Systemic Illnesses Involving the Gastrointestinal Tract

Cardiac Surgery and Heart Transplantation

GI complications after open heart surgery are uncommon, occurring in approximately 4% of cases; however, the mortality rate can be high (approximately 16% for those with infective endocarditis). ^, The most common complication is postoperative ileus (which has the lowest mortality). Other complications typically consist of GI hemorrhage secondary to stress ulceration, vascular insufficiency with ischemic necrosis of bowel, and acute diverticulitis. Additional risk factors for ischemia include end-stage renal disease, female sex, non–coronary artery bypass graft, and long pump times.

In contrast with GI complications after open heart surgery, GI complications after cardiac transplantation have been reported in as many as 20% of patients. ^, Complications include all of the hemorrhagic conditions mentioned previously. In addition, the use of steroids and immunosuppressive agents increases the risks of intestinal perforation, fistula formation, and infectious GI diseases. These patients are also at risk for posttransplantation lymphoproliferative disorders (see Chapter 53 ).

Ischemic Disease

Intestinal ischemic disease can be divided into two major subsets: nonthrombotic (approximately 60% of cases) and thrombotic (approximately 40% of cases). 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 older adults. 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%. The classic presentation is “pain out of proportion to examination.” Histologically, resultant lesions range from epithelial and lymphocytic apoptosis to mucosal necrosis and transmural infarction of the bowel ( Fig. 7.1 ). Specifics concerning histology and pathology are discussed in Chapter 11 . The most critical factor influencing outcomes in patients is the speed of diagnosis and intervention.

Bullous Diseases

The majority of primary dermatological 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 morphological features are the level of the plane of separation (vesicle formation), the type of inflammatory infiltrate, and the presence or absence of acantholysis. 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 histological 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. ^, 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). 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.

Dermatological Disorders Associated with Malignancies of the GI Tract

Adrenal Gland

Addison’s disease (primary chronic adrenocortical insufficiency) may cause common GI disturbances such as anorexia, nausea, vomiting, and diarrhea. Pheochromocytomas are characterized by hypertension resulting from 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.

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 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 resulting from 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, and an increased prevalence of colonic adenomas and colonic carcinoma has been observed. An increased risk of gastric carcinoma has also been suggested but is less well established.

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 40 .

Diabetes can involve significant GI symptoms. 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. 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. Histological features are nonspecific. Neuropathic findings with silver stains have been described, as have periodic acid–Schiff (PAS)–positive vascular deposits in the vessels of the submucosa.

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.

Parathyroid

Both hyperparathyroidism and hypoparathyroidism can cause GI symptoms. GI symptoms occur in one-half of patients with hyperparathyroidism and may be the presenting symptom in 15% of cases. These patients typically have abdominal pain, nausea, vomiting, and constipation. Many of these symptoms are thought to be caused by hypercalcemia, which results in altered neuronal transmission and neuromuscular excitability. 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.

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. 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. 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.

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 gland. Patients may have prominent “explosive” watery diarrhea as the result of ectopic hormone production. Papillary carcinoma of the thyroid also can be associated with Gardner’s syndrome.

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. 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.

Hemorrhagic Disorders

Patients with bleeding disorders may develop spontaneous hemorrhage in any part of the GI tract. Between 10% and 25% of patients with hemophilia suffer from GI hemorrhage. Von Willebrand’s disease, heparin or warfarin overdose, vitamin K deficiencies, platelet deficiency, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome (HUS) can all result in hemorrhage of the GI tract. This is most commonly seen in the upper GI tract and typically is most prominent in the submucosa. It can be severe enough to involve the entire thickness of the bowel wall and give rise to an intramural hematoma. More severe lesions can cause luminal narrowing, rigidity with obstruction, and, rarely, intussusception.

Thrombotic Disorders

Sickle cell anemia, polycythemia rubra vera, and other thrombotic disorders 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. 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 B ₁₂ . 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. As a result of impaired DNA synthesis, actively dividing cells in the gastric pits, small bowel, and colonic crypts typically show enlarged, immature-appearing nuclei ( Fig. 7.2 ). 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. 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. 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. These infiltrates can cause aphthous-type ulcers (typical of leukemic infiltrations) or can result in polypoid, masslike, or large ulcers (typical of lymphomatous involvement). The larger mass lesions can occasionally cause obstruction or intussusception. Histological 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. 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. 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.

Acrodermatitis Enteropathica

Acrodermatitis enteropathica is a systemic disorder that occurs secondary to zinc deficiency resulting from a congenital defect in absorption of dietary zinc. This disorder has been localized to a gene (SLC39A4) that codes for a transmembrane zinc uptake protein (hZIP4). It typically manifests after infancy and weaning (although rare cases have been described in adulthood ). It is characterized by chronic diarrhea associated with failure to thrive, periorofacial dermatitis, paronychia, nail dystrophy, alopecia, susceptibility to infection, and behavioral changes. Serum zinc levels are typically decreased. Treatment is provided in the form of oral zinc. Mucosal biopsy of the small bowel can be normal or can show mild, patchy villous lesions. Abnormal inclusion bodies have been described in Paneth cells on electron microscopy. Acrodermatitis may also be caused by zinc deficiency secondary to Crohn’s disease or malnutrition.