The general impact of gastrointestinal (GI) disorders is often underestimated. Diseases of the GI tract are frequently misdiagnosed, untreated, or undertreated. Approximately 70 million Americans are diagnosed with GI disorders accounting for more than 105 million physician visits per year. GI diseases are associated with significant morbidity, mortality, and decreased quality of life. This chapter will review the more common GI disorders.
Description of Disease/Condition
Dyspepsia is classically described as an episodic or recurrent pain or discomfort arising from the proximal GI tract. Dyspepsia is a group of symptoms associated with heartburn, weight loss, regurgitation, indigestion, bloating, early satiety, and gastroesophageal reflux. Therefore, prevalence of dyspepsia cannot be accurately estimated due to lack of a standardized definition. In an effort to further refine the term dyspepsia, an international panel of clinical investigators published a consensus opinion and the term functional dyspepsia is now preferred:
- Functional dyspepsia is the presence of gastroduodenal symptoms without any causative organic, systemic, or metabolic disease.
- Functional dyspepsia has been separated into two distinct subgroups:
- postprandial distress syndrome (postprandial fullness and early satiety);
- epigastric pain syndrome (constant non-meal-related pain).
Gastroesophageal Reflux Disease
Gastroesophageal reflux disease (GERD) is an excessive retrograde movement (reflux) of acid-containing gastric secretions or bile and acid-containing secretions from the duodenum and stomach into the esophagus, causing troublesome symptoms and/or complications. The condition of gastroesophageal reflux is experienced occasionally by most people, especially after meals. Typical symptoms of GERD include heartburn, regurgitation, and dysphagia. Atypical symptoms include noncardiac chest pain, aspiration, asthma, hoarseness, and pneumonia. Complications include Barrett’s esophagus, which is the premalignant lesion that links GERD and the most rapidly increasing cancer of the GI tract, esophageal adenocarcinoma. Erosion of the teeth may also occur.
Peptic Ulcer Disease
Peptic ulcer disease (PUD) is ulceration of the stomach or duodenum, the first section of the small intestine. Ulcerations are caused by decreased protective mucosal factors or by various mucosal damaging mechanisms.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a chronic condition that includes ulcerative colitis (UC) and Crohn’s disease (CD) and is characterized by acute flare-ups separated by periods of quiescence. Remission can occur without therapy. More recently, the less common microscopic colitis has been categorized as a type of IBD1:
- UC is an inflammatory disorder resulting in ulcerations of the lining of the colon and rectum. UC patients typically present with mild-to-moderate diarrhea without constitutional symptoms. The number of bowel movements increases with severity of UC and constitutional symptoms such as dehydration, fatigue, fever, and weight loss are more likely to occur. With rectal involvement, there are frequent small, more urgent, bloody stools.
- CD is an inflammatory disease of the bowel more commonly affecting the terminal ileum, the most distant part of the small intestine. CD symptoms also include diarrhea, fatigue, weight loss, and abdominal pain. With mild CD, abdominal pain can be vague, diarrhea intermittent, and no weight loss noted.
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is an inclusive term for multiple potential physiological issues including disturbed central nervous system (CNS) pain processing, mucosal inflammation, abnormal colon motility, and anxiety disorders. Discussion of IBS is beyond the scope of this chapter. But it is important to note that IBS is much more prevalent than IBD, and IBD patients are frequently mislabeled with a diagnosis of IBS.
Pseudomembranous colitis (PC) is an inflammation of the colon associated with antibiotic use. It is generally caused by Clostridium difficile, a gram-positive, anaerobic, spore-forming bacteria. C. difficile releases an enterotoxin (toxin A) and a cytotoxin (toxin B) that cause mucosal inflammation and lead to apoptosis.2
Celiac disease (gluten-sensitive enteropathy) is a chronic digestive disease characterized by small intestine malabsorption. Individuals with celiac disease have an abnormal immune reaction to gliadin, the alcohol-soluble fraction of gluten. Gluten is found in wheat and related species including rye and barley. Gluten is a source of protein in many parts of the world and is also used as an additive to foods low in protein or as a meat substitute.3
An immunologically mediated inflammatory response occurs when gliadin is ingested. As a result, the villi, the tiny, fingerlike protrusions lining the small intestine, are damaged or destroyed. Malabsorption results from the immunomodulated process and diarrhea may occur. Some individuals may have subtle symptoms or are asymptomatic.
Gastric cancer is an adenocarcinoma of the stomach. Approximately 15% of gastric cancers occur in the upper part of the stomach while 40% of cancers develop in the middle part and 40% develop in the lower part of the stomach. Anatomically, the location of gastric cancer is related to differing vascular supply sources.
Colorectal cancer is a complex disease where genetic changes are often associated with progression from a premalignant lesion (adenoma) to invasive adenocarcinoma in the lower GI tract. Approximately 10% of adenomas will progress to adenocarcinomas, and this process may take up to 10 years. Adenocarcinomas make up the majority of colon and rectal cancers. Other rarer rectal cancers include lymphoma, sarcoma, and carcinoid adenocarcinoma.
Dysmotility has been the prime focus of research in functional dyspepsia. Visceral hypersensitivity also plays a role in 30–40% of patients with functional dyspepsia. The role of aberrant cerebral processing of visceral stimuli and visceral events is also being explored in functional dyspepsia. The evidence to date does not suggest a significant genetic contribution to functional dyspepsia.
The pathophysiology of GERD is multifactorial. The normal highly efficient barrier between stomach and esophagus becomes weakened in GERD. Patients with GERD have defective esophageal peristalsis; more frequent and prolonged transient lower esophageal sphincter relaxation; abnormal gastric emptying resulting in increased gastric pressure; and esophagitis and mucosal damage from gastric hydrochloric acid, bile salts, and pancreatic enzyme refluxate, with resultant dysmotility. Some will have hiatal hernias, Helicobacter pylori infection, and Barrett’s esophagus.4
The damaging mechanisms associated with PUD include the following:
- Infection by H. pylori bacteria:
- Fecal–oral infection with H. pylori is higher in populations who have a lower standard of living than routinely seen in industrialized countries. In the United States, approximately 40% of duodenal ulcer patients are infected with H. pylori. Successful eradication of H. pylori is associated with elimination of ulcer recurrence. This is the strongest evidence to support the role of H. pylori as an etiology of PUD.
- Increasing and widespread use of both nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin:
- In H. pylori-negative patients, the use and overuse of NSAIDs and aspirin is the most common cause of PUD.
- Idiopathic causes and hypersecretory causes are less common.
IBDs (CD and UC)
A key feature in the pathogenesis of IBD is a failure to downregulate the immune system and control local GI inflammation. The exact etiology of UC is unknown and the disease appears to be multifactorial. Environmental factors, immune dysfunction, smoking, NSAID use, low levels of antioxidants, psychological stress, consumption of milk products, and a genetic predisposition have all been proposed as causes of UC. First-degree relatives of IBD patients have a 10% lifetime risk of developing UC. The genetic component in the pathogenesis of CD has been identified as the gene NOD2 located on chromosome 16q12 and is related to the immune response to bacteria activating inflammatory cell signals.
A variety of immunological changes occur in IBD. T-lymphocyte cell subsets accumulate in the lamina propria of the affected area of the colon and are cytotoxic to colon epithelium. An increase in number of B lymphocytes and plasma cells, and an increase in the production of immunoglobulin G (IgG) and immunoglobulin E (IgE) follow. A small proportion of patients with UC develop smooth muscle and anticytoskeletal antibodies.
Microscopically, there is an inflammatory infiltrate of the lamina propria, crypt branching, and erosion of the tiny villi in the intestines that absorb nutrients. The ulcerated areas are eventually covered by granulation tissue. This leads to the formation of inflammatory polyps also known as pseudopolyps.1
PC is associated with increased GI colonization with C. difficile. C. difficile can be found in 2–3% of healthy adults and up to 70% of healthy infants. C. difficile forms heat-resistant spores that persist in the environment for months to years. In hospital and other health-care facilities, outbreaks may occur as a result of contamination with these spores. Colonization occurs by the fecal–oral route, and as many as 30% of hospitalized adults are colonized with C. difficile. Normal gut flora resists colonization and overgrowth with C. difficile. In PC, the antibiotic disruption of the normal colon flora allows C. difficile overgrowth.
Many antibiotics may be responsible for C. difficile overgrowth, but third-generation cephalosporins are implicated most frequently. Third-generation cephalosporins have an intramuscular or intravenous route of administration with the exception of cefixime, which has an oral route of administration. Cefixime is used to treat community-acquired pneumonia, sinusitis, pharyngitis, and urinary tract infections. Third-generation cephalosporins including cefixime are not typically used to treat odontogenic infections. Immunosuppression is also a predisposing factor for C. difficile colitis.
Celiac disease is a multifactorial, multisystem disorder with a genetic predisposition. The majority of persons with celiac disease have the human leukocyte antigen (HLA) DQ2 haplotype found on chromosome 6. Interestingly, approximately 40% of general populations also have this haplotype but do not express the disease. Presence of this halpotype is required for the expression of celiac disease but not all who have this haplotype express disease. Relatives of individuals with celiac disease have a higher incidence of the disease than the general population. First-degree relatives have a prevalence rate of 10%. Environmental factors associated with celiac disease are ingestion of the gliadin found in gluten chiefly from wheat, rye, and barley. Some individuals also show sensitivity to oats. Grains not associated with celiac disease activity include rice, corn, sorghum, buckwheat, amaranth, quinoa, and millet.3
In susceptible individuals, exposure of small intestine mucosa to gluten triggers an inflammatory reaction causing villi destruction. Additionally, an immunological response occurs resulting in large numbers of CD8+ T lymphocytes, B lymphocytes, and other lymphocytes. As a result, various immunoglobulins, cytokines, interferons, tumor necrosis factor, and other inflammatory mediators are secreted with an end result of villous atrophy. The Marsh criteria are used to characterize abnormalities noted in the small bowel biopsy specimens. Marsh 0 represents a pre-infiltrative or normal stage, while Marsh 4 represents hypoplastic lesions as seen in T-cell lymphoma.5,6
Gastric cancer can be subdivided using the Lauren classification for adenocarcinomas into two different histology subtypes. These subtypes have different genetic and biological patterns and treatment options:
- The intestinal type (IT) of gastric cancer is structurally similar to colon cancer with formation of gland-like tubular structures. This type of cancer is usually preceded by chronic gastritis and intestinal metaplasia. IT gastric cancer is more closely linked to environmental and dietary risk factors. This was the most common form of cancer in areas with a high incidence of gastric cancer and is now declining worldwide.
- The diffuse type (DT) of gastric cancer lacks glandular structure and instead consists of poorly differentiated, discohesive cells that infiltrate the wall of the stomach and secrete mucus. DT gastric cancer is associated with a worse prognosis and occurs at a younger age than the intestinal form. This subtype can result in a rigid thickened stomach.
- Approximately 5% of gastric cancers are lymphomas.
A multiple step model (the Correa pathway) has been proposed in the development of IT gastric cancer. In this model, preneoplastic changes eventually lead to the development of gastric cancer. Specifically, alterations in the DNA are caused by chronic inflammation, which in tandem with imbalanced epithelial cell proliferation and apoptosis in a local environment of atrophy and achlorhydria, colonization of intestinal bacteria that have nitrate reductase activity leads to the formation of carcinogenic nitrosamines. The development of gastric cancer has been attributed to loss of specialized glandular cell types such as parietal and chief cells (corpus-predominant atrophy), and this appears to be the critical initiating step in cancer progression.7
Other risk factors include use of alcohol and tobacco, ingestion of food additives (nitrosamines), smoked foods, and occupational exposure to heavy metals, rubber, and asbestos.
Three mechanisms in the development of colon and rectal carcinoma have been described:
The majority of colorectal cancers (75%) develop in people with no known risk factors. The remaining 25% occur in people with risk factors such as familial history of colorectal polyps or cancer. Relative risk for the development of colorectal cancer is 2.42 when a first-degree relative has the diagnosis and 4.25 when more than one first-degree relative is affected. Other significant risk factors include genetic conditions such as HNPCC, IBD, and familial adenomatous polyposis. The incidence of colorectal cancer in patients with CD is up to 20 times greater than that of the general population.
A high-fat, low-fiber diet has been associated with the development of colorectal cancer while a high-fiber diet may have a protective role. Smoking and alcohol intake increase the risk for the development of colon cancer. Colon cancer can be detected; therefore, routine screening is indicated especially in individuals with high risk for disease development.
Functional dyspepsia is not life-threatening, and it h/>