The Gastrointestinal Tract

Pathogenesis

The enteric neuronal plexus develops from neural crest cells that migrate into the bowel wall during embryogenesis. Hirschsprung disease, also known as congenital aganglionic megacolon, results when the migration of neural crest cells from cecum to rectum is arrested prematurely or when the ganglion cells undergo premature death. This produces a distal intestinal segment that lacks both the Meissner submucosal plexus and the Auerbach myenteric plexus, termed aganglionosis. Coordinated peristaltic contractions are absent, and functional obstruction occurs, resulting in dilation proximal to the affected segment.

Heterozygous loss-of-function mutations in the receptor tyrosine kinase RET account for the majority of familial and approximately 15% of sporadic Hirschsprung disease cases. The association between Down syndrome and Hirschsprung disease may be linked to the Down syndrome cell adhesion molecule gene on chromosome 21, overexpression of which leads to neural defects in experimental models. In patients without trisomy 21, germline mutations in several genes that are required for normal gut innervation have been implicated, the most common of which involve RET and EDNRB or EDN3 (which encode a receptor-ligand pair). These proteins appear to participate in signaling pathways that regulate development of the enteric nervous system. Defects in known genes cannot explain all cases, however, and penetrance in those carrying pathogenic mutations is incomplete, suggesting that modifying genes or environmental factors are also important. Some of these modifying genes may be sex-linked, since the disease is more common in males, but, when present in females, the affected aganglionic segment tends to be longer.

Morphology

Diagnosis of Hirschsprung disease requires histologic confirmation that ganglion cells are absent within the affected segment. In addition to their characteristic morphology in hematoxylin and eosin–stained sections, ganglion cells can be identified using immunohistochemical stains for acetylcholinesterase.

The rectum is always affected, but the length of the additional involved segments varies widely. In most cases the abnormality extends to the sigmoid colon, but in severe cases, the entire colon may be involved. Disease limited to the rectosigmoid is termed short-segment Hirschsprung disease, while cases with more proximal extension are termed long-segment Hirschsprung disease.

The aganglionic region may have a grossly normal or contracted appearance. In contrast, the normally innervated proximal colon undergoes progressive dilation ( Fig. 17.3 ) and may become massively distended (megacolon) as a result of the distal obstruction. The colonic wall may be stretched to the point of rupture, which occurs most frequently near the cecum. Mucosal inflammation or shallow ulcers may also be present in normally innervated segments, making gross identification of the extent of aganglionosis difficult. Hence, intraoperative histopathologic analysis (frozen section) is commonly used to confirm the presence of ganglion cells at the anastomotic site.

Clinical Features

Hirschsprung disease typically presents with a failure to pass meconium in the immediate postnatal period. Obstruction or constipation follows, often with visible but ineffective peristalsis. When only a few centimeters of rectum are involved, some stool may be passed, obscuring the diagnosis. More often, the obstruction is obvious and is marked by abdominal distention and bilious vomiting as luminal material backs up into the proximal colon. The major threats to life are enterocolitis, fluid and electrolyte disturbances, perforation, and peritonitis. Treatment consists of surgical resection of the aganglionic segment and anastomosis of the normal proximal colon to the rectum. Even after successful surgery, it may take years to attain normal bowel function and continence.

In contrast to the congenital megacolon of Hirschsprung disease, acquired megacolon may occur at any age as a result of Chagas disease, obstruction by a neoplasm or inflammatory stricture, a complication of ulcerative colitis, visceral myopathy, or in association with psychosomatic disorders. Of these, only Chagas disease (discussed later) shares the same pathophysiology as Hirschsprung disease; the loss of ganglion cells.

Key Concepts

Congenital Malformations of the Gastrointestinal Tract

• The GI tract is a common site of developmental abnormalities, often in association with congenital defects of other organ systems.

• Atresia and fistulae are developmental anomalies that typically present at birth. Imperforate anus is the most common form of congenital intestinal atresia, while the esophagus is the most common site of fistulization.

• Stenosis may be developmental or acquired. Both forms are characterized by a thickened wall and partial or complete luminal obstruction. Acquired forms are often due to inflammatory scarring.

• Diaphragmatic hernia is characterized by incomplete diaphragm development and herniation of abdominal organs into the thorax, often producing pulmonary hypoplasia. Omphalocele and gastroschisis refer to ventral herniation of abdominal organs.

• Ectopia refers to normally formed tissues at an abnormal site. This is common in the GI tract, with ectopic gastric mucosa in the upper third of the esophagus being the most common form.

• Meckel diverticulum is a true diverticulum, defined by the presence of all three layers of the bowel wall, that stems from failed involution of the vitelline duct. It is a frequent site of gastric ectopia, which may result in peptic injury and occult bleeding.

• Congenital hypertrophic pyloric stenosis presents between the third and sixth weeks of life and is more common in males.

• Hirschsprung disease is caused by the failure of neural crest–derived ganglion cells to migrate into the distal colon. The defect, which always involves the rectum, extends proximally for variable distances.

Pathogenesis

Transient lower esophageal sphincter relaxation is thought to be a major cause of GERD. This relaxation is mediated via vagal pathways and can be triggered by gastric distention. Gastroesophageal reflux can also occur following abrupt increases in intra-abdominal pressure, e.g., after coughing, straining, or bending. Other conditions that are associated with GERD include alcohol and tobacco use, obesity, central nervous system depressants, pregnancy, hiatal hernia (discussed later), delayed gastric emptying, and increased gastric volume.

Morphology

Simple hyperemia, evident to the endoscopist as redness, may be the only alteration in mild GERD; mucosal histology is often unremarkable. More significant gastric reflux is associated with erosions ( Fig. 17.5A ) and influx of eosinophils into the squamous mucosa ( Fig. 17.6A ). Basal zone hyperplasia and elongation of lamina propria papillae are also common. Neutrophil infiltration is less frequent and is generally associated with bacterial or fungal infection or chemical damage.

Clinical Features

GERD has an estimated prevalence of 10% to 20% in the West, but less than 5% in Asia, and is most common in individuals older than age 40. Typical symptoms include heartburn, dysphagia, and regurgitation of sour-tasting gastric contents, most often postprandially. Rarely, GERD-associated chest pain may be mistaken for ischemic heart disease. Treatment with proton pump inhibitors to reduce gastric acidity typically provides symptomatic relief. Endoscopy is not required for the diagnosis and is usually reserved for those who are refractory to proton pump inhibitors. Endoscopic biopsy can also detect eosinophilic esophagitis as well as Barrett esophagus, strictures, ulcerations, and other GERD complications. Notably, the severity of symptoms is not closely related to the degree of histologic damage, and substantial histologic abnormalities may be found in those without typical GERD symptoms.

Hiatal hernia may cause lower esophageal sphincter incompetence and symptoms that are similar to GERD but it is symptomatic in fewer than 10% of adults. The majority of hiatal hernias are of the sliding type, in which the diaphragmatic crura are spread and the gastroesophageal junction herniates into the thorax. Less common paraesophageal hiatal hernias penetrate through a defect in the phrenoesophageal membrane, can involve the stomach and other organs, and generally require surgical repair.

Clinical Features

Gastroesophageal varices are present in 30% of those with compensated cirrhosis and in 60% of those with decompensated cirrhosis. Variceal hemorrhage is an emergency that can be treated medically by inducing splanchnic vasoconstriction or endoscopically by sclerotherapy (injection of thrombotic agents), balloon tamponade, or variceal ligation. Despite these interventions, each episode of variceal hemorrhage confers a 15% to 20% risk of mortality, and over half of patients who survive a first variceal bleed have recurrent hemorrhage within 1 year, with mortality risk similar to the first episode. Risk factors for hemorrhage include large or tortuous varices, elevated hepatic venous pressure gradient, previous bleeding, and advanced liver disease. Treatments include beta-blockers to reduce portal blood flow and endoscopic variceal ligation.

Clinical Features

Barrett esophagus can be identified only thorough endoscopy and biopsy, which are usually prompted by GERD symptoms. Once diagnosed, the best course of management is a matter of debate. Many support surveillance by periodic endoscopy with biopsy, but randomized trials have failed to demonstrate that this improves overall survival. Furthermore, uncertainties regarding the potential of dysplasia, particularly low-grade dysplasia, to regress spontaneously and limited information on the risk of progression complicate clinical decisions.

Intramucosal or invasive carcinoma requires therapeutic intervention. Treatment options include surgical resection, or esophagectomy, as well as newer modalities such as photodynamic therapy, laser ablation, and endoscopic mucosectomy. Multifocal high-grade dysplasia, which carries a significant risk of progression to intramucosal or invasive carcinoma, is treated as intramucosal carcinoma. At present, many physicians follow low-grade dysplasia or a single focus of high-grade dysplasia with endoscopy and biopsy at regular intervals.

Pathogenesis

Molecular studies indicate that progression of Barrett esophagus to adenocarcinoma occurs over an extended period through the stepwise acquisition of genetic and epigenetic changes. Chromosomal abnormalities and mutations of the tumor suppressor genes TP53 and CDKN2A are detected at early stages. In the case of CDKN2A, which you will recall encodes two tumor suppressor proteins, p16 and p19-ARF, both allelic loss and hypermethylation-induced epigenetic silencing have been described. With progression, there may be amplification of several oncogenes, including the EGFR, ERBB2, MET, cyclin D1, and cyclin E genes.

Morphology

Esophageal adenocarcinoma usually occurs in the distal third of the esophagus and may invade the adjacent gastric cardia ( Fig. 17.10A ). It initially appears as flat or raised patches in otherwise intact mucosa, and may grow into large masses of 5 cm or more in diameter. Alternatively, tumors may infiltrate diffusely or ulcerate and invade deeply.

Microscopically, tumors typically produce mucin and form glands ( Fig. 17.11A ), often with intestinal-type morphology; less frequently, tumors are composed of diffusely infiltrative signet-ring cells (similar to those seen in diffuse gastric cancers) or, in rare cases, small poorly differentiated cells (similar to small cell carcinoma of the lung). Barrett esophagus is frequently present adjacent to the tumor.

Clinical Features

Although esophageal adenocarcinomas are occasionally discovered incidentally during the evaluation of GERD or surveillance of Barrett esophagus, they more commonly present with pain or difficulty in swallowing, progressive weight loss, hematemesis, chest pain, or vomiting. By the time symptoms appear, the tumor has often spread to submucosal lymphatic vessels. As a result, overall 5-year survival is less than 25%. In contrast, 5-year survival is approximately 80% in cases in which adenocarcinoma is limited to the mucosa or submucosa.

Pathogenesis

The majority of esophageal squamous cell carcinomas in Europe and the United States are linked to alcohol and tobacco use, which synergize to increase the risk. However, esophageal squamous cell carcinoma is also common in some regions where alcohol and tobacco use is uncommon. Thus, nutritional deficiencies, as well as polycyclic hydrocarbons, nitrosamines, and other mutagenic compounds, such as those found in fungus-contaminated foods must be considered. Some data suggest that human papillomavirus (HPV) infection may contribute to esophageal squamous cell carcinoma in high-risk, but not in low-risk, regions. The molecular pathogenesis of esophageal squamous cell carcinoma remains incompletely defined, but recurrent abnormalities include amplification of the transcription factor gene SOX2, which is involved in stem cell self-renewal; overexpression of the cell cycle regulator cyclin D1; and loss-of-function mutations in the tumor suppressor genes TP53, CDH1 (which encodes E-cadherin), and NOTCH1 .

Morphology

In contrast to the distal location of adenocarcinoma, half of squamous cell carcinomas occur in the middle third of the esophagus ( Fig. 17.10B ). Squamous cell carcinoma begins as an in situ lesion termed squamous dysplasia (this histopathology is referred to as intraepithelial neoplasia or carcinoma in situ at sites outside the GI tract, e.g., uterine cervix). Early lesions appear as small, gray-white, plaque-like thickenings. Over months to years they grow into tumor masses that may be polypoid, or exophytic, and protrude into and obstruct the lumen. Other tumors are ulcerated or diffusely infiltrative lesions that spread within the esophageal wall and cause thickening, rigidity, and luminal narrowing. Tumors may invade surrounding structures including the respiratory tree (causing pneumonia), the aorta (causing catastrophic exsanguination), or the mediastinum and pericardium.

Most squamous cell carcinomas are moderately to well differentiated ( Fig. 17.11B ). Less common histologic variants include verrucous squamous cell carcinoma, spindle cell carcinoma, and basaloid squamous cell carcinoma. Regardless of histology, symptomatic tumors are generally large and invasive at diagnosis. The rich lymphatic network of the esophagus promotes metastases as well as circumferential and longitudinal spread; intramural satellite tumor nodules may be present several centimeters away from the principal mass. The sites of lymph node metastases vary with tumor location: cancers in the upper third of the esophagus favor cervical lymph nodes; those in the middle third favor mediastinal, paratracheal, and tracheobronchial nodes; and those in the lower third spread to gastric and celiac nodes.

Clinical Features

The onset of esophageal squamous cell carcinoma is insidious. Patients typically have dysphagia, odynophagia (pain on swallowing), or obstruction at presentation and may have unknowingly adjusted to progressive esophageal obstruction by altering their diet from solid to liquid foods. Weight loss and debilitation result from both impaired nutrition and tumor cachexia. Hemorrhage and sepsis may accompany tumor ulceration, and symptoms of iron deficiency are often present. Occasionally, the first symptoms are caused by aspiration of food via a tracheoesophageal fistula (caused by extension of the tumor into the trachea).

Increased prevalence of endoscopic screening has led to earlier detection of esophageal squamous cell carcinoma. This is significant because 5-year survival rates are 75% in individuals with superficial lesions but much lower in patients with more advanced tumors. Lymph node metastases are associated with poor prognosis. The overall 5-year survival rate in the United States remains less than 20% and varies by tumor stage and patient age, race, and sex.

Key Concepts

Esophageal Diseases

• Abnormalities of esophageal motility include nutcracker esophagus and diffuse esophageal spasm.

• Achalasia, characterized by incomplete lower esophageal sphincter relaxation, increased lower esophageal sphincter tone, and esophageal aperistalsis, is a common form of functional esophageal obstruction. It can be primary or secondary, with the latter form most commonly due to Trypanosoma cruzi infection.

• Mallory-Weiss tears of mucosa at the gastroesophageal junction develop as a result of severe retching or vomiting.

• Esophagitis can result from chemical or infectious mucosal injury. Infection is most common in immunocompromised individuals.

• The most prevalent cause of esophagitis is reflux of gastric acid into the esophagus (GERD).

• Eosinophilic esophagitis is strongly associated with food allergy, allergic rhinitis, or asthma. It is a common cause of GERD-like symptoms in children living in high income countries.

• Gastroesophageal varices are a consequence of portal hypertension and are present in half of cirrhosis patients.

• Barrett esophagus develops in patients with chronic GERD and represents columnar metaplasia of the esophageal squamous mucosa.

• Barrett esophagus is a risk factor for development of esophageal adenocarcinoma.

• Esophageal squamous cell carcinoma is associated with alcohol and tobacco use, poverty, caustic esophageal injury, achalasia, tylosis, and Plummer-Vinson syndrome.

Pathogenesis

The gastric lumen has a pH of close to 1, more than a million times more acidic than the blood. This harsh environment contributes to digestion but also has the potential to cause damage. Multiple mechanisms have evolved to protect the gastric mucosa ( Fig. 17.12 ). Foveolar cell secretions form a thin layer of mucus and phospholipids that prevents large food particles from directly touching the epithelium. Mucus also promotes formation of an “unstirred” layer of fluid with a neutral pH as a result of bicarbonate ion secretion by surface epithelial cells. Beneath the mucus, gastric epithelial cells form a physical barrier that limits back diffusion of acid and leakage of other luminal materials, including digestive enzymes, into the lamina propria. Surface foveolar cells are replaced every 3 to 7 days, while parietal and chief cells are more long-lived. The rich mucosal vasculature delivers oxygen and nutrients and removes whatever gastric acid may have diffused into the lamina propria.

Gastropathy and gastritis occur when the damaging forces overwhelm the protective factors ( Fig. 17.12 ). Disruption of protective mechanisms is illustrated by the following examples:

• Inhibition of cyclooxygense (COX) by NSAIDs. NSAIDs inhibit COX-dependent synthesis of prostaglandins E ₂ and I ₂ , which contribute to nearly all of the above defense mechanisms, including: mucus, bicarbonate, and phospholipid secretion; mucosal blood flow; and epithelial restitution. They also reduce acid secretion. Although COX-1 plays a larger role than COX-2, both isoenzymes contribute to mucosal protection. Thus, while the risk of NSAID-induced gastric injury is greatest with nonselective inhibitors such as aspirin, ibuprofen, and naproxen, selective COX-2 inhibitors such as celecoxib can also cause gastropathy or gastritis.

• Inhibition of gastric bicarbonate transporters by ammonium ions can result in gastric injury in uremic patients and those infected with urease-secreting H. pylori.

• Reduced mucin and bicarbonate secretion have been suggested as factors that explain the increased susceptibility of older adults to gastritis.

• Decreased oxygen delivery may account for an increased incidence of acute gastritis at high altitudes.

Ingestion of harsh chemicals, particularly acids or bases, either accidentally or as a suicide attempt, causes severe gastric injury. Direct cellular damage also contributes to gastritis induced by alcohol consumption, NSAIDs, radiation therapy, and chemotherapy. Agents that inhibit DNA synthesis or the mitotic apparatus, including those used in cancer chemotherapy, may cause generalized mucosal damage by inhibiting epithelial renewal.

Morphology

Histologically, gastropathy and mild acute gastritis may be difficult to recognize, since the lamina propria shows only moderate edema and slight vascular congestion. The surface epithelium is intact, but foveolar cell hyperplasia, with characteristic corkscrew profiles and epithelial proliferation, is often present. Neutrophils may be found among the epithelial cells or within mucosal gland lumina in gastritis. The lamina propria contains only a few lymphocytes and plasma cells.

The presence of neutrophils above the basement membrane in direct contact with epithelial cells is abnormal in all parts of the GI tract and signifies active inflammation, or, in this case, gastritis (rather than gastropathy). The term active inflammation is preferred over acute inflammation, since neutrophils may be present in both acute and chronic disease states. Thus, within the GI tract, the term acute refers to disease duration rather than the inflammatory pattern.

As injury progresses, erosions, i.e., superficial mucosal defects, are accompanied by neutrophilic infiltrates and fibrin-containing exudate within the lumen. Hemorrhage may cause dark puncta within hyperemic mucosa. Concurrent erosion and hemorrhage is termed acute erosive hemorrhagic gastritis. Although large areas of the gastric surface may be denuded, the involvement is typically superficial.

Pathogenesis

The pathogenesis of stress-related gastric mucosal injury is most often related to local ischemia. This may be due to systemic hypotension or reduced blood flow caused by stress-induced splanchnic vasoconstriction. Upregulation and increased release of the vasoconstrictor endothelin-1 also contribute to ischemic gastric mucosal injury.

Lesions associated with intracranial injury are thought to be caused by direct stimulation of vagal nuclei, which causes hypersecretion of gastric acid. Systemic acidosis, a frequent finding in these settings, may also contribute to mucosal injury by lowering the intracellular pH of mucosal cells and reducing the pH gradient that promotes washout of acid that has back-diffused into the lamina propria.

Morphology

Stress-related gastric mucosal injury ranges from shallow erosions to lesions that penetrate the mucosa. Ulcers are rounded, less than 1 cm in diameter, and have a base that is frequently stained brown to black by acid digestion of extravasated blood. Unlike peptic ulcers, which are usually solitary and located in the antrum, acute stress ulcers are found anywhere in the stomach and are often multiple. Microscopically, acute stress ulcers are sharply demarcated, with relatively normal adjacent mucosa. Serositis may be present, but the scarring and blood vessel thickening that characterize chronic peptic ulcers are conspicuously absent. Healing with complete re-epithelialization occurs within days to weeks after successful treatment of the underlying condition.

Clinical Features

Most critically ill patients admitted to hospital intensive care units have histologic evidence of gastric mucosal damage. Bleeding from these lesions is sufficiently severe to require red cell transfusions in 1% to 4% of such patients. Other complications, including perforation, can also occur. Prophylactic proton pump inhibitors may blunt the impact of stress ulceration, but the most important determinant of clinical outcome is whether the underlying condition can be corrected.

Non–stress-related causes of gastric bleeding include the following two conditions:

• Dieulafoy lesion consists of an abnormal submucosal arteriole that is usually found within the lesser curvature of the stomach near the gastroesophageal junction. Erosion of the overlying epithelium can cause recurrent gastric bleeding that, while usually self-limited, can be copious. NSAID use may enhance bleeding risk.

• Gastric antral vascular ectasia (GAVE) is responsible for 4% of non-variceal upper GI bleeding. It can be recognized endoscopically as longitudinal stripes of edematous, erythematous mucosa that alternate with less severely injured, paler mucosa and is sometimes referred to as watermelon stomach. The erythematous stripes are created by ectatic mucosal vessels. Histologically, the antral mucosa shows reactive gastropathy with dilated capillaries containing fibrin thrombi. While most often idiopathic, GAVE can be associated with cirrhosis and systemic sclerosis. Recurrent bleeding may produce a positive test for fecal blood and lead to iron deficiency anemia.

Pathogenesis

H. pylori infection most often presents as a predominantly antral gastritis with normal or increased acid production. When inflammation remains limited to the antrum, modestly increased local gastrin production can augment parietal cell mass within the gastric body and increase acid secretion that leads to greater risk of gastric or duodenal peptic ulcer disease (see later). Alternatively, long-standing H. pylori gastritis may progress to involve the gastric body and fundus. This may result in atrophic gastritis with reduced parietal cell mass and intestinal metaplasia. In contrast to autoimmune gastritis (see later), atrophy induced by H. pylori is not associated with autoantibodies and is typically patchy. The loss of parietal cells leads to reduced acid secretion that, in turn, stimulates gastrin production. However, because some parietal cells survive, limited acid secretion continues and gastrin increases are not as great as those in autoimmune gastritis. Nevertheless, decreased acid secretion in H. pylori gastritis with atrophy reduces the risk of gastric and duodenal ulcers. This results in an inverse relationship between gastric adenocarcinoma, which is associated with atrophy and intestinal metaplasia, and duodenal ulcers, which are associated with increased acid secretion.

H. pylori organisms have adapted to the ecologic niche provided by gastric mucus. Its virulence is linked to the following factors:

• Flagella, which allow the bacteria to be motile in viscous mucus

• Urease, which generates ammonia from endogenous urea and thereby elevates local gastric pH and enhances bacterial survival

• Adhesins that enhance bacterial adherence to surface foveolar cells

• Toxins, such as cytotoxin-associated gene A (CagA)

Variation in these and other bacterial factors are strongly linked to outcome. For example, the CagA gene is present in 50% of H. pylori isolates overall but in 90% of H. pylori isolates in populations with an increased prevalence of gastric cancer. This may, in part, be because CagA -expressing strains colonize the gastric body and induce proinflammatory cytokine secretion, atrophy, and intestinal metaplasia more effectively than CagA -negative H. pylori .

Host factors also play an important role in the outcome of H. pylori infection. Genetic polymorphisms that lead to increased expression of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin (IL)-1β or decreased expression of the anti-inflammatory cytokine IL-10 seem to be associated with development of pangastritis, atrophy, intestinal metaplasia, and gastric cancer. The course of H. pylori gastritis is, therefore, the result of interplay between gastroduodenal mucosal defenses, host immune responses, and bacterial virulence factors.

Morphology

Gastric biopsy specimens generally demonstrate H. pylori in infected individuals. The organism is concentrated within the superficial mucus overlying epithelial cells in the surface and neck regions. The distribution can be irregular, with areas of heavy colonization adjacent to those with few organisms. Organisms are most easily demonstrated with immunostains or histochemical stains ( Fig. 17.13A ).

The antrum is the preferred biopsy site for evaluation of H. pylori gastritis because it is most commonly infected. In dense colonization, organisms may also be found in oxyntic (acid-producing) mucosa of the fundus and body. H. pylori –infected antral mucosa is usually erythematous and has a coarse or even nodular appearance. The inflammatory infiltrate includes large numbers of plasma cells, often in clusters or sheets, within the superficial lamina propria. These are accompanied by increased numbers of lymphocytes, macrophages, and neutrophils within the lamina propria. Neutrophils infiltrate across the basement membrane ( Fig. 17.13B ) and accumulate in the lumens of gastric glands, or pits, to create pit abscesses. When intense, inflammatory infiltrates may create thickened rugal folds, mimicking the endoscopic appearance of early cancers. Lymphoid aggregates, some with germinal centers, are frequently present ( Fig. 17.13C ) and represent induced mucosa-associated lymphoid tissue (MALT) that has the potential to transform into lymphoma. Thus, chronic H. pylori gastritis is associated with increased risk of both gastric adenocarcinoma and lymphoma.

Clinical Features

The changes seen in atrophic H. pylori gastritis are sometimes referred to as environmental metaplastic atrophic gastritis, to distinguish it from autoimmune metaplastic atrophic gastritis (described next). In addition to histologic identification of the organism, several noninvasive diagnostic tests have been developed, including serology for antibodies to H. pylori, fecal bacterial detection, and the urea breath test, which is positive due to ammonia produced by the bacterial urease. Other diagnostic tests performed on biopsies include the rapid urease test, bacterial culture, or polymerase chain reaction (PCR)-based detection of H. pylori DNA.

Effective treatments for H. pylori infection include combinations of antibiotics and proton pump inhibitors. Individuals with H. pylori gastritis usually improve after treatment, although relapses can occur after incomplete eradication or re-infection, particularly in regions with high endemic colonization rates.

Pathogenesis

Autoimmune atrophic gastritis is associated with loss of parietal cells, which are responsible for secretion of gastric acid and intrinsic factor. The absence of acid production stimulates gastrin release, resulting in hypergastrinemia and hyperplasia of antral gastrin-producing G cells. Intrinsic factor loss results in defective ileal vitamin B ₁₂ absorption, which ultimately leads to vitamin B ₁₂ deficiency and pernicious anemia (a form of megaloblastic anemia described in Chapter 14 ). The high frequency of associated intestinal metaplasia has led to the term autoimmune metaplastic atrophic gastritis .

CD4+ T cells directed against parietal cell components, including hydrogen potassium adenosine triphosphatase (H ⁺ ,K ⁺ -ATPase), are considered to be the principal agents of injury in autoimmune atrophic gastritis. This is supported by the observation that transfer of H ⁺ ,K ⁺ -ATPase–reactive CD4+ T cells into naïve mice results in gastritis and production of H ⁺ ,K ⁺ -ATPase autoantibodies. There is no evidence of an autoimmune reaction to chief cells, suggesting that these may be lost through gastric gland destruction during autoimmune attack on parietal cells. If autoimmune destruction is controlled by immunosuppression, the glands can repopulate, demonstrating that gastric stem cells survive and are able to differentiate into parietal and chief cells.

Autoantibodies to parietal cell components, most prominently H ⁺ ,K ⁺ -ATPase, or proton pump, and intrinsic factor are present in up to 80% of patients with autoimmune atrophic gastritis. However, these antibodies are not thought to be pathogenic because neither secreted intrinsic factor nor the luminally oriented proton pump is accessible to circulating antibodies, and passive transfer of these antibodies does not produce gastritis in experimental animals.

Morphology

Autoimmune atrophic gastritis is characterized by diffuse damage to the oxyntic (acid-producing) mucosa within the body and fundus. The antrum and cardia are typically spared. With diffuse atrophy, oxyntic mucosa of the body and fundus appears markedly thinned, and rugal folds are lost. If vitamin B ₁₂ deficiency is severe, nuclear enlargement (megaloblastic change) occurs within epithelial cells. Neutrophils may be present, but the inflammatory infiltrate is typically composed of lymphocytes, macrophages, and plasma cells, often in association with lymphoid aggregates and follicles. In contrast to the superficial lamina propria inflammation that is typical of H. pylori gastritis, inflammation in autoimmune atrophic gastritis is deeper and centered on the gastric glands ( Fig. 17.14A ). Loss of parietal and chief cells can be extensive. When atrophy is incomplete, residual islands of oxyntic mucosa may give the appearance of multiple small polyps or nodules. In other areas, small surface elevations may represent sites of intestinal metaplasia, characterized by the presence of goblet cells and columnar absorptive cells ( Fig. 17.14B ). Endocrine and enterochromaffin-like cell hyperplasia is commonly present. Rarely, endocrine cell hyperplasia may progress to form small, multicentric, low-grade neuroendocrine (carcinoid) tumors.

Clinical Features

Antibodies to parietal cells and intrinsic factor are present 2 to 3 decades before the appearance of gastric atrophy and other complications such as pernicious anemia; hence, progression to clinically evident disease is slow. The median age at diagnosis is 60. Slightly more women than men are affected, and there does not appear to be an ethnic or racial bias. Pernicious anemia and autoimmune atrophic gastritis are often associated with other autoimmune diseases including Hashimoto thyroiditis, type 1 diabetes mellitus, Addison disease, and others. These associations, along with concordance in some monozygotic twins and clustering of disease in families, support a genetic predisposition. Nevertheless, there is little evidence of linkage between autoimmune gastritis and specific human leukocyte antigen (HLA) alleles.

The clinical features are mainly related to vitamin B ₁₂ deficiency, including megaloblastic anemia ( Chapter 14 ); atrophic glossitis, in which the tongue becomes smooth and beefy red; epithelial megaloblastosis; malabsorptive diarrhea; and many others (see Chapter 28 ). Clinical features and pathologic changes related to the effects of vitamin B ₁₂ deficiency in the marrow and the CNS (e.g., subacute combined degeneration of the spinal cord) are described in detail in Chapters 14 and 28 , respectively.

Pathogenesis

PUD results from imbalances between defense mechanisms and damaging factors that cause chronic gastritis (discussed earlier). Thus, PUD generally develops on a background of chronic gastritis. The reasons why some people develop only chronic gastritis while others develop PUD are poorly understood. However, as with H. pylori gastritis, it is likely that host factors as well as variation in pathogenicity of bacterial strains are involved.

Morphology

Peptic ulcers occur in the context of chronic gastritis but are most frequently found in the proximal duodenum, within a few centimeters of the pyloric valve. Foveolar metaplasia, in which gastric-type mucus cells are present, is common in chronic duodenal peptic disease and may be a protective response, as gastric epithelia are less sensitive to acid than intestinal epithelia. Gastric peptic ulcers are predominantly located along the lesser curvature near the interface of the body and antrum.

Peptic ulcers are solitary in more than 80% of patients and form a round to oval, sharply punched-out defect ( Fig. 17.15A ). The mucosal margin is usually level with the surrounding mucosa but may overhang the base, particularly on the proximal side. In contrast, heaped-up margins are more characteristic of cancers. The depth of ulcers correlates with diameter, and deep extension may be limited by the thick gastric muscularis propria, adherent pancreas, omental fat, or the liver. Perforation into the peritoneal cavity is a surgical emergency that may be identified as free air under the diaphragm on upright abdominal radiographs.

The base of peptic ulcers is smooth and clean as a result of peptic digestion of exudate. Active ulcers may be lined by a thin layer of fibrinoid debris with a predominantly neutrophilic inflammatory infiltrate. Beneath this, granulation tissue with immature vessels, mononuclear leukocytes, and a fibrous or collagenous scar forms the ulcer base ( Fig. 17.15B ). Larger vessels within the scarred area are typically thickened and are occasionally thrombosed. Bleeding from these vessels may cause life-threatening hemorrhage. Scarring may involve the entire thickness of the wall and draw the surrounding mucosa into folds that radiate outward.

Clinical Features

Peptic ulcers typically come to clinical attention because of epigastric burning or aching pain. Others present with iron deficiency anemia, hemorrhage, or perforation ( Table 17.4 ). The pain tends to occur 1 to 3 hours after meals during the day, is worse at night (usually between 11 p.m. and 2 a.m.), and is relieved by alkali or food. Nausea, vomiting, bloating, belching, and significant weight loss are additional manifestations. With penetrating ulcers the pain is occasionally referred to the back, left upper quadrant, or chest, where it may be misinterpreted as cardiac in origin.

Current therapies for PUD are aimed at H. pylori eradication and neutralization of gastric acid, primarily with proton pump inhibitors. It is also important to withdraw other offending agents such as NSAIDs, including selective COX-2 inhibitors, that may interfere with mucosal healing. While peptic ulcers were previously notoriously difficult to eradicate, the recurrence rate is now less than 20% following successful clearance of H. pylori .