Ischemic Disease

Intestinal ischemic disease can be divided into two major subsets: nonthrombotic (approximately 60% of cases) and thrombotic (approximately 40% of cases).⁶ Nonthrombotic causes of ischemic disease include decreased mesenteric blood flow secondary to cardiac failure, shock, atherosclerotic vascular disease, disseminated intravascular coagulation, vasculitis, and fibromuscular dysplasia. Thrombotic causes can be divided into arterial embolism, arterial thrombosis, and venous thrombosis. These are a heterogeneous group of disorders usually seen in elderly individuals.⁷ Colonic ischemia, the most common disorder (typically nonthrombotic), has a favorable prognosis. Acute mesenteric ischemia, in contrast, has a poor prognosis, with a survival rate of only 50%.⁶ Histologically, resultant lesions range from epithelial and lymphocytic apoptosis⁸ to mucosal necrosis and transmural infarction of the bowel (Fig. 6.1). Specifics concerning histology and pathology are discussed in Chapter 10.

Bullous Diseases

The majority of primary dermatologic bullous disorders that involve the GI tract occur in conjunction with a skin disorder (excluding dermatitis herpetiformis). These diseases typically involve the upper portion of the esophagus. Patients are seen with symptoms of dysphagia and odynophagia. Histologically, the lesions in esophageal squamous mucosa appear similar to those in the skin. The key distinguishing morphologic features are the level of the plane of separation (vesicle formation), the type of inflammatory infiltrate, and the presence or absence of acantholysis.⁹ Because the bullae rarely remain intact, diagnosis of these lesions on GI biopsy specimens is challenging. The diagnosis is usually made on the basis of appropriate clinical information combined with biopsies of the skin lesions. In the esophagus, lesions often rupture and produce erosions; occasionally, fibrosis and stricture formation are also seen.

Dermatogenic Enteropathy

Many GI symptoms and histologic findings have been described in patients with active psoriasis and eczema. Steatorrhea and malabsorption are not uncommon, and the terms dermatogenic enteropathy and psoriatic enteropathy have been applied to these syndromes.^28,29 Histologically, the duodenal mucosa shows an increase in the numbers of mast cells and eosinophils. A subset of patients have increased numbers of duodenal intraepithelial lymphocytes and antibodies to gliadin (suggestive of latent celiac sprue).³⁰ In addition, the colon may show increased lamina propria cellularity, active inflammation, and occasional gland atrophy in mucosal biopsy specimens from patients who have psoriasis without bowel symptoms.³¹

Acanthosis nigricans consists of numerous brown, hyperpigmented, velvety skin plaques located in the axillae, groin, and flexural areas. The lesion has two major forms—one associated with internal malignancies and the other associated with insulin resistance. Microscopically, dermal lesions are characterized by diffuse hyperkeratosis and papillomatosis. Epithelial hyperplasia of the esophagus also has been described.

When present, this lesion is usually associated with adenocarcinomas of the stomach and colon. At least one report has suggested that it is caused by the production of transforming growth factor-α by tumor cells.³²

Adrenal Gland

Addison disease (primary chronic adrenocortical insufficiency) may cause common GI disturbances such as anorexia, nausea, vomiting, and diarrhea.³⁸ Pheochromocytomas are characterized by hypertension due to high catecholamine levels. Intestinal pseudo-obstruction, megacolon, and even bowel ischemia have also been described and are thought to be secondary to the vasoconstrictive action of excess catecholamine levels.³⁹

Hypothalamus and Pituitary

The hypothalamus and pituitary function as a unit. Disorders of either one infrequently affect the GI tract. Hypopituitarism affects intestinal motility, as does hypothyroidism. Pituitary adenomas are part of the multiple endocrine neoplasia (MEN) syndrome, discussed later in this chapter. Of the hyperpituitary lesions, acromegaly is of interest with respect to GI neoplasia. Acromegaly is characterized by chronic hypersecretion of growth hormone and insulin-like growth factor, usually due to a pituitary adenoma. It is associated with overgrowth of the musculoskeletal system and all organs, including the GI tract. Acromegaly has been shown to increase epithelial cell proliferation in the colon,⁴⁰ and an increased prevalence of colonic adenomas and colonic carcinoma has been observed.⁴¹ An increased risk of gastric carcinoma has also been suggested but is less well established.⁴²

Pancreas

Diseases of the exocrine and endocrine pancreas commonly affect the GI tract. These include pancreatic exocrine insufficiency, diabetes, and hormonal effects of functional pancreatic endocrine neoplasms. Pancreatic exocrine insufficiency typically gives rise to steatorrhea and malabsorption and is discussed further in Chapter 39.

Diabetes can involve significant GI symptoms.⁴³ These result from decreased motility secondary to autonomic nervous system dysfunction. Patients have symptoms such as abdominal pain, bloating, early satiety, nausea, and vomiting. Abdominal bloating appears to correlate best with decreased gastric emptying.⁴⁴ The delayed gastric emptying associated with gastric atony and gastric dilation is called gastroparesis diabeticorum, and an increased risk of bezoar formation is apparent. Patients can also experience periodic intractable diarrhea and crampy abdominal pain. Because of hypomotility, these patients are at risk for bacterial infection and malabsorption. Patients are also at increased risk for Candida infection of the esophagus.⁴⁵ Histologic features are nonspecific. Neuropathic findings with silver stains have been described,⁴⁶ as have periodic acid–Schiff (PAS)-positive vascular deposits in the vessels of the submucosa.⁴⁷

Excess hormonal production from the pancreatic islets of Langerhans can be a result of diffuse hyperplasia (nesidioblastosis) or pancreatic endocrine tumors. Many hormones, such as insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, adrenocorticotropic hormone, calcitonin, parathormone, and serotonin, can be produced by these lesions. All GI manifestations reflect altered digestive function and motility.⁴⁸

Parathyroid

Both hyperparathyroidism and hypoparathyroidism can cause GI symptoms. GI symptoms occur in half of patients with hyperparathyroidism and may be the presenting symptom in 15% of cases.⁴⁹ These patients typically have abdominal pain, nausea, vomiting, and constipation. Many of these symptoms are thought to be due to hypercalcemia, which results in altered neuronal transmission and neuromuscular excitability.⁵⁰ Hypoparathyroidism can be associated with malabsorption and steatorrhea. The small intestinal mucosa is typically histologically normal, but rare associations with celiac sprue have been reported.⁵¹

Thyroid

Both hyperthyroidism and hypothyroidism can cause GI symptoms. Hyperthyroidism produces hypermotility of the gut, and hypothyroidism causes hypomotility. Hyperthyroidism can result in rapid gastric emptying, watery diarrhea, and steatorrhea.⁵² No constant structural changes in the mucosa or in the wall of the bowel have been consistently reported. Hypothyroidism can be associated with gastric bezoar formation, ileus, volvulus, constipation, and megacolon.⁵² In patients with marked myxedema, dilation and thickening of the bowel wall with microscopic accumulation of mucopolysaccharide substances in the submucosa, muscularis propria, and serosa have been described.⁵³

Thyroid neoplasms may also produce GI effects. Medullary carcinoma of the thyroid is a tumor of the calcitonin-producing endocrine C cells of the thyroid. Patients may have prominent “explosive” watery diarrhea as the result of ectopic hormone production.⁵⁴ Papillary carcinoma of the thyroid also can be associated with Gardner syndrome.⁵⁵

Multiple Endocrine Neoplasia

The MEN syndromes are a group of autosomal dominant inherited disorders associated with hyperplasia or neoplasms of several endocrine organs. Three main varieties of this syndrome can occur—MEN I, MEN IIa, and MEN IIb (or III). GI manifestations are caused by the products of endocrine proliferations.⁵⁶ Each of these syndromes is associated with a mutant gene locus—MEN I with the MEN1 gene locus, and MEN IIa and IIb with the RET gene locus. MEN I is associated with pancreatic endocrine tumors (often gastrinomas) and with the Zollinger-Ellison syndrome, which is associated with gastric and duodenal disease. MEN IIb may be associated with ganglioneuromatosis, ganglion cell hyperplasia, and hypertrophy of the plexuses of Meissner and Auerbach in the GI tract. Chronic constipation, diarrhea, or both may be associated with MEN IIb.⁵⁷

Thrombotic Disorders

Sickle cell anemia,⁶¹ polycythemia rubra vera,⁶² and other thrombotic disorders⁶³ can produce thrombosis, leading to infarction and hemorrhage of the intestines. Sickle cell anemia causes sickling of red blood cells and hyperviscosity of the blood and typically produces arterial and capillary obstruction.⁶¹ It involves the watershed areas of the distal transverse colon and splenic flexure, which have the lowest oxygen tension. Sickled red blood cells may be found in the vessels. Polycythemia usually leads to venous obstruction of the portal and mesenteric veins. These lesions involve the deeper parts of the bowel wall, including the muscularis propria. Diagnosis is based on the finding of venous thrombi in the mesenteric and mesocolic tissues not in the field of infarction, which occur in conjunction with appropriate clinical history.

Megaloblastic Anemia

Megaloblastic anemias are associated with deficiencies of folic acid and vitamin B₁₂. These anemias are characterized by megaloblastic proliferation of actively growing cells, as is typically described in bone marrow aspirations but is also seen in the epithelial cells of the GI tract. Owing to impaired DNA synthesis, actively dividing cells in the gastric pits, small bowel, and colonic crypts typically show enlarged, immature-appearing nuclei (Fig. 6.2). The nucleus-to-cytoplasm ratio is decreased. The overall numbers of mitotic figures are also reduced. In addition, PAS-negative, Alcian blue–negative cytoplasmic vacuoles have been described in duodenal enterocytes.⁶⁴ Megaloblastic anemia can be caused by pernicious anemia secondary to autoimmune gastritis; therefore, gastric findings of atrophic autoimmune gastritis may also be present.

Leukemia and Lymphoma

Involvement of the GI tract is often noted in patients with leukemia and lymphoma. This can occur directly by tumor (primary or secondary), secondary to complications of disease, or secondary to therapy (see Chapter 31 for details).

Autopsy studies have revealed GI involvement in 50% of patients with leukemia.⁶⁵ In secondary involvement of the GI tract by either leukemia or lymphoma, tumor infiltrates are often multifocal and may be present anywhere from the esophagus to the rectum.⁶⁶ These infiltrates can cause aphthous-type ulcers (typical of leukemic infiltrations) or can result in polypoid, masslike, or large ulcers (typical of lymphomatous involvement).⁶⁷ The larger mass lesions can occasionally cause obstruction or intussusception.⁶⁸ Histologic features are those typical of the particular type of leukemia or lymphoma. Malignant cells are typically found in the mucosal and submucosal tissue. Tissue should be collected for molecular and cytogenetic analysis, because many leukemias and lymphomas include diagnostic and clinically important changes.⁶⁹ Primary lymphomas of the GI tract are often solitary lesions, although diffuse forms do occur (usually in the small bowel).

Secondary effects of tumor overgrowth, or of chemotherapy, resulting in decreased numbers of platelets and inflammatory cells can lead to hemorrhagic lesions of the GI tract and opportunistic infections. In addition, neutropenic colitis, which is a necrotizing inflammatory disorder of the colon that occurs in neutropenic patients, can occur with chemotherapy and, rarely, as a complication of acute leukemia.⁷⁰ Finally, patients who have received a bone marrow transplant may develop graft-versus-host disease, which is characterized by apoptotic destruction of the epithelium throughout the GI tract. It typically manifests with diarrhea. Histologically, it is characterized by apoptosis of the epithelial cells, followed by crypt and gland loss and, ultimately, mucosal erosion and ulceration.⁷¹

Plummer-Vinson Syndrome (Paterson–Brown Kelly Syndrome)

The unusual Plummer-Vinson syndrome has shown a recent decrease in incidence.⁷⁷ It is characterized by iron deficiency (its presumed cause), dysphagia, and esophageal webs.⁷⁸ Dermatologic findings of angular stomatitis, atrophic tongue, and brittle nails are also seen. Long-standing disease is associated with an increased incidence of postcricoid carcinoma. Iron repletion improves all lesions.

Vitamin Disorders

In general, vitamin disorders are not associated with specific GI symptoms or lesions. Exceptions are brown bowel syndrome, which is thought to be caused by a deficiency of vitamin E (discussed later), and pellagra, which is associated with niacin deficiency (discussed in this section). Multiple vitamin deficiencies are often noted in malabsorptive disorders. Vitamins, macronutrients, and minerals are thought to have a protective effect with respect to neoplasia of the GI tract, especially for esophageal^79,80 and gastric⁸¹ malignancies. Deficiency in vitamin K or anticoagulation therapy leads to a decrease in coagulation factors and can result in hemorrhagic lesions throughout the body.⁸² In the GI tract, these range from focal petechial hemorrhages to frank exsanguination. No specific histologic features are associated with these lesions. Similarly, vitamin C deficiency (scurvy) can lead to hemorrhage and delayed wound healing. Deficiencies of folic acid and vitamin B₁₂ are associated with megaloblastic anemia and megaloblastic changes in the epithelial cells of the stomach and small intestine.⁸³ Olestra (a nonabsorbed fat replacement) may decrease the absorption of fat-soluble vitamins.⁸⁴

Abetalipoproteinemia (discussed further in Chapter 9) is an autosomal recessive disorder characterized by a defect in the secretion of plasma lipoproteins that contain apolipoprotein B. Patients have steatorrhea, usually in infancy, with central nervous system symptoms such as disturbance in gait and balance and fatigue.⁹⁰ On peripheral smear, acanthocytes are usually prominent (in 50% of red blood cells). Laboratory findings show an absence of very-low-density lipoproteins, the presence of chylomicrons, and a reduction in triglycerides and other lipids. The defect occurs in a microsomal triglyceride transfer protein required for the secretion of plasma lipoproteins containing apolipoprotein B.⁹¹ Normal intraluminal digestion of lipids occurs, along with transport of triglycerides and monoglycerides and their reesterification in enterocytes. However, lipids cannot be excreted on the basal lateral membrane of the enterocytes into blood and lymphatics. Histologically, this translates into prominent accumulation of fine lipid droplets within the basal aspect of the enterocytes (Fig. 6.3). These can be stained with Oil Red O on frozen-section tissue or seen by electron microscopic examination. The overall architecture of the small bowel is normally well maintained. One pitfall in diagnosis is the similar appearance of lipid droplets identified in normal individuals after a recent lipid-rich meal; therefore, the diagnosis should be made only in fasting patients.

Tangier Disease

Tangier disease is an autosomal recessive disorder characterized by deposition of cholesteryl esters in the reticuloendothelial system, almost complete absence of high-density lipoprotein in the plasma, and aberrant cellular lipid trafficking.⁹² Clinically, patients present with hepatosplenomegaly, enlarged tonsils, peripheral neuropathy, and, occasionally, diarrhea. Laboratory studies reveal low blood levels of high-density lipoprotein and cholesterol (due to lack of apoprotein A) and high levels of triglycerides. Endoscopically, the lesions are described as tiny yellow nodules or orange-brown spots.⁹³ Microscopic examination reveals clusters of foamy histiocytes in the lamina propria (Fig. 6.4). Electron microscopic findings include intracytoplasmic vacuoles unbounded by membranes; these are often confluent in appearance⁹⁴ (see Chapter 9 for details).

Lysosomal Storage Disorders

Lysosomes, which are a major component of the intracellular digestive tract, contain hydrolytic enzymes made in the endoplasmic reticulum. These enzymes break down a variety of complex macromolecules that are either a component of the cell or are taken up by phagocytosis. Lysosomal storage disorders are inherited disorders (usually autosomal recessive) caused by lack of a functional enzyme or defective enzyme lysosome targeting. Substances typically accumulate within cells at the site where most of the degraded material is found; degradation typically occurs at this location.

Storage disorders can be divided based on the biochemical nature of the accumulated metabolite into glycogenoses, sphingolipidoses (lipidoses), mucopolysaccharidoses, mucolipidoses, and others. Most of these diseases have prominent central or peripheral nervous system effects.⁹⁵ Except for Fabry disease, they do not have significant GI effects. Case reports of malabsorption in GM1 gangliosidosis,⁹⁶ diarrhea in Niemann-Pick disease,⁹⁷ and diarrhea and vomiting in Wolman disease have been described.⁹⁸

The importance of these diseases is that depositions can be identified in a variety of cells in the GI tract (Table 6.2), typically in the phagocytic cells (macrophages) in the lamina propria. The histologic appearance typically reveals an accumulation of cells with foamy cytoplasm. The material may be positive for fat stains such as Oil Red O or Sudan black on frozen-section tissue or PAS stain, depending on the particular substance that has accumulated. Electron microscopic examination typically reveals enlarged, unusually shaped lysosomes. Historically, many of these diagnoses have been made on rectal biopsy with histochemical stains and subsequent electron microscopic examination.^99–101 This technique has largely been supplanted by specific enzyme content analysis of circulating lymphocytes or biopsy material. Differentiation among the common mimics of storage disorders is described in the next section.