neurotoxicity. Hypophosphatemia and gastric bezoar formation have also been reported rarely. Standard dosing of sucralfate is 1 g qid.


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InternalMed_Harrison. Bismuth-Containing Preparations Sir William Osler considered bismuth-containing compounds the drug of choice for treating PUD. The resurgence in the use of these agents is due to their effect against H. pylori. Colloidal bismuth subcitrate (CBS) and bismuth subsalicylate (BSS, Pepto-Bismol) are the most widely used preparations. The mechanism by which these agents induce ulcer healing is unclear. Adverse effects with short-term use include black stools, constipation, and darkening of the tongue. Long-term use with high doses, especially with the avidly absorbed CBS, may lead to neurotoxicity. These compounds are commonly used as one of the agents in an anti-H. pylori regimen (see below).


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InternalMed_Harrison. Prostaglandin Analogues In view of their central role in maintaining mucosal integrity and repair, stable prostaglandin analogues were developed for the treatment of PUD. The mechanism by which this rapidly absorbed drug provides its therapeutic effect is through enhancement of mucosal defense and repair. The most common toxicity noted with this drug is diarrhea (10–30% incidence). Other major toxicities include uterine bleeding and contractions; misoprostol is contraindicated in women who may be pregnant, and women of childbearing age must be made clearly aware of this potential drug toxicity. The standard therapeutic dose is 200 μg qid. Miscellaneous Drugs A number of drugs including anticholinergic agents and tricyclic antidepressants were used for treating acid 1922 peptic disorders, but in light of their toxicity and the development of potent antisecretory agents, these are rarely, if ever, used today. THERAPY OF H. PYLORI


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InternalMed_Harrison. THERAPY OF H. PYLORI The physician’s goal in treating PUD is to provide relief of symptoms (pain or dyspepsia), promote ulcer healing, and ultimately prevent ulcer recurrence and complications. The greatest influence of understanding the role of H. pylori in peptic disease has been the ability to prevent recurrence. Documented eradication of H. pylori in patients with PUD is associated with a dramatic decrease in ulcer recurrence to <10–20% as compared to 59% in GU patients and 67% in DU patients when the organism is not eliminated. Eradication of the organism may lead to diminished recurrent ulcer bleeding. The effect of its eradication on ulcer perforation is unclear.


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InternalMed_Harrison. Extensive effort has been made in determining who of the many individuals with H. pylori infection should be treated. The common conclusion arrived at by multiple consensus conferences around the world is that H. pylori should be eradicated in patients with documented PUD. This holds true independent of time of presentation (first episode or not), severity of symptoms, presence of confounding factors such as ingestion of NSAIDs, or whether the ulcer is in remission. Some have advocated treating patients with a history of documented PUD who are found to be H. pylori–positive by serology or breath testing. Over one-half of patients with gastric MALT lymphoma experience complete remission of the tumor in response to H. pylori eradication. The Maastricht IV/Florence Consensus Report recommends a test-and-treat approach for patients with uninvestigated dyspepsia if the local incidence of H. pylori is greater than 20%. In addition, recommendations from this consensus report include testing