Introduction
The gastrointestinal (GI) tract performs energy-demanding functions of digestion and absorption of nutrients while maintaining a critical barrier between the internal milieu and the external (luminal) environment. It also contributes to the activities of the immune system. These functions depend on a reliable blood supply. It is not surprising, therefore, that vascular disorders have important clinical manifestations. Vascular disorders usually manifest clinically as bleeding or ischemia, both of which occur in acute and chronic forms. In this chapter, vascular disorders are discussed in the context of these two types of clinical presentation, although there is considerable overlap between them. Vascular tumors (e.g., angioma, angiosarcoma, glomus tumor, Kaposi sarcoma) are discussed in Chapter 30 .
Anatomy of the GI Vascular System
The proximal esophagus derives its blood supply from the superior and inferior thyroid arteries, the middle esophagus from the bronchial and right intercostal arteries, and the distal esophagus from the left gastric, left inferior phrenic, and splenic arteries. The middle and lower esophagus also receives arterial blood directly from the aorta. Venous drainage is likewise segmental. Blood from the proximal esophagus drains into the superior vena cava, that from the middle esophagus into the azygos vein, and that from the distal esophagus through the left and short gastric veins into the portal vein. Anastomoses among the vessels that supply each of these regions result in complex arterial and venous networks. For instance, the venous network in the mucosa and submucosa of the middle and distal esophagus is the source of esophageal varices in patients with portal hypertension.
The stomach, proximal duodenum, liver, and pancreas are supplied by branches of the celiac artery. The distal duodenum is supplied by a branch of the superior mesenteric artery. As in the esophagus, there are numerous anastomoses between feeding vessels that result in a complex vascular network. The presence of extensive esophageal and gastric vascular anastomoses helps explain why ischemia and infarction occur only rarely in these organs. The gastric and duodenal veins drain into the portal system.
The remainder of the small intestine is supplied by the jejunal and ileal branches of the superior mesenteric artery, which also supplies the cecum and ascending and proximal transverse colon through its ileocolic, middle colic, and right colic branches. The inferior mesenteric artery supplies the distal transverse colon to the proximal rectum, whereas the distal rectum is supplied by the internal iliac and pudendal arteries. The arterial supply of the small and large intestines consists of numerous vascular arcades (vasa recta) with abundant anastomoses that result in a rich collateral circulation that helps protect the bowel against damage from pathologic processes in individual blood vessels. Detailed anatomic studies and isolated reports have suggested areas of the large bowel that are predisposed to vascular insult. The most commonly characterized of these are the splenic flexure and rectosigmoid regions. Reports suggest that the ileocecal region is also predisposed to ischemic injury, but to a lesser extent. Venous drainage of the colon and rectum follows the arterial supply. The vascular collaterals in the rectum provide another location in which varices may develop in patients with portal hypertension.
The anus is supplied by the superior, middle, and inferior rectal arteries. Branches of these arteries have multiple small arteriovenous anastomoses with submucosal venous plexuses. Interestingly, the blood flow to the anal canal exceeds its metabolic requirements. Venous drainage of the anus is mainly to the superior rectal vein.
Blood flow to the GI tract is normally under tight physiologic regulation. For example, the blood supply increases by as much as 100% immediately after ingestion of a meal. On the other hand, in states of shock, when it is vital to maintain blood flow to critical organs such as the central nervous system, splanchnic blood flow may be drastically reduced, sometimes beyond the critical level needed to maintain viability of the intestinal mucosa.
Upper GI Bleeding
General Comments
Bleeding from the upper GI tract is a frequent indication for endoscopy and is common worldwide. In the United States, acute GI bleeding accounts for 250,000 to 300,000 hospitalizations per year. As many as 14% of patients admitted on an emergency basis and as many as 28% of those who are hospitalized die of their acute GI bleeding. Upper GI tract bleeding, defined as bleeding proximal to the ligament of Treitz, is four times more common than lower GI tract bleeding. Upper GI bleeds occur most commonly in elderly patients, although in conditions such as hereditary hemorrhagic telangiectasia (HHT), onset of disease may occur as early as the third decade of life. Risk factors for upper GI tract bleeding include older patient age, alcohol use, and concomitant use of drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) and anticoagulants.
Patients often are seen with direct evidence of a GI bleed, such as hematemesis, melena, heme-positive stools, and, less commonly, hematochezia. They may also be seen with signs and symptoms of iron deficiency anemia, such as syncope, chest pain, dizziness, and shortness of breath. In severe, acute, life-threatening hemorrhage, the clinical presentation is usually a result of shock or cardiovascular collapse.
Esophagus
The most important causes of esophageal bleeding are varices that develop as a result of portal hypertension, Mallory-Weiss lacerations, or esophagitis ( Table 10.1 ).
| Entity | Key Clinical Features | Key Pathologic Features | Treatment |
|---|---|---|---|
| Gastroesophageal reflux disease | Most common symptoms are heartburn, regurgitation, and dysphagia More prevalent after age 40 yr | Typically distal 7 cm of esophagus Background esophagitis: squamous hyperplasia, intraepithelial neutrophils, and increased eosinophils and lymphocytes | Medical options: PPI and H 2 antagonists Surgical options: fundoplication and gastropexy |
| HSV infection | Main symptom: odynophagia Common in immunocompromised patients, particularly organ and bone marrow transplant recipients Occurs in immunocompetent patients | Vesicles early feature; coalesce to form ulcer Ground-glass nuclear inclusions in squamous cells at edge of shallow, punched-out ulcers Immunostain when in doubt | Antivirals (e.g., acyclovir) In immunocompetent patients may resolve spontaneously |
| Candida infection | Main symptom: substernal dysphagia More common in immunocompromised patients Often coexists with other etiologies | Patchy white mucosal plaques Neutrophils, yeast and pseudohyphae in superficial squamous epithelium Usually with desquamation: often detached fragments in biopsies Fungal stains (PAS, GMS) often helpful | Antifungals (e.g., fluconazole, itraconazole) |
| CMV infection | Main symptom: odynophagia Common in immunocompromised patients In HIV-infected patients, more common than HSV | Ulcers deeper, more linear than in HSV Single large nuclear and multiple amphophilic cytoplasmic inclusions in capillary endothelial or stromal cells in granulation tissue at base Immunostaining may be necessary because inclusions can be rare | Antivirals (e.g., ganciclovir, foscarnet) |
| NSAIDs | Concomitant illnesses necessitating NSAID (e.g., chronic back pain, arthritis) Simultaneous alcohol use common | Shallow, large ulcers with broad base, usually in middle esophagus Usually devoid of background esophagitis | Discontinue medication Supportive therapy |
| Pill/Medication induced | Sudden onset of symptoms Pills swallowed without fluids Can be caused by many medications (e.g., tetracycline, potassium chloride, biphosphonate, quinidine) | Nonspecific superficial desquamation of squamous epithelium, spongiosis, necrotic keratinocytes Exudate seen commonly with quinidine-induced ulcers | Educate patient to take pills with fluids Discontinue medication or start liquid therapy if necessary Supportive therapy |
| Radiation | Usually history of head and neck, mediastinal, pulmonary, or esophageal malignancy | Fibrinoid necrosis and dilatation of blood vessels, vascular intimal proliferation, stromal fibrosis, stellate fibroblasts ± cytologic atypia and increased apoptosis | Supportive therapy Surgery if perforation or fistula develops |
| Foreign body injury | Most common in children; also seen in elderly, psychiatric patients, inmates Sudden onset of symptoms; may lead to esophagovascular fistula | Nonspecific necrosis, inflammation, and ulceration; may progress to perforation | Endoscopic or surgical removal Resection or repair of perforation or fistula |
| Chemical injury | Similar to foreign body injury Alkaline ingestions damage esophagus more commonly | Necrosis more common | Supportive therapy May require resection |
| Varices * | Occur in portal hypertension, cirrhotic and noncirrhotic Schistosomiasis and viral hepatitis are common causes worldwide Typically asymptomatic until rupture; rebleeding common | Most common in distal 3-4 cm of esophagus Dilated tortuous veins of lamina propria and submucosa bulging into lumen, fresh hemorrhage and adjacent thrombosis Erosions and ulcers uncommon Thrombosis, ulceration, necrosis, and inflammation more likely after therapy | Sclerosing and banding varices Portosystemic shunting Medical management of portal hypertension |
| Mallory-Weiss tears * | Strong association with chronic alcoholism, ASA use common Typical history (retching or forceful vomiting) in only 30% Related to upward diaphragmatic movement | Minority involve esophagus; majority on lesser curve of proximal stomach, may be at esophagogastric junction Nonspecific mucosal breach with acute hemorrhage, seldom into submucosa Usually no acute inflammatory response | Usually self-limited If therapy is required: balloon tamponade, embolization, medical management Surgery rare |
Esophageal Varices
Esophageal varices are dilated, tortuous veins within the lamina propria and submucosa that bulge into the esophageal lumen because of portal hypertension and portosystemic shunting. Esophageal varices may develop in any condition that leads to portal hypertension, but they are most often associated with alcoholic cirrhosis. The demographic features of patients with esophageal varices are similar to those of patients with cirrhosis and portal hypertension (see Chapter 50 ). Worldwide, hepatic schistosomiasis is a common cause of esophageal varices. Varices are typically asymptomatic until they rupture into the esophageal lumen, resulting in hematemesis or melena.
Bleeding varices are most common in the caudal portion of the esophagus; however, a discrete bleeding site is usually difficult to identify pathologically. Varices tend to collapse at the time of autopsy and therefore are best diagnosed endoscopically. In autopsy specimens, eversion and formalin fixation of the esophagus are techniques that can be used to help demonstrate varices. Grossly dilated, tortuous veins may be seen in the distal 3 to 4 cm of the esophagus when they bulge into the lumen ( Fig. 10.1, A ). Thrombosis may be observed in the dilated veins.
Histologically, dilated submucosal veins are characteristic, and these are usually associated with fresh hemorrhage or organizing thrombi (see Fig. 10.1, B ). Surface ulcers or erosions are uncommon. In specimens examined after treatment with sclerotherapy or endoscopic ligation, findings may include thrombosis, ulceration, necrosis, inflammation, and fibrosis.
Although variceal bleeding is the most important cause of hematemesis in patients with portal hypertension, other causes of upper GI bleeding are implicated in approximately 50% of patients who are seen with hematemesis ( Table 10.2 ; see also Table 10.1 ).
| Entity | Key Clinical Features | Key Pathologic Features | Treatment |
|---|---|---|---|
| Helicobacter pylori –induced peptic ulcer disease | Most common cause Decreasing prevalence rates | Gastritis more common in antrum Typically superficially oriented lymphoplasmacytic gastritis with neutrophil infiltrate and spiral forms of H. pylori May have reactive lymphoid follicles, intestinal metaplasia, mucosal atrophy Ulcers may be located in duodenum | H. pylori eradication therapy Antisecretory therapy |
| Chemical-induced ulcers | NSAID use is a clear predisposing factor to gastric bleeding | Erosions or shallow ulcers More common in fundus and body Usually without background gastritis | Discontinue medication or significantly reduce dose |
| Mucin loss with nuclear enlargement and hyperchromasia in adjacent epithelium | Supportive therapy | ||
| Stress related | Patients with multiple comorbidities; risk factors include prior PUD, CNS trauma or surgery, sepsis, multiple trauma, liver and kidney failure, and organ transplantation In hospital patients, duodenal ulcers more later in course Curling ulcer: following burns Cushing ulcer: following neurologic injury or surgery | Erosions or shallow ulcers Usually without background gastritis More common in fundus and body, may also be seen in duodenum Abrupt erosions or ulcers with interstitial hemorrhage, reactive epithelial atypia Adjacent mucosa with acute hemorrhagic gastritis, diffuse mucosal hyperemia, edema | Supportive therapy; may include blood transfusion. Prophylactic therapy to prevent additional ulcers (includes PPI, antacids, H 2 antagonists, sucralfate, prostaglandin analogs) |
| Dieulafoy lesion | Most common in middle-aged and elderly men | Most common in proximal stomach on lesser curve Similar lesions reported in distal esophagus, small and large bowel Small mucosal defect with abnormally large, thick-walled artery in base Adjacent mucosa usually lacks inflammation | Therapeutic endoscopy (e.g., clipping, electrocoagulation, injection sclerotherapy, banding) Surgical ligation or resection |
| Cameron ulcers | Associated with hiatal hernias | Linear ulcers in hiatal hernias Histologic features of a benign ulcer | Therapeutic endoscopy to control bleeding Surgical management of hernia. |
| Varices * | Most commonly in continuity with esophageal varix with similar morphology | See Table 10.1 | |
| Portal hypertensive gastropathy and gastric vascular ectasia | See Table 10.3 | See Table 10.3 | |
| Hereditary hemorrhagic telangiectasia (HHT) | Autosomal dominant disease with variable penetrance and expression Telangiectases on skin and mucous membranes Frequently have history of GI bleeding 20% have no family history of symptoms | More common in stomach but also seen in esophagus and duodenum Lesions include telangiectasias, arteriovenous malformations, aneurysms, venous varicosities, and arteriovenous fistulas Classically clusters or tufts of dilated, tortuous arteriolar-venular connections without intervening capillaries | Medical therapy includes danazol, estrogen, aminocaproic acid Therapeutic endoscopy (coagulation, cautery or laser) Surgical resection |
| Hemodialysis-associated telangiectasia | Long-term hemodialysis | Morphologically similar to HHT, may appear reddish and fern-like grossly | Therapeutic endoscopy (thermal coagulation) |
Esophageal varices often rebleed, and the risk of dying within 6 weeks of an initial bleed is 20% to 30% in patients with cirrhosis-related portal hypertension. Variceal bleeding may precipitate hepatic encephalopathy in cirrhotic patients. Treatment modalities include sclerosis and banding of individual varices, portosystemic shunting, and pharmacologic management of portal hypertension.
Mallory-Weiss Lacerations
Mallory-Weiss lacerations are longitudinal tears of the mucosa located in the region of the gastroesophageal junction. These lesions may bleed profusely. A clinical history of retching or forceful vomiting is identified in approximately 30% of patients. Mallory-Weiss lacerations develop mainly in patients with chronic alcoholism and typically occur in the third to fifth decades of life. Concomitant aspirin use has been reported in approximately 30% of patients. Other risk factors include upward diaphragmatic movement related to coughing, heavy lifting, pregnancy, and abdominal trauma. Mallory-Weiss laceration is an uncommon complication of upper GI endoscopy, in association with retching and hiatal hernia. In addition, some patients are seen with melena or iron deficiency anemia.
The pathogenesis of Mallory-Weiss lacerations is related to upward movement of the diaphragm and an increase in intraabdominal pressure, which leads to protrusion of the proximal stomach into the thoracic cavity. This is often preceded by nausea, which causes distention of the stomach and reflux of gastric contents into the esophagus. When protrusion of the distended stomach is forceful, longitudinal lacerations may develop. Lacerations are more likely in patients with a hiatus hernia.
Most Mallory-Weiss lacerations are located on the gastric side of the gastroesophageal junction. Only a minority involve the tubular esophagus. They occur most commonly on the lesser curve of the proximal stomach ( Fig. 10.2 ) but may also occur at the gastroesophageal junction. Histologically, Mallory-Weiss lacerations are characterized by a longitudinal breach of the mucosa that extends into the submucosa, but generally not into the muscularis propria, usually accompanied by hemorrhage, either with or without an acute inflammatory response. Healing Mallory-Weiss lacerations show granulation tissue, fibrosis, epithelial regeneration, and other features of healing ulcers.
Mallory-Weiss lacerations are usually treated supportively. In occasional patients with persistent bleeding, pharmacologic management, balloon tamponade, embolization, and, rarely, surgery may be required to establish hemostasis. Boerhaave syndrome (acute rupture of the esophagus) is a catastrophic event that is sometimes considered to be a complication of Mallory-Weiss lacerations. However, patients with Boerhaave syndrome are not typically seen with severe acute GI bleeding.
Esophagitis and Esophageal Ulcers
Esophagitis and esophageal ulcers are most commonly caused by GERD, infection (e.g., herpesvirus, Candida , cytomegalovirus), drugs, chemical or physical injury from ingestion of toxic substances, or foreign objects. Bleeding from esophagitis is usually occult, and patients commonly are seen with anemia. Bleeding from esophageal ulcers varies in severity depending on the cause, but it is most often acute. Signs and symptoms include hematemesis, epigastric pain, and odynophagia. Most patients with acute bleeding are seen in the emergency department, and many of them have significant comorbid conditions.
Overall, GERD-associated ulcers are most common, and they are seen in all age groups, although they are more prevalent after the age of 40 years. Ulcers caused by infections are more likely to occur in immunocompromised patients. However, herpes simplex virus esophagitis has been documented in immunocompetent patients as well. Other causes of esophageal ulcers include Crohn’s disease and use of NSAIDs. Concomitant alcohol use has been reported in a subset of patients with NSAID-induced esophageal ulcers, suggesting that it may have a synergistic effect. Ulcers related to medication injury are common in the elderly, whereas those caused by foreign objects are more common in children. Reflux is less likely to be associated with bleeding than use of NSAIDs, which cause injury by direct mucosal contact. Radiation-induced injury is mediated by vascular compromise. Injury from chemical agents, such as lye, is caused by their corrosive effect on the mucosa.
Ulcers resulting from GERD occur mainly in the distal third of the esophagus. Adjacent mucosal changes typical of reflux, such as squamous hyperplasia with prominent fibrovascular papillae and intraepithelial inflammation (eosinophils, neutrophils, and lymphocytes), are usually present. Herpesvirus inclusions are identified most readily in squamous cells at the edges of herpetic ulcers ( Fig. 10.3 ). In contrast, cytomegalovirus inclusions are most often found in endothelial cells or stromal cells at the ulcer base. Candida should be sought wherever neutrophils accumulate in the surface epithelium, usually in association with superficial desquamation. Morphologic features of radiation injury include dilated and thickened capillaries with deposition of hyaline, prominent endothelial cells, and reactive stroma with atypical stellate fibroblasts. NSAID-induced ulcers are typically large, shallow lesions with a broad base and are most common in the middle esophagus. Pill esophagitis shows superficial epithelial sloughing, keratinocyte necrosis, spongiosis, and intraepithelial eosinophils. Ulcerating malignant neoplasms may also be a source of bleeding, but this is an unusual presentation of esophageal cancer. However, the most common indication for endoscopy in patients with a secondary malignant neoplasm of the esophagus is GI bleeding. Bleeding from NSAID-induced ulcers is usually active and infrequently complicated by strictures. Rarely, esophageal or gastric ulcers perforate or penetrate into contiguous vascular organs, such as the heart and aorta, leading to massive bleeding ( Fig. 10.4 ). Ulcers resulting from foreign bodies are particularly prone to this complication.
Esophageal Diverticula
Esophageal diverticula are rare and usually asymptomatic. However, patients with diverticula may occasionally present with upper GI tract bleeding. Bleeding may occur in association with an ulcer, entrapped pills, or use of anticoagulants.
Stomach
Aside from bleeding resulting from varices, which commonly involves both the esophagus and the proximal stomach, gastric bleeding is most often caused by benign ulcers and erosive gastritis (see Table 10.2 ).
Gastric Varices
Gastric varices have clinical and pathologic features similar to those of esophageal varices. They most commonly occur on the lesser curve of the proximal stomach, in continuity with esophageal varices. Reports vary as to whether gastric varices, compared with esophageal varicies, are less likely or equally likely to bleed. Bleeding from gastric varices, when it does occur, is usually severe.
Gastritis and Gastric Ulcers
Clinical Features and Etiology
An estimated 350,000 cases of acute gastric ulcers are diagnosed annually. There are many causes of acute gastric (and duodenal) ulceration. Overall, gastric ulcers are more common in men than in women, and they are seen most often in the middle-aged and elderly population.
Peptic ulcers, both acute and chronic (including those located in the duodenum), account for 20% to 50% of cases of upper GI bleeding. Risk factors for peptic ulcer disease include Helicobacter pylori infection, NSAIDs, and alcohol.
Stress ulcers are acute gastric ulcers that develop in patients suffering from shock, sepsis, or trauma. Stress ulcers have numerous synonyms, such as acute hemorrhagic gastritis . Curling ulcers develop after severe burns. Cushing ulcers develop after severe head trauma. Steroid ulcers develop because of steroid use. Risk factors for stress ulcers include respiratory failure, coagulopathy, recent major surgery, major trauma, severe burns, hepatic or renal disease, sepsis, and hypotension.
Bleeding from acute gastritis may occur in long-distance runners and is of uncertain pathogenesis. Cocaine can cause gastric erosions and bleeding. Bleeding may also occur when an ulcer erodes into an underlying blood vessel. Dieulafoy lesions (also called caliber-persistent artery ) are bleeding ulcers that occur most commonly in the stomach but can also occur in the small and large intestines and, rarely, in the esophagus. Dieulafoy lesions are characterized by the presence of a single, unusually large-diameter mural arteriole that penetrates the submucosa ( Fig. 10.5, A ). These large vessels erode through the mucosa and cause massive bleeding (see Fig. 10.5, B and C ). Cameron ulcers are linear ulcers that form in a sliding hiatal hernia; they also can cause gastric bleeding.
Mass lesions, located either in the mucosa or deeper within the gastric wall, may erode the overlying mucosa and cause chronic low-grade bleeding ( Fig. 10.6 ). Fundic gland polyps, gastric adenomas, ectopic pancreas, malignant tumors (e.g., primary gastric adenocarcinomas, lymphomas, endocrine tumors), GI stromal tumors, and metastatic tumors (e.g., melanomas, breast carcinomas) can all cause upper GI bleeding. Gastric bleeding may also be iatrogenic in origin, such as after surgery for obesity.
Pathologic Features
Gastric ulcers consist of full-thickness loss of the gastric mucosa. Gastric erosions, in contrast, are characterized by partial loss of mucosa, with preservation of the muscularis mucosae. On gross examination, erosions appear as small, focal, erythematous areas of mucosa. Gastric ulcers are sharply demarcated, usually circular depressions in the luminal surface. Acute ulcers may have an erythematous base covered with clotted blood. Chronic ulcers have a distinctive gross appearance resulting from scarring of the underlying tissue, which results in the formation of radiating cicatricial folds in the mucosa surrounding the ulcer. Histologically, erosions show loss of superficial mucosa, scant fibrinopurulent exudate, and reactive changes in the surrounding epithelium (loss of mucin, nuclear hyperchromasia, and increased mitotic activity). Acute ulcers show necrosis, granulation tissue, and hemorrhage. Chronic ulcers have a granulation tissue base with underlying fibrosis that often disrupts the muscularis propria.
Portal Hypertensive Gastropathy
Portal hypertensive gastropathy occurs in as much as 90% of patients with cirrhosis-related portal hypertension. It is characterized endoscopically by the presence of a mosaic mucosal pattern, with or without petechial hemorrhages, usually of the proximal stomach. Portal hypertensive gastropathy may also occur in patients without cirrhosis. It is usually detected in patients with portal hypertension who are being evaluated for variceal bleeding. Portal hypertensive duodenopathy has been described in 51% of portal hypertensive patients and is an uncommon cause of occult GI bleeding. Endoscopic features include erythema, erosions, ulcers, telangiectases, and duodenal varices.
Altered gastric blood flow has been implicated in the pathogenesis of portal hypertensive gastropathy. Other postulated mechanisms include nitric oxide production, tumor necrosis factor-α synthesis, and sensitivity to prostaglandin inhibition.
Portal hypertensive gastropathy occurs most commonly in the fundus and body of the stomach. Histologic features include the presence of numerous ectatic capillaries and venules in otherwise normal mucosa and submucosa. Fibrin thrombi, inflammation, mucosal fibrosis, and fibrohyalinosis are not histologic components of portal hypertensive gastropathy ( Fig. 10.7, A ). There is no association with atrophic gastritis, CREST syndrome ( c alcinosis, R aynaud phenomenon, e sophageal involvement, s clerodactyly, and t elangiectases), or bone marrow transplantation ( Table 10.3 ). Portal hypertensive duodenopathy usually occurs in association with gastropathy; it is characterized by capillary congestion, capillary angiogenesis, and edema in the duodenal mucosa (see Fig. 10.7, B through D ) but only minimal inflammation.
| Features | Portal Hypertensive Gastropathy | Gastric Antral Vascular Ectasia |
|---|---|---|
| Clinical | ||
| Age | Adults and children | Middle aged to elderly |
| Gender | Male predominance | Female : male = 4 : 1 |
| Cirrhosis | ~95% | ~40% |
| Portal hypertension | 100% | ~40% |
| Iron deficiency anemia | Uncommon | Typical |
| Atrophic gastritis | Not associated | Associated |
| CREST syndrome | Not associated | Associated |
| Bone marrow transplantation | Not associated | Associated |
| Endoscopic | ||
| Location | Proximal stomach | Antrum |
| Red spots | Present | Present |
| Mosaic pattern | Present | Absent |
| Watermelon pattern | Absent | Often present |
| Pathologic | ||
| Background mucosa * | Oxyntic | Antral |
| Ectatic mucosal vessels | Present | Present |
| Fibrin thrombi * | Absent | Present |
| Spindle cell proliferation * | Absent | Present |
| Fibrohyalinosis * | Absent | Present |
| Treatment | ||
| Endoscopic ablation | Not required | Effective |
| Control of portal hypertension | Effective | May also be necessary |
Bleeding from portal hypertensive gastropathy is usually chronic and often controllable by medical or surgical management of the underlying cause of the patient’s portal hypertension.
Gastric Antral Vascular Ectasia
Gastric antral vascular ectasia (GAVE) affects mainly women of middle age, frequently causes iron deficiency anemia, and is associated with portal hypertension in about 30% to 40% of cases. It is sometimes associated with achlorhydria, atrophic gastritis, and the CREST syndrome. Autoimmune disorders are present in approximately 62% of patients with GAVE. At endoscopy, GAVE is characterized by a linear pattern of mucosal hyperemia on the antral rugae that appears similar to the stripes of a watermelon; hence, the synonym, watermelon stomach . This endoscopic appearance tends to be more diffuse in cases of cirrhosis but usually involves only the gastric antrum. The pathogenesis of GAVE is believed to be altered gastric motility.
Histologically, GAVE is characterized by the presence of dilated capillaries in the mucosa and submucosa, often containing microthrombi. Fibromuscular hyperplasia of the intervening lamina propria and focal hyalinosis are characteristic features, along with edema, congestion, and reactive changes of the foveolar epithelium ( Fig. 10.8 ). Inflammation is typically minimal. Surface erosion is uncommon.
In mucosal biopsies, both portal hypertensive gastropathy and GAVE should be distinguished histologically from chronic radiation gastritis, which also shows ectatic mucosal capillaries. In contrast, radiation injury is characterized by prominent endothelial cells and hyaline thickening of dilated capillaries and small blood vessels, sometimes associated with thrombosis ( Fig. 10.9 ). Features that differentiate portal hypertensive gastropathy and GAVE are summarized in Table 10.3 .
Endoscopic mucosal coagulation is the treatment of choice for most patients with GAVE. Antrectomy is reserved for patients with uncontrollable bleeding.
Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber Disease)
HHT, also referred to as Rendu-Osler-Weber disease, is an autosomal dominant condition in which telangiectases involve the mucous membranes of the oral cavity, but also any portion of the GI tract, where they may bleed. The disorder affects both sexes equally and occurs in all races. The typical clinical triad consists of telangiectasia and recurrent epistaxis in a patient with a family history of the disorder. The clinical features are variable. About 20% of patients do not reveal a family history of either telangiectasia or recurrent bleeding. Most patients express at least two of the following four manifestations: epistaxis, telangiectasia, visceral lesions (including GI telangiectasia), and a positive family history. At least two gene loci ( HHT1 and HHT2 ) have been implicated in HHT. GI bleeding is more likely in patients with HHT1 mutations. Upper GI bleeding is common and can be difficult to distinguish from epistaxis; the two are the most common manifestations of HHT. GI bleeding is often difficult to control. Blood transfusion requirements in excess of 100 units have been reported.
GI tract lesions include telangiectases, arteriovenous malformations (AVMs), and angiodysplasias. Telangiectases, which are the most common lesions, appear grossly as bright red spots on the mucosa. These lesions are composed of a tuft of dilated venules and arterioles that communicate directly with one another, thereby bypassing capillaries ( Fig. 10.10 ). The precise vascular architecture is often difficult to appreciate in routine histologic sections, but evaluation of serial sections may help.
Telangiectasia may also occur in patients with scleroderma, as part of the CREST syndrome. The morphology of telangiectases associated with scleroderma is similar to that in HHT, and distinction therefore requires clinical and serologic correlation (rheumatoid factor, antinuclear antibody, SCL-70 antibody, and anticentromeric protein antibody). Telangiectases may also develop in patients with chronic renal failure after hemodialysis.
Treatment options for GI hemorrhage associated with HHT include drug therapy with estrogen, danazol, or aminocaproic acid; endoscopic coagulation, cautery, or laser therapy; and surgical resection.
Lower GI Bleeding
Lower GI tract bleeding refers to any type of bleeding from a source located distal to the ligament of Treitz. Hemodynamically significant bleeding from the lower GI tract is most commonly caused by colonic diverticula and angiodysplasia (angiectasia). Other causes are listed in Table 10.4 . Colorectal causes are more prevalent than small intestinal causes. Chronic low-grade bleeding is often not visible to the patient and may be detected only by fecal occult blood testing.
| Entity | Key Clinical Features | Key Pathologic Features |
|---|---|---|
| Diverticular disease * | Most frequent in elderly Accounts for 30-40% of cases of significant lower GI hemorrhage | Most common in sigmoid colon Thickened muscularis propria, exaggerated mucosal folds Pseudodiverticula extend through muscularis at points of entry of vasa recta Inflammation of diverticula may lead to vascular erosion and bleeding |
| Angiodysplasia * | Common in elderly patients Bleeding chronic and recurrent Common cause of bleeding in renal failure | Usually in right colon Dilated, tortuous, thin-walled submucosal veins, capillaries, and arterioles with arteriovenous anastomoses Most commonly submucosal, may involve mucosa |
| Arteriovenous malformation | Developmental defects but may present at any age | Most common in sigmoid colon and rectum Arterialized veins with thick muscular walls are associated with a knot of tortuous, dilated veins and arteries |
| Dieulafoy lesion | See Table 10.2 | See Table 10.2 |
| Varices (rectal, stomal) | Associated with portal hypertension and mesenteric and splenic vein obstruction | Occur at portosystemic anastomoses in rectum and at enterocolic-cutaneous stomas Histologic features similar to upper GI varices |
| Portal hypertensive colopathy | Seen in portal hypertension Strong association with cirrhosis but no correlation with degree | Dilated tortuous mucosal and submucosal capillaries correspond to red spots seen at endoscopy |
| Hereditary hemorrhagic telangiectasia | See Table 10.2 | See Table 10.2 |
| Hemodialysis-associated telangiectasia | See Table 10.2 | See Table 10.2 |
| Hemorrhoids | Common in adults, increase in prevalence after third decade | Dilated, submucosal and mucosal blood vessels, usually with thrombosis and hemorrhage |
| Infections | See Table 10.5 | See Table 10.5 |
| Mucosal prolapse | History of prior lower GI tract trauma or surgery Diverticular disease | Reactive, hyperplastic mucosa with muscularization of lamina propria and inflammation |
| Meckel diverticulum | GI bleed most common presentation in children | True diverticulum on antimesenteric border of ileum Heterotopic oxyntic mucosa with peptic ulcer in 65% |
| Stercoral ulcers | Acute GI bleed in elderly patients Typically a history of constipation Common in renal patients treated for hyperkalemia | Sharply demarcated ulcers in rectosigmoid, formed as pressure sores caused by hard feces High risk of perforation |
| Ulcerative colitis | Intermittent rectal bleeding, bloody diarrhea, and abdominal pain | Typically continuous colonic involvement proceeding proximally from rectum with mucosal architectural distortion, a lymphoplasmacytic infiltrate, basal plasmacytosis, cryptitis, crypt abscesses, and ulceration |
| Crohn’s disease | More variable symptoms than ulcerative colitis, including abdominal pain, fatigue, weight loss, and fever | Typically patchy transmural involvement of small and/or large bowel by deep ulcers and lymphoplasmacytic inflammation with reactive lymphoid follicles, variable degrees of architectural distortion, pyloric gland metaplasia, cryptitis and crypt abscesses, with or without granulomas |
| Ischemic enterocolitis | See Table 10.9 | See Table 10.9 |
| Radiation enterocolitis | History of prostate cancer common in men, cervical cancer in women Rare cause of lower GI bleeding | Dilated, tortuous mucosal capillaries with prominent endothelial cells in mucosa Hyalinized vessels with prominent endothelial cells, stellate fibroblasts, and fibrosis in submucosa |
| Collagenous colitis | Watery diarrhea Female predominance: 4 : 1 Rare cause of lower GI bleeding | Marked subepithelial collagenous deposition and submucosal fibrosis, increased lamina propria lymphoplasmacytic inflammation and intraepithelial lymphocytes; subepithelial collagen may mimic hyalinosis of ischemic colitis |
| Diversion colitis | History of previous bowel resection with fecal stream diversion May cause bloody rectal discharge | Friable mucosa with normal architecture, mucin depletion, a lymphoplasmacytic infiltrate most dense in the upper mucosa, rare cryptitis, Paneth cell metaplasia, and prominent reactive lymphoid follicles |
| Diaphragm disease | History of use of NSAIDs | Transverse stenosing membrane composed of submucosa lined on both sides by mucosa, with central aperture |
| Ehlers-Danlos syndrome, vascular type | Acute hemorrhage and bowel perforation in young patients due to deficiency of collagen type 3 | Most commonly affects the sigmoid colon Thinned muscularis propria and diminished submucosa Proliferating fibroblasts surrounding fat Frayed, degenerated vascular and stromal collagen |
Lower GI bleeding occurs most commonly in the seventh decade of life. Although it is less common than upper GI bleeding, patients with lower GI bleeding are more likely to require surgery. The most common clinical presentation of patients with lower GI bleeding is passage of bright red blood per rectum (hematochezia). Similar to upper GI bleeding, lower GI bleeding may result in melena, anemia, or hemodynamic instability. Investigative modalities useful for identification of the source of lower GI bleeding include colonoscopy, angiography, nuclear scan, barium enema, and push enteroscopy.
Diverticulosis
Diverticulosis accounts for 30% to 40% of cases of significant lower GI hemorrhage. Left-sided diverticula are acquired outpouchings of the colonic mucosa that protrude through the muscularis propria at the points of entry of the vasa recta ( Fig. 10.11 ). They are usually situated in intimate contact with penetrating blood vessels, where inflammation and ulceration of diverticula can lead to erosion of the vessel wall and bleeding. Diverticular bleeding may be slow and chronic if venous in origin or acute and severe if an artery is involved. Right-sided diverticula are not usually associated with penetrating vessels. GI bleeding in Meckel diverticula is usually from foci of gastric heterotopia that cause peptic ulceration of the adjacent mucosa ( Fig. 10.12 ).
Most episodes of bleeding caused by colonic diverticula resolve spontaneously. However, as much as one third of patients require transfusion or therapeutic intervention. Treatment options include contact coagulation, epinephrine injection, hemoclip application, fibrin sealant, and surgical resection.
Angiodysplasia
Angiodysplasia (angiectasia) is the second most common cause of lower GI bleeding in elderly patients. Angiodysplasia is characterized by the presence of a cluster of abnormally dilated blood vessels in the submucosa and mucosa of the lower GI tract. Bleeding from angiodysplasia is usually chronic and recurrent, but massive hemorrhage occurs in approximately 10% to 15% of affected patients.
Angiodysplasias are acquired lesions associated with aging. They are usually located in the right colon but may occur anywhere in the large or small intestine. The incidence of angiodysplasia increases with age. This increase is thought to be related to changes in the composition and structure of the extracellular matrix of the bowel wall. Although usually readily seen by colonoscopy and angiography, angiodysplasia is often extremely difficult to detect on gross examination of a resection specimen without the use of specific injection techniques. By performing vascular injection studies of resected colons, Boley and Brandt determined that angiodysplasia develops as a result of intermittent partial obstruction of small veins that drain the colonic mucosa and submucosa as they course through the muscularis propria. They postulated that obstruction was caused by muscle contraction and increased tension within the bowel wall, which is highest in the region of colon with the greatest diameter (i.e., the cecum). With time, obstruction of the penetrating veins in the muscularis propria leads to dilation and tortuosity of the submucosal veins and, consequently, the venules and capillaries that drain them. Dilation of capillaries ultimately leads to loss of capillary sphincter function, which creates arteriovenous fistulas and secondary effects on the structure of the feeding arteries.
Angiodysplasias are often difficult to diagnose in pathologic specimens. In resection specimens examined in the fresh state, one may see only a small focus of enhanced vascular markings and erythema, and even these subtle signs may be absent. In specimens examined after formalin fixation, the lesions are usually not visible on the mucosal surface. Few laboratories are equipped to perform injection studies, which require processing of fresh specimens. With fixed resection specimens, slicing the bowel wall with a sharp blade at the site of suspected mucosal abnormalities helps reveal the lesion. If a vascular lesion is detected, histologic examination usually reveals a discrete cluster of dilated, tortuous veins and venules within the submucosa ( Fig. 10.13, A ), some associated with dilated capillaries in the overlying mucosa as well (see Fig. 10.13, B ).
Diagnosis of angiodysplasia in biopsy specimens is also problematic. The main histologic component of angiodysplasia is usually situated in the submucosa, which may not be sampled in superficial endoscopic biopsies. When capillary dilation involves the mucosa, biopsy specimens may show only one or two ectatic capillaries, and these may collapse when the specimen is immersed in formalin. In more advanced lesions with more extensive mucosal involvement, clusters of dilated capillaries may distort the architecture of the mucosa, displacing glands and separating the crypts from each other.
In most instances, bleeding can be controlled adequately by therapeutic endoscopy. Angiographic techniques not only enable precise localization of angiodysplasia but allow for treatment by superselective embolization. Surgical resection is reserved for patients with uncontrolled bleeding.
Arteriovenous Malformation
In contrast to angiodysplasia, which is an acquired lesion that develops mainly in elderly patients, arteriovenous malformation (AVM) develops during embryologic or fetal life and is typically present at birth. AVM also differs from angiodysplasia in that it results in an abnormal direct communication between arteries and veins. Because of this communication, arterial blood flows directly into the venous system at higher-than-normal pressure, bypassing the (high-resistance) capillary bed. AVMs can manifest clinically with bleeding at any age.
In the GI tract, AVMs occur most often in the sigmoid colon and rectum and are usually located external to the muscularis propria—that is, in the subserosa. The malformation consists of a tangled mass of tortuous, variably dilated arteries, veins, and vessels with intermediate characteristics. Veins in AVMs undergo “arterialization” in response to exposure to elevated (arterial) blood pressure. They develop a thick, muscular wall as a result of myointimal hyperplasia ( Fig. 10.14 ). It has been proposed that idiopathic myointimal hyperplasia of the mesenteric veins (discussed later) is an example of venous arterialization as a complication of AVM. Histologically, AVMs are characterized by the presence of complex clusters of tortuous, dilated vascular channels and vessels that appear intermediate in structure between arteries and veins. However, the vascular architecture is more easily deciphered by angiographic studies.
Most AVMs of the GI tract are treated angiographically by superselective embolization. Large lesions may require surgical resection.
Hemorrhoids
Hemorrhoids are very common. Clinically, most patients are seen in middle age with anal pain or bleeding. Hemorrhoids arise from the anal cushions, which are normal anatomic structures of the anorectal canal. The anal cushions are composed of tufts of anastomosing arterioles and venules in the submucosa; they are embedded within compact, dense, submucosal collagenous and elastic fibrous stroma and covered by anorectal mucosa. Hemorrhoids develop as a result of degenerative changes that occur in the supporting stroma or as a result of locally increased intravascular pressure. The blood vessels become engorged and the cushions prolapse, strangulate, thrombose, ulcerate, and bleed. Histologic sections of hemorrhoids show tufts of engorged, dilated veins and arteries with thrombi and hemorrhage, in a dense stroma, covered by anal or rectal mucosa, which often is ulcerated. Treatment options for hemorrhoids include dietary modification, sclerotherapy, photocoagulation, diathermy, banding, laser ablation, cryotherapy, and surgical hemorrhoidectomy.
Diaphragm Disease
Diaphragm disease is a rare cause of GI bleeding linked to chronic use of NSAIDs. This entity was first described in the small intestine in 1988. Similar abnormalities have been described in the large intestine as well. GI bleeding associated with diaphragm disease is usually occult. Obstructive symptoms tend to dominate the clinical picture. The pathogenesis of this disorder is unclear. Some suggest that inhibition of the cyclooxygenase pathway leads to erosions in the GI tract, modulation of nuclear factor-κB and peroxisome proliferator–activated receptor-γ, and increased intestinal permeability, which lead to mucosal injury. Alternatively, NSAID-associated circumferential ulceration, followed by the development of submucosal fibrosis and mucosal regeneration, may result in diaphragm formation.
Diaphragms may be single or multiple. They are composed exclusively of mucosa and submucosa, without involvement of the muscularis propria or adventitia. Histologically, the diaphragm represents a disc of submucosa lined by mucosa, with a central opening. Typically, the submucosa is fibrotic. The connective tissue fibers are usually oriented perpendicular to the lumen of the bowel and are often associated with haphazardly arranged nerves, blood vessels, and smooth muscle fibers (see Chapter 16 for photograph).
Ehlers-Danlos Syndrome, Vascular Type (Type IV)
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited disorders characterized by defective collagen and connective tissue synthesis. Of these, EDS type IV (vascular type) causes GI tract pathology, leading to significant complications in as much as 25% of patients by the age of 20 years and as much as 80% by age 40 years. Patients usually succumb to complications of this disease by the fourth or fifth decade of life. The diagnosis is established by the presence of two or more of the following features: distinctive facial features (slender face, prominent facial bones, bulging eyes with telangiectasia, and thin, pinched nose), translucent skin, excessive bleeding or hematomas, and blood vessel or visceral organ rupture. In most cases, this disorder is inherited in an autosomal dominant manner, although many cases are sporadic. EDS type IV is caused by mutations in the COL3A1 gene, which result in defective synthesis of type III procollagen and diminished extracellular type III collagen. The result is weakening of the supporting connective tissue stroma, including the submucosa and blood vessels.
The sigmoid colon is most commonly affected, but the small bowel, stomach, and even the esophagus may also be involved in rare cases. EDS type IV causes thinning of the muscularis propria and submucosa of the GI tract. Complications include diverticula, perforation, and hemorrhage. Microscopically, vascular and stromal collagen is often frayed and fragmented. The submucosal blood vessels may be thin, thick, or nodular in appearance. The outer layers of the blood vessel walls may appear discontinuous. The muscularis propria often shows secondary ischemic changes. Inflammation is uncommon. Diminished expression of type III collagen (vascular and extravascular) can be demonstrated by immunohistochemical staining.
As many as 8% of patients die of bowel rupture and sepsis. Bleeding may occur as a result of rupture of blood vessels in the bowel wall. Treatment is by surgical resection of the affected segment. As much as one third of patients have recurrent perforations.
Miscellaneous Entities
Chronic radiation injury in the GI tract is characterized by the presence of dilated, tortuous capillaries with hyaline thickening and prominent capillary endothelial cell nuclei ( Fig. 10.15 ). Dilated capillaries located near the mucosal surface may rupture and cause hemorrhage. Histologically, this condition should be distinguished from portal hypertensive colopathy in patients with portal hypertension. In that condition, the dilated capillaries typically lack the hyalinization and prominent endothelial cell nuclei typical of radiation injury ( Fig. 10.16 ). In resection specimens with chronic radiation injury, sclerosis of submucosal and extramural arteries is characteristic and is associated with fibrosis and stenosis, the presence of atypical stellate fibroblasts, and secondary chronic ischemic changes.
Many types of inflammatory conditions can cause lower GI bleeding. Microbial agents that can cause GI bleeding include cytomegalovirus ( Fig. 10.17 ), which predominantly affects immunocompromised patients; Salmonella; Shigella; enterohemorrhagic Escherichia coli ( Fig. 10.18 ); Clostridium difficile ( Fig. 10.19 ); Clostridium perfringens ( Fig. 10.20 ); and Klebsiella oxytoca ( Table 10.5 ). Certain GI parasites can also cause bleeding, such as Entamoeba histolytica , Strongyloides , and hookworms. Active ulcerative colitis ( Fig. 10.21 ) or Crohn’s disease ( Fig. 10.22 ), mucosal ulceration or injury caused by mucosal prolapse, use of NSAIDs, and endoscopic procedures may lead to bleeding as well. In some patients with collagenous colitis, the thickened subepithelial collagen layer may render the colon susceptible to tearing of the mucosa during colonoscopy ( Fig. 10.23 ). Stercoral ulcers in the rectum of elderly patients are a common cause of lower GI bleeding ( Fig. 10.24 ).
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